Anchanling reduces pathology in a lactacystin-induced Parkinson's disease model

A rat model of Parkinson＇s disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson’s disease model rats, tyrosine hydroxylase expression was increased, α-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson＇s disease pathology possibly by enhancing degradation activity of the ubiquitin-proteasome system.

Construction of Enriched Resource for Primary Therapeutic Targets of Approved and Clinical Trial Drugs

An assessment of the efficacy targets of drugs that represent an opportunity for targeted therapy is fundamental to the development of post-genomic research strategies within the pharmaceutical industry. Identification and validation of efficacy target is an important process in drug discovery and development. Extensive drug discovery efforts have yielded many approved and candidate drugs. Although sever drug databases provide the drug and their corresponding targets, there is an insufficient coverage of the clinical trial drugs over the past decades. Here, we conduct a comprehensive survey for current clinical trial drugs, therapeutic targets. The analysis contents include: 1) collect clinical trial drugs from different sources, 2) By analysis of the literature, we summarize the criteria for assign therapeutic targets for each drug based on its indication. The knowledge of these drugs and their targets is useful not only for drug discovery and development of targeted therapy, but also for facilitating the discovery of systems pharmacology.

Fructus Broussonetae extract improves cognitive function and endoplasmic reticulum stress in Alzheimer's disease models

This study investigated the effects and possible targets of Fructus Broussonetiae extract, a traditional Chinese medicinal herb, on a model of Alzheimer＇s disease induced by beta-amyloid peptide 25 35 and D-galactose. The results revealed that intragastric administration of Fructus Broussonetiae significantly increased the expression of immunoglobulin-binding protein, a key factor in the endoplasmic reticulum stress-signaling pathway in rat hippocampus. In contrast, the treatment significantly decreased expression levels of PKR-like endoplasmic reticulum kinase and C/EBP homologous protein, and substantially improved learning, memory and spatial recognition dysfunction in rats. This evidence indicates that Fructus Broussonetiae extract improves spatial learning and memory abilities in rats by affecting the regulation of hippocampal endoplasmic reticulum stress and activation of the apoptosis pathway.

Effects of serum containing natural cerebrolysin on glucose-regulated protein 78 and CCAAT enhancer-binding protein homologous protein expression in neuronal PC12 cells following tunicamycin-induced endoplasmic reticulum stress

BACKGROUND： Glucose-regulated protein 78 （GRP78）, a marker of endoplasmic reticulum stress, can prolong cell survival. Alternatively, CCAAT enhancer-binding protein homologous protein （CHOP）, a transcription factor specific for endoplasmic reticulum stress, can cause cell cycle arrest and cell apoptosis. OBJECTIVE： To study the protective effects of serum containing natural cerebrolysin on endoplasmic reticulum stress in tunicamycin-induced neuronal PC12 cells, and analyze the influence on GRP78 and CHOP expressions. DESIGN, TIME AND SETTING： A parallel controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, between March 2006 and August 2008. MATERIALS： Adult Sprague-Dawley rats were perfused with natural Cerebrolysin aqueous extract （0.185 g/kg/d） to produce serum containing natural Cerebrolysin. Physiological saline was used to produce blank serum. PC12 cell line was provided by Shanghai Institute of Cell Biology, Chinese Academy of Science. Tunicamycin was provided by Sigma （St. Louis, USA）, and natural Cerebrolysin, containing ginseng, rhizoma gastrodiae, and gingko leaf （1：2：2）, by Shengzhen Institute of Integrated Western and Traditional Chinese Medicine. METHODS： PC12 cells were treated with DMEM culture media containing 10% blank serum （normal control group）, tunicamycin （1 μg/mL; model group）, and 5%, 10%, and 15% serum containing natural cerebrolysin and tunicamycin （1 μ g/mL; low-, moderate-, and high-dose serum containing natural cerebrotysin groups）, for 2 hours. MAIN OUTCOME MEASURES： PC12 cells were treated with tunicamycin for 48 hours after which apoptosis was measured using the TUNEL method to calculate apoptotic index. GRP78 expression was detected using immunocytochemistry. After 24 hours of treatment with tunicamycin, GRP78 and CHOP mRNA expressions were measured using RT-PCR. RESULTS： The apoptotic index and CHOP mRNA expression were in the model group and three cerebrolysin groups were significantly increased when compared to the normal control group （P 〈 0.05）. In contrast, GRP78 mRNA and protein expressions were significantly decreased （P 〈 0.05）. CONCLUSION： Serum containing natural cerebrolysin significantly reduced apoptosis in neuronal PC12 cells following tunicamycin-induced endoplasmic reticulum stress. These results may be related to an up-regulation of GRP78 expression and down-regulation of CHOP expression, both of which displayed dose-dependent effects.

Analysis of hippocampal gene expression profile of Alzheimer's disease model rats using genome chip bioinformatics

In this study, an Alzheimer＇s disease model was established in rats through stereotactic injection of condensed amyloid beta 1-40 into the bilateral hippocampus, and the changes of gene expression profile in the hippocampus of rat models and sham-operated rats were compared by genome expression profiling analysis. Results showed that the expression of 50 genes was significantly up-regulated （fold change 〉 2）, while 21 genes were significantly down-regulated in the hippocampus of Alzheimer＇s disease model rats （fold change 〈 0.5） compared with the sham-operation group. The differentially expressed genes are involved in many functions, such as brain nerve system development, neuronal differentiation and functional regulation, cellular growth, differentiation and apoptosis, synaptogenesis and plasticity, inflammatory and immune responses, ion channels/transporters, signal transduction, cell material/energy metabolism. Our findings indicate that several genes were abnormally expressed in the metabolic and signal transduction pathways in the hippocampus of amyloid beta 1 40-induced rat model of Alzheimer＇s disease, thereby affecting the hippocampal and brain functions.

Effects of natural-cerebrolysin-containing serum on neurotoxicity and synaptogenesis in amyloid-beta 1-40-induced Alzheimer's disease in vitro models

BACKGROUND： Neuronal loss, synapse mutilation, and increasing malnourished axons are pathologically related to Alzheimer＇s disease. Microtubule-associated protein 2 （MAP2） is of importance for neuronal, axonal, and dendritic generation, extension, and stabilization, as well as for the regulation of synaptic plasticity. OBJECTIVE： To investigate the antagonistic effects of natural-cerebrolysin-containing serum on beta amyloid protein 1-40 （Aβ1-40）-induced neurotoxicity from the standpoints of cell proliferation, synaptogenesis, and cytoskeleton formation （MAP2 expression）. DESIGN, TIME AND SETTING： A paralleled, controlled, neural cell, and molecular biology experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University between February 2006 and April 2008. MATERIALS： PC12 cells, derived from the rat central nervous system, were purchased from Shanghai Institute of Cell Biology, Chinese Academy of Sciences, China. A β1-40 was provided by Sigma, USA. Natural-cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. The natural-cerebrolysin was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yixingye （Ginkgo Leaf） in a proportion of 1：2：2. Following conventional water extraction technology, an extract （1：20） was prepared. Each gram of extract equaled 20 grams of crude drug. In a total of 12 adult male New Zealand rabbits, six underwent intragastric administration of natural-cerebrolysin extract for 1 month to prepare natural-cerebrolysin-containing serum, and the remaining six rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： An AIzheimer＇s disease in vitro model was induced in PC12 cells using Aβ1-40. The cells were incubated with varying doses of natural-cerebrolysin-containing serum （2.5%, 5%, and 10%）. Normal blank serum-treated PC12 cells served as a blank control group. MAIN OUTCOME MEASURES： Through the use of inverted phase contrast microscope, cell morphology and neurite growth were observed, neurite length was measured, and the percentage of neurite-positive cells was calculated. Cell proliferation rate was determined by MTT assay, and MAP 2 expression was detected by fluorescent immunocytochemistry. RESULTS： Following Aβ1-40 treatments, some PC12 cells were apoptotic/dying, and only a few short neurites were observed. Following interventions with natural-cerebrolysin-containing serum, the PC12 cells proliferated, there was an increased number of neurites, and neurite length was enhanced. After middle- and high-dose natural-cerebrolysin treatments, the percentage of neurite-positive cells, as well as the average length of neurites, was significantly greater than the normal blank serum-treated PC12 cells （P 〈 0.05 or P 〈 0.01）. Compared with the blank control group, MAP2 expression in the Aβ1-40-treated PC12 cells was significantly inhibited, and the cell proliferation rate was significantly decreased （P 〈 0.01）. Following incubations with natural-cerebrolysin-containing serum, MAP2 expression and cell proliferation rate in the PC12 cells were significantly increased in a dose-dependent manner, compared with treatments with blank control serum （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Natural-cerebrolysin exhibited antagonistic effects on neurotoxicity in Aβ1-40 induced Alzheimer＇s disease in vitro models. These effects were likely related to cell proliferation and the upregulation of intracellular MAP2 expression.

Effects of natural cerebrolysin on protective proteins and pro-apoptotic molecules in mesenchymal stem cells following beta-amyloid peptide1-40-induced endoplasmic reticulum stress

BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mechanisms of traditional Chinese medicine against ERS in AD are poorly understood. OBJECTIVE： To measure expression levels of protective proteins （GRP78 and GRP94） of ER molecular partners and pro-apoptotic Caspase-12 ER membrane expression following application of traditional Chinese medicine natural cerebrolysin （NC） to treat Aβ1-40-induced ERS. DESIGN, TIME AND SETTING： A parallel-controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University between September 2006 and November 2008. MATERIALS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of mesenchymal stem cells （MSCs） were established from the whole bone marrow by removing non-adherent cells in primary and passage cultures. Aβ1-40 was provided by Sigma, USA. NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. NC was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） in a proportion of 1 ： 2： 2. Following conventional water extraction technology, an extract （1 ： 20） was prepared. Six adult, male, New Zealand rabbits underwent intragastric administration of NC extract （0.976 g/kg per day） for 1 month to prepare NC-positive serum, and the remaining 6 rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： A total of 500 nmol/L Aβ1-40 was used to establish ERS models of primary cultured MSCs. AD cell models were incubated with different doses of NC-positive serum （2.5%, 5%, and 10%）. MSCs treated with normal blank serum served as normal blank controls. MAIN OUTCOME MEASURES： Reverse transcription-polymerase chain reaction and fluorescent immunocytochemistry were respectively used to measure mRNA and protein expression levels of GRP78, GRP94, and Caspase-12 in MSCs. RESULTS： Following Aβ1-40 exposure, mRNA and protein expression levels of GRP78 and GRP94, as well as Caspase-12, significantly increased （P 〈 0.05）, suggesting successful establishment of ERS models. Following NC-positive serum application, mRNA and protein expression levels of GRP78 and GRP94 in MSCs significantly increased （P 〈 0.05 or P 〈 0.01）. However, mRNA and protein expression levels of Caspase-12 significantly decreased （P 〈 0.05, or P 〈 0.01） compared with the ERS model group. These effects were dose-dependent. CONCLUSION： NC downregulated Caspase-12 expression and upregulated GRP78 and GRP94 expression in MSCs in a dose-dependent manner under the state of Aβ1-40-induced ERS.

Natural cerebrolysin induces neuronal differentiation in bone marrow mesenchymal stem cells

BACKGROUND： Bone marrow mesenchymal stem cells （MSCs） have been shown to differentiate into neuronal-like cells through the use of several factors, such as 2-mercaptoethanol, dimethyl sulfoxide, or monothioglycero However, these factors are not suitable for human use due to toxicity. Theoretically speaking, traditional Chinese medicine could be used as potential and safe factors. OBJECTIVE： To investigate the effect of natural cerebrolysin on neuronal-like differentiation of MSCs, based on protein and mRNA analyses. DESIGN, TIME AND SETTING： A parallel controlled, in vitro experiment was performed at the Institute of Integrated Chinese and Western Medicine, Shenzhen Hospital, Southern Medical University, between June 2006 and April 2008. MATERIALS： Natural cerebrolysin was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. It primarily consisted of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） at a proportion of 1：2：2. Natural cerebrolysin extract （1：20） was prepared using conventional water extraction methodology. Each gram of extract equaled 20 grams of the crude drug. Twelve adult, male, New Zealand rabbits were included, six of which underwent intragastric administration of natural cerebrolysin extract （0.976 g/kg per day） for 1 month for natural cerebrolysin-containing serum. The remaining six rabbits received intragastric administration of equal volumes of physiological saline for normal blank serum. METHODS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of MSCs were established from the whole bone marrow by removing the non-adherent cells in primary and passage cultures. For cellular identification, MSCs from four to five passages were co-cultured with LG-DMEM media containing 10% natural cerebrolysin. Simultaneously, MSCs cultured in/G-DMEM media containing 10% blank rabbit serum served as the control group. MAIN OUTCOME MEASURES： Morphology of MSCs and neurite outgrowth during differentiation was observed under inverted phase contrast microscope. Neurite-positive cells were classified by neurite length that was longer than 1.5x the cell body diameter. Immunocytochemistry was used to identify purity of MSCs following passage, as well as expression of nidogen, neuron-specific enolase, glial fibrillary acidic protein, and microtubule-associated protein 2 following treatment with natural cerebrolysin, mRNA expression of neuron-specific enolase and glial fibrillary acidic protein was detected using semi-quantitative RT-PCR. RESULTS： After MSCs were treated with natural cerebrolysin for 3-5 hours, the cell bodies were larger, and small neurites - similar to neuronal neurites - were observed. The number of neurite-positive cells significantly increased compared with the control group （P 〈 0.05）. After MSCs were treated with natural cerebrolysin for 12 hours, most expressed nidogen, neuron-specific enolase, and microtubule-associated protein 2 at higher levels than the control group （P 〈 0.01）. No evident expression of glial fibrillary acidic protein was found （P 〉 0.05）. CONCLUSION： Natural cerebrolysin promoted neurite outgrowth and induced neuronal-like differentiation of MSCs.

Discovery and development of tricyclic matrinic derivatives as anti-diabetic candidates by AMPKαactivation

We found compound 12N-p-trifluoromethylbenzenesulfonyl matrinane(1)was a potent anti-diabetic agent.Thirty-five tricyclic matrinic derivatives were synthesized and determined for their stimulatory effects on glucose consumption in L6 myotubes,taking 1 as the lead.In high-fat diet(HFD)and STZ induced diabetic mice,9a significantly lowers blood glucose,improves glucose tolerance,and especially alleviates diabetic nephropathy and islet damage.Mechanism study indicates that 9a simultaneously targets mitochondrial complex I to increase AMP/ATP ratio,as well as liver kinase B1(LKB1)and calcium/calmodulindependent protein kinase(Ca MKK),which synergistically activates AMPKαand then stimulates glucose transporter 4(GLUT4)membrane translocation and 2-deoxyglucose(2-DG)uptake to exert anti-diabetic efficacy.Therefore,compound 9a with a novel structure is a promising anti-diabetic candidate with the advantage of multiple-target mechanism,worthy of further investigation.

Machine learning for predicting fatigue properties of additively manufactured materials

Fatigue properties of materials by Additive Manufacturing(AM) depend on many factors such as AM processing parameter, microstructure, residual stress, surface roughness, porosities, post-treatments, etc. Their evaluation inevitably requires these factors combined as many as possible, thus resulting in low efficiency and high cost. In recent years, their assessment by leveraging the power of Machine Learning(ML) has gained increasing attentions. A comprehensive overview on the state-of-the-art progress of applying ML strategies to predict fatigue properties of AM materials, as well as their dependence on AM processing and post-processing parameters such as laser power, scanning speed, layer height, hatch distance, built direction, post-heat temperature,etc., were presented. A few attempts in employing Feedforward Neural Network(FNN), Convolutional Neural Network(CNN), Adaptive Network-Based Fuzzy Inference System(ANFIS), Support Vector Machine(SVM) and Random Forest(RF) to predict fatigue life and RF to predict fatigue crack growth rate are summarized. The ML models for predicting AM materials' fatigue properties are found intrinsically similar to the commonly used ones, but are modified to involve AM features. Finally, an outlook for challenges(i.e., small dataset, multifarious features,overfitting, low interpretability, and unable extension from AM material data to structure life) and potential solutions for the ML prediction of AM materials' fatigue properties is provided.

Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1

Thirty-one new 10,12-disubstituted aloperine derivatives were subtly constructed through a selective oxidation on the 10-α-C-H induced by sulfonyl and a nucleophilic substitution with the stereoselectivity and scalability.Of them,compound 6b displayed a moderate anti-human coronavirus OC43(HCoV-OC43)potency and blocked the viral entry stage through a host mechanism of action.Using chemoproteomic techniques,both transmembrane serine protease 2(TMPRSS2)and scavenger receptor class B type 1(SR-B1)proteins,which act as host cofactors of viral entry,were identified to be the direct targets of 6b against HCoV-OC43.Furthermore,6b may deactivate the TMPRSS2 by inducing a change in protein conformation,rather than binding to its catalytic center,thus suppressing the viral membrane fusion.Accordingly,our study provided key scientific data for the development of aloperine derivatives into a new class of antiviral candidates against humanβ-coronavirus,including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).

Author correction to‘Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects’[Acta Pharmaceutica Sinica B 13(2023)2138-2151]

The authors regret that there are some misplaced figure numbers in the body of this article due to negligence in the layout and proofreading of the figures.Although it does not affect the conclusion,it is an obvious error.The authors have now modified as below.The authors apologize for any inconvenience caused to the journal and readers.

Flight safety oriented ice shape modulation using distributed plasma actuator units

Ice accretion on the wings seriously threatens the flight safety of an aircraft.From the perspectives of ensuring flight safety and saving power consumption,the ice shape modulation method using distributed plasma is proposed.Distributed plasma actuator units are designed to modulate the spanwise continuous ice at the leading edge into periodically segmented ice pieces,forming a wavy leading edge.Both airfoil and scaled aircraft model,with continuous and modulated ice,are experimentally investigated and simulated.Compared with the continuous ice,ice shape modulation can significantly improve the aerodynamic performance,flight control characteristics and flight safety.This method can save about half electric power,which is very beneficial for application.

Synthesis and biological evaluation of novel tricyclic matrinic derivatives as potential anti-filovirus agents

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus(EBOV)activities. Structure–activity relationship analysis indicated:(i) 12 N-dichlorobenzyl motif was beneficial for the activity;(ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC_(50) value of 5.29 μmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of 7d identified its high effectiveness, and in vivo anti-MARV assay of 7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.

A review of high‐velocity impact on fiber‐reinforced textile composites: Potential for aero engine applications

Considerable research has indicated that fiber‐reinforced textile composites are significantly beneficial to the aerospace industry,especially aero engines,due to their high specific strength,specific stiffness,corrosion resistance,and fatigue re-sistance.However,damage caused by high‐velocity impacts is a critical limitation factor in a wide range of applications.This paper presents an overview of the development,material characterizations,and applications of fiber‐reinforced textile composites for aero engines.These textile composites are classified into four ca-tegories including two‐dimensional(2D)woven composites,2D braided composites,3D woven composites,and 3D braided composites.The complex damage me-chanisms of these composite materials due to high‐velocity impacts are discussed in detail as well.

Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects

Using chemoproteomic techniques,we first identified EIF2AK2,eEF1A1,PRDX3 and VPS4B as direct targets of berberine(BBR)for its synergistically anti-inflammatory effects.Of them,BBR has the strongest affinity with EIF2AK2 via two ionic bonds,and regulates several key inflammatory pathways through EIF2AK2,indicating the dominant role of EIF2AK2.Also,BBR could subtly inhibit the dimerization of EIF2AK2,rather than its enzyme activity,to selectively modulate its downstream pathways including JNK,NF-κB,AKT and NLRP3,with an advantage of good safety profile.In EIF2AK2 gene knockdown mice,the inhibitory IL-1β,IL-6,IL-18 and TNF-a secretion of BBR was obviously attenuated,confirming an EIF2AK2-dependent anti-inflammatory efficacy.The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target,and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammationrelated disorders.

Improving aircraft aerodynamic performance with bionic wing obtained by ice shape modulation

For Unmanned Aerial Vehicles(UAVs)with limited electrical power to achieve effectively anti-/de-icing at the leading edge of the wing,a strategy of ice shape modulation was proposed.Isolated simulated ice shape pieces printed by 3D printing technology are mounted on a NACA0012 finite wing model,and its lift/drag coefficients and suction-side velocity fields are measured by the six-component force balance and the Particle Imaging Velocimetry(PIV),respectively.The ratio of the spanwise length of a single ice shape piece to chord length and the spanwise length of the non-icing area between the two adjacent single ice shape pieces are defined as dimensionless ice shape length(w/c)and dimensionless modulation ratio(w/λ),respectively.The results indicate that for a fixed w/λ,the wing lift coefficient first increases and then drops with increasing w/c,and a peak value exists when w/c is between 0.1 and 0.2.The lower the w/λis,the higher the wing lift coefficient will be.The periodical variation of the flow separation area along the spanwise direction is attributed on the one hand to the acceleration effect of the flow field in the non-icing area which reduces the separation area,and on the other hand to the cross-flow caused by the streamwise vortices from the non-icing area to the icing area which promotes the mixing of the flow field(similar to vortex generators).The obtained modulation law is verified through flight tests and provides guidance for the use of ice shape modulation scheme for UAVs that cannot be completely anti-/deicing under severe weather conditions.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria.Compound 33a(IMBZ18G)is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant(MDR)Gram-negative strains,with a highly druglike nature.The checkerboard assay reveals its significant synergistic effect withβ-lactamase inhibitor avibactam,and the MIC values against MDR enterobacteria were reduced up to 4—512folds.X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and Cβ-lactamases.Accordingly,preclinical studies of 33a alone and 33a-avibactam combination as potential innovative candidates are actively going on,in the treatment ofβ-lactamase-producing MDR Gram-negative bacterial infections.

Synthesis and biological evaluation of 12-N-p-chlorobenzyl sophoridinol derivatives as a novel family of anticancer agents

Taking 12-N-p-chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 30-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine(1), a natural antitumor medicine. Among them, the sophoridinic ketones 5a–b, alkenes 7a–b and sophoridinic amines 14a–b displayed reasonable antiproliferative activity with IC50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin(AMD)-susceptible and resistant MCF-7 breast carcinoma cells,indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1. Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.

Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents

Chronic hepatitis C virus(HCV)infection has become a major public health burden worldwide.Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro.The structure-activity analysis revealed that(i)sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold;(ii)the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonylΔβγsophocarpinic acids was beneficial for the antiviral activity against HCV.Among them,compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9,respectively.Therefore,both were selected as antiviral candidates for further investigation.