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Seven photoaffinity-based and sixteen biotin-based berberine (BBR) probes were constructed and screened for their effects on c-Jun N-terminal protein kinases (JNK) phosphorylation (p-JNK) suppressi...

Indium Tin Oxide (ITO) films were prepared, at room temperature, on a fluorphlogopite substrate using magnetron sputtering technology. At various temperatures of 500 °C, 600 °C, 700 °C, 800 °C, and 900 °C, the samples were (had) annealed for 2 h (a 2-h duration). The results showed improvement in the crystalline performance of ITO film at selected annealing temperatures, with a significant reduction in resistivity at 800 °C. The lowest resistivity is 4.08 × 10−4 Ω-cm, which is nearly an order of magnitude lower than the unannealed sample. All samples have an average light transmittance above 85% in the visible light range (400–800 nm), and with increasing annealing temperature, the average light transmittance tends to decrease. Besides, at the sensitive wavelength of 550 nm, the light transmittance is as high as 93.74%. The sheet resistance testing of the sample was through the number of bending times, which revealed that with the increase of the number of bending, the sheet resistance increases. However, after 1200 bending times, the change rate of the sheet resistance remains below 5%. Thus, the ITO film prepared on the flexible fluorphlogopite substrate revealed excellent optical and electrical properties, good flexibility, and improved stability after high-temperature annealing, which guarantees successful application in flexible electronic devices.

In this study, various structurally similar aliphatic dicarboxylic acids, namely, succinic acid, glutaric acid, adipic acid, and pimelic acid, were employed as coformers to obtain phase pure cocrystals with berberine chloride (BCl) by a slow solvent evaporation method. The structures of the four novel salt-cocrystals of BCl were determined by single crystal X-ray diffraction analysis and their solid-state properties were characterized. Compared with BCl·2H2O, all the cocrystals showed a higher melting point, improved powder dissolution and intrinsic dissolution rate (IDR), and lower hygroscopicity. It is noteworthy that the melting points and IDRs of these cocrystals exhibit an odd-even alternation with the carbon chain length of the acids.

The problem of identifying one block structure nonlinear system, consisting of four linear blocks and one static nonlinear block, is considered here. Under the assumptions that static nonlinear is a polynomial form, the block structure nonlinear system can be transformed into one state space form. Then this nonlinear system identification is formulated into identifying the state space form for these four linear blocks. After transforming the formal state space form, we obtain a polynomial nonlinear state space equation. Then the parallel distributed algorithm is used to identify each system matrix, while using the relationship between the formal state space equation and its transformed state space equation. Finally the simulation example is used to prove the efficiency of our algorithm.

The reprogramming of host physiology has been considered an essential process for baculovirus propagation. Trehalose, the main sugar in insect blood, plays a crucial role as an instant energy source. Although the trehalose level is modulated following infection with Bombyx mori nucleopolyhedrovirus (BmNPV), the mechanism of trehalose metabolism in response to BmNPV infection is still unclear. In this study, we demonstrated that the trehalose level tended to be lower in BmNPV-infected hemolymph and higher in the midgut. The omics analysis revealed that two trehalose transporters, BmTret1-1 and BmTret1-2, and trehalase, BmTRE1 and BmTRE2, were differentially expressed in the midgut after BmNPV infection. BmTret1-1 and BmTret1-2 had the ability to transport trehalose into the cell and promoted cellular absorption of trehalose. Furthermore, the functions of BmTret1-1, BmTret1-2, BmTRE1 and BmTRE2 in BmNPV infection were analyzed. These genes were upregulated in the midgut after BmNPV infection. Virus amplification analysis revealed that these genes could promote BmNPV proliferation in BmN cells. In addition, these genes could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO in the phosphoinositide 3-kinase (PI3K)-Akt signalling pathway. Similarly, the increased trehalose level in BmN cells could promote the expression of BmPI3K, BmPDK1 and BmAkt and inhibit the expression of BmFoxO. Taken together, BmNPV infection promote the expression of trehalose hydrolysis and transport-related genes. These changes affect the PI3K-Akt signalling pathway to facilitate BmNPV proliferation. These findings help clarify the relationship between trehalose metabolism and BmNPV infection.

Comparative analysis among multiple gene lists on their functional features is now a routine task due to the advancement of high-throughput experiments. Several enrichment analysis tools were developed in the past. However, these tools mainly focus on one gene list and contain only gene ontology or interaction features. What makes it worse, comparative investigation and customized feature set reanalysis are still unavailable. Therefore, we constructed the YMLA (Yeast Multiple List Analyzer) platform in this research. YMLA includes 39 yeast features and facilitates comparative analysis among multiple gene lists via tabular views, heatmaps, and network plots. Moreover, the customized feature set reanalysis function was implemented in YMLA to help form mechanism hypotheses based on a selected enriched feature subset. We demonstrated the biological applicability of YMLA via example lists consisting of genes with top/bottom translation efficiency values. The analysis results provided by YMLA reveal novel facts consistent with previous experiments. YMLA is available at https://cosbi7.ee.ncku.edu.tw/YMLA/.

Interfacial engineering plays a very significant role in suppressing charge recombination and improving the photovoltaic performance in solar cells. The introduction of a buffer or passivation layer is an effective way to modify interfacial behaviours. In this paper, a new approach involving the deposition of a MnS passivation layer was studied to improve the photoelectric conversion efficiency (PCE) of CdS/CdSe quantum dot co-sensitized solar cells (QDSSCs). Compared to the pure CdS/CdSe co-sensitized solar cells, the introduction of the MnS passivation layer can not only modify the surface defects of the quantum dots and suppress charge recombination at the photoelectrode/electrolyte interface, but also enhance the light harvesting capability in terms of both the absorbance intensity and absorption range. This work may provide inspiration for future studies on the interfacial modification of QDSSCs. The best device performance with a ZnO photoanode could be achieved when the MnS passivation layer was deposited for 1 min for each of two successive ionic layer adsorption and reaction (SILAR) cycles. The PCE, open circuit voltage (Voc), short circuit current density (Jsc), and fill factor (FF) were 3.70%, 0.60 V, 13.74 mA cm−2, and 0.44, respectively.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure–activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 μM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1β release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.

Graphic abstract Compound 8a exhibited the promising activity against anti-SARS-CoV-2 via inhibiting host Cat B activity, and had the advantage of broad-spectrum anti-coronavirus and anti-cytokine activity in the treatment of COVID-19., So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1β, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.

We propose a controllable non-reciprocal transmission model. The model consists of a Mobius ring, which is connected with two one-dimensional semi-infinite chains, and with a two-level atom located inside one of the cavities of the Mobius ring. We use the method of Green function to study the transmittance of a single photon through the model. The results show that the non-reciprocal transmission can be achieved in this model and the two-level atom can behave as a quantum switch for the non-reciprocal transport of the single photon. This controllable non-reciprocal transmission model may inspire new quantum non-reciprocal devices., 7 pages, 6 figures

This study aimed to investigate the effect and mechanism of ligustilide, the main active ingredient in Ligusticum wallichii, on mitochondria fission after PC12 cell injury induced by oxygen and glucose deprivation/reperfusion(OGD/R). In the experiment, an OGD/R model was established in vitro, and PC12 cells were pre-treated with ligustilide for 3 h, and then the cell viability was detected by CCK-8 method. The effect of different concentrations of ligustilide on the morphology of PC12 cells after OGD/R injury was observed under an inverted microscope. Transmission electron microscopy was used to observe the mitochondrial fission of PC12 cells after OGD/R injury. DCFH-DA immunofluorescence staining method was used to detect intracellular reactive oxygen species(ROS) changes. Changes in mitochondria membrane potential(MMP) were detected by flow cytometry. Hochest 33258 was used to observe the apoptosis of PC12 cells. Western blot was used to detect changes in cytochrome C(Cyt C) content in mitochondria and cytoplasm, and mitochondrial fission-related proteins Drp 1 and Fis 1. All results showed that compared with the model group, ligustilide significantly increased the survival rate of PC12 cells and the number of cells. Further experiments showed that ligustilide inhibited the release of ROS and decline of mitochondrial membrane potential in PC12 cells after OGD/R injury. Moreover, ligustilide reduced the release of Cyt C and promoted the expressions of Drp1 and Fis1 in mitochondrial fission proteins. Verification experiments showed that mitochondrial fission inhibitor mdivi-1 decreased cell survival rate and inhibited fission. The results indicated that ligustilide exerted neuro-protective effects by promoting mitochondrial fission and reducing cell damage. It preliminary proves that the mechanism of ligustilide on ischemic brain injury may be related to the promotion of mitochondrial fission and the maintenance of cell homeostasis.

Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)-resistant Helicobacter pylori (H. pylori) strains. The structure&ndash, activity relationship (SAR) indicated that the introduction of a suitable secondary amine substituent at the 9-position might be beneficial for potency. Among them, compound 1c exhibited the most potent activities against MTZ-resistant strains, with minimum inhibitory concentration (MIC) values of 4&ndash, 16 &mu, g/mL, better than that of the lead. It also exhibited a good safety profile with a half-lethal dose (LD50) of over 1000 mg/kg. Meanwhile, 1c might exert its antimicrobial activity through targeting H. pylori urease. These results suggested that PMT derivatives might be a new family of anti-H. pylori components.

We theoretically investigate the intra-band transitions in Mobius molecules. Due to the weak magnetic response, the relative permittivity is significantly modified by the presence of the medium while the relative permeability is not. We show that there is hyperbolic dispersion relation induced by the intra-band transitions because one of the eigen-values of permittivity possesses a different sign from the other two, while all three eigen-values of permeability are positive. We further demonstrate that the bandwidth of negative refraction is 0.165 eV for the $H$-polarized incident light, which is broader than the ones for inter-band transitions by 3 orders of magnitude. Moreover, the frequency domain has been shifted from ultra-violet to visible domain. Although there is negative refraction for the $E$-polarized incident light, the bandwidth is much narrower and depends on the incident angle.

A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1–4 μg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD50 values of 65.6 and 41.2 mg kg−1 in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.

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) 12N-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 IC50 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., Graphical abstract Twenty-six new tricyclic matrinic derivatives were designed, synthesized and evaluated for their activities against Ebola virus in vitro using a pHIV-EBOVGP-Fluc model. Compound 7d exhibited better in vivo anti-EBOV and anti-MARV effects than the positive control sertraline. The results suggested its inspiring broad-spectrum anti-filovirus activity.fx1

Aqueous solution of Zn(NO₃)₂*6H₂O-C₆H₂N₄-PEI and Zn(NO₃)₂*6H₂O-CO(NH₂)₂ were used as raw materials to fabricate hierarchically structured films of ZnO nanorods/nanosheets (ZnO NRs/NSs) via a two-step hydrothermal synthesis, and the films of ZnO NRs/NSs were applied as photoanodes for application in dye-sensitized solar cells (DSSCs). Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) were utilized to characterize the morphologies of the ZnO films. The current density-voltage curves and the incident monochromatic photon-to-electron conversion efficiency of DSSCs were measured. Through electrochemical impedance spectroscopy, intensity modulated photovoltage spectroscopy , and intensity modulated photocurrent spectroscopy, the conditions of the internal electron transport and transfer of ZnO-based DSSCs were tested and analyzed. The results indicate that the ZnO NRs/NSs photoanodes not only have properties of rapid electron transport and high electron collection efficiency but also show a relatively large amount of dye absorption. Therefore, for DSSCs based on ZnO NRs/NSs, the short-circuit current density (Jsc), open-circuit voltage (Voc), fill factor (FF), and photoelectric conversion efficiency (PCE) were 11.82 mA cm-2, 0.66 V, 0.58, and 4.59%, respectively. The PCE of the DSSCs was improved by 178.18% with respect to that of pure ZnO NRs cells (1.65%) and was improved by 21.42% with respect to the pure ZnO NSs cells (3.78%).

Many identification strategies for closed loop linear time invariant system assume that an open loop system is closed by a feedback mechanism, which contains a known, linear time invariant controller. This assumption means that these identification strategies are feasible under some prior knowledge of feedback controller. To relax this assumption in some complex systems with unknown controller, a new stealth identification strategy is proposed to tackle the identification problem for closed loop linear time invariant system with unknown controller. Stealth identification modifies the closed loop system, so that the new prediction error and inverse covariance matrix are all independent of the unknown controller. This independence can simplify the problems of estimating parameter vector and designing optimal input. By using this simplified prediction error to construct an objective function, a candidate domain of attraction for the objective function is introduced and one convergence condition is derived to guarantee a given set be a candidate domain of attraction. Finally a simulation example confirms our theoretical results.

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.

In this paper, γ-butyrolactone (GBL) solvent vapor post-annealing (SVPA) on CH3NH3PbI3 thin films is reported, aiming to improve the complete transformation of PbI2 and increase the grain size of the CH3NH3PbI3 crystal, thus boosting the performance of mesoporous CH3NH3PbI3 perovskite solar cells (PSCs). The influence of GBL SVPA on the microstructure of perovskite layers and performance of PSCs was studied. The short circuit current density (Jsc) of the devices significantly increased, yielding a high efficiency of 16.58%, which was 27.05% higher than that of thermally annealed films. A model was derived to explain the effect of GBL SVPA on PSCs. The perovskite films prepared by this method present several advantages such as complete transformation of PbI2 to CH3NH3PbI3, high crystallinity, large grain size, and fewer grain boundaries than those prepared without GBL SVPA. This improvement is beneficial for charge dissociation and transport in hybrid photovoltaic devices.

The van der Waals forces between the layers of fluorphlogopite make it flexible, and its stability under strong acid, strong alkali, and high temperature conditions has potential applications as a new base material for flexible electronics. In this article, using magnetron sputtering technology, the focus is on the influence of the change of sputtering pressure on the photoelectric properties of the prepared ITO thin film. In this study, indium tin oxide (ITO) film samples were prepared on a fluorphlogopite substrate using the magnetron sputtering technique and adjusting the sputtering pressure from 0.6 Pa to 11 Pa at room temperature. The film was characterized using SEM, XRD, four-probe tester, and ultraviolet–visible spectrophotometer to understand its microstructure and photoelectric properties. The number of bending times of the sample's square resistance around the steel cylinder characterized its flexibility. The results showed that the sample crystal grains decreased significantly with the increase in pressure. Further, it can be seen from SEM images that all samples contained extremely uniform particles. The light transmittance and resistivity of the sample synthesized below 3 Pa increased sharply with the increase of sputtering pressure, and the change above 3 Pa tended to be stable. The average transmittance of visible light in the wavelength range of 400–800 nm ​​is higher than 86%, the highest being 92.7%; the sputtering pressure of 0.6 Pa yielded a sample with the lowest resistivity of 1.51 × 10−3 Ωcm. All the samples were bent 1200 times around a steel cylinder with a radius of 3.65 mm, and the change in sheet resistance did not exceed 5%.

Simple Summary In this study, a differentially expressed β-1,3-glucan recognition protein, BmβGRP4, was identified from a transcriptome database. Significant downregulation of BmβGRP4 expression was detected after BmNPV infection in the P50 larvae midgut. Subsequently, the overexpression of BmβGRP4 suppressed BmNPV proliferation in BmN cells; however, the siRNA-mediated knockdown of BmβGRP4 facilitated BmNPV proliferation in B. mori larvae. Furthermore, we demonstrated that BmβGRP4 overexpression promoted BmNPV induced cellular apoptosis. Then, we found that BmβGRP4 positively regulated BmPTEN and negatively regulated BmIAP. Consequently, we speculated that BmNPV inhibited BmβGRP4 to suppress BmPTEN and facilitate BmIAP to inhibit cell apoptosis to evade host antiviral defense. These findings will lay a foundation for further study of the functions of BmβGRP4 in response to BmNPV. Abstract β-1,3-glucan recognition proteins (βGRPs) as pattern recognition receptors (PRRs) play an important role in recognizing various pathogens and trigger complicated signaling pathways in insects. In this study, we identified a Bombyx mori β-1,3-glucan recognition protein gene named BmβGRP4, which showed differential expression, from a previous transcriptome database. The full-length cDNA sequence was 1244 bp, containing an open reading frame (ORF) of 1128 bp encoding 375 amino acids. BmβGRP4 was strongly expressed in the larval stages and highly expressed in the midgut of B. mori larvae in particular. After BmNPV infection, the expression of BmβGRP4 was reduced significantly in the midgut. Furthermore, a significant increase in the copy number of BmNPV was observed after the knockdown of BmβGRP4 in 5th instar larvae, while the overexpression of BmβGRP4 suppressed the proliferation of BmNPV in BmN cells. Subsequently, the expression analysis of several apoptosis-related genes and observation of the apoptosis morphology demonstrated that overexpression of BmβGRP4 facilitated apoptosis induced by BmNPV in BmN cells. Moreover, BmβGRP4 positively regulated the phosphatase and tensin homolog gene (BmPTEN), while expression of the inhibitor of apoptosis gene (BmIAP) was negatively regulated by BmβGRP4. Hence, we hypothesize that BmNPV infection might suppress BmPTEN and facilitate BmIAP to inhibit cell apoptosis by downregulating the expression of BmβGRP4 to escape host antiviral defense. Taken together, these results show that BmβGRP4 may play a role in B. mori response to BmNPV infection and lay a foundation for studying its functions.

A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure–activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N′-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N′-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC50 between 0.55 and 1.7 μM. The underlying mechanism of 6b against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound 6b is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth.

Novel ZnO nanosheets (NSs)/nanocrystalline aggregates (NAs) composite films were constructed by depositing a ZnO NAs directly on the surfaces of pre-fabricated ZnO NSs through a dip-coating method. The morphology and performance of dye-sensitized solar cells (DSSCs) were studied. The top layers of ZnO NAs improved the light scattering of composite films. The bottom layers of ZnO NSs consisted of 20–30 nm nanoparticle has a single crystal structure. In addition, ZnO NSs is vertical conductive substrate, so the bottom layers of ZnO NSs layer have a larger specific surface area and good electron transport. Based on the above advantages, the photoelectric conversion efficiency (PCE) of DSSCs assembled by the ZnO NSs/NAs composite films is 7.95%, which is 81.51% higher than that of ZnO NSs and is close to the highest PCE that has ever been reported (8.03%).

In this study, the formation of a MnS layer on the surface of ZnO films was investigated for improving the power conversion efficiency of CdS/CdSe co-sensitized quantum dot solar cells. The results showed that the MnS layer had a remarkable effect on the light-absorption characteristics and short-circuit current density of the solar cells by ensuring that a greater number of quantum dots were adsorbed and by reducing the charge-recombination rate. As a result, the CdS/CdSe/ZnS electrode based on the ZnO film modified with the MnS layer exhibited a power conversion efficiency of 3.45%, which was much higher than for the solar cells without a MnS layer (2.27%).

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125–32 μg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a β-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight β-lactamase-producing resistant Gram-negative bacteria.

Aiming at the problem that kiwifruit invisible damage is difficult to detect and identify by conventional detection methods, this paper proposes to use the visible near-infrared hyperspectral imaging technology to detect the identify and identify models based on deep learning VGG-16 neural network. Detection and recognition of hyperspectral images of kiwifruit invisible damage. The network is implemented by the caffe framework and python and is a 16-layer deep learning neural network. The reflection spectroscopy images of 50 kiwifruit samples were obtained at wavelengths of 400-1000 nm. According to whether they were subjected to invisible damage, they were classified into invisible damage and undamage, with 40 and 10 samples respectively. The training set and the test set are used to obtain the implicit damage discriminant model by using the principal component analysis image obtained from the spectral data as the input image of deep learning. The experimental results show that the highest accurate recognition rate reaches 100% and has a good recognition effect.

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25&ndash, 0.5 &mu, g/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg&middot, kg&minus, 1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 &mu, g/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.

A series of new 7-substituted cycloberberine (CBBR) derivatives were synthesized and evaluated for their antibacterial activities against Gram-positive pathogens, taking CBBR as the lead. The SAR revealed that the introduction of a substituent at the C7 position resulted in a potency against both the reference Gram-positive bacteria and MDR clinical isolates, much higher than that of CBBR. Compound 1f with a 7-phenyl group exhibited higher activities against MRSA and VRE than that of vancomycin, with MIC values of 1–8 μg/mL. Its rapid bactericidal action against MRSA was further confirmed in time-kill study. The preliminary mechanism study indicated that 1f might target bacterial DNA Topo IV ParE subunit, indicating a mode of action distinct from the currently used antibacterial drugs such as quinolones. These results supplemented and enriched the SAR of its kind, and provided powerful information for developing these compounds into a novel class of antibacterial candidates against MRSA.

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G+) and Gram-negative (G&minus, ) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G+ and G&minus, strains with MIC values of 0.125&ndash, 8 &mu, g/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action.

Forty-three tricyclic matrinic derivatives with a unique scaffold were prepared and evaluated for their stimulation effects on glucose consumption in HepG2 cells. The structure-activity relationship was systematically elucidated for the first time. Among them, compound 17a exhibited the most promising potency, and dose-dependently increased glucose consumption in L6 myotubes. It significantly lowered blood glucose, glucosylated haemoglobin and AGE level, and improved glucose tolerance and insulin resistance in KK-Ay mice as well. More importantly, 17a effectively ameliorated diabetic nephropathy (DN), as indicated by the improvement of renal function and pathological changes, and decrease of urinary protein. Furthermore, 17a could induce glycolysis but suppressed aerobic oxidation of glucose, in a similar mechanism to Metform. Our results indicated that in addition to hyperglycemia, 17a may be developed to treat diabetic complication such as DN.

A series of novel berberine (BBR) analogues were prepared and tested for their antiviral potencies against six different genotype Coxsackievirus B (CVB1–6) strains, taking BBR core for structural modification. Structure-activity relationship (SAR) research revealed that introduction of a primary amine through a linker at position 3 might be beneficial for both antiviral activity and safety. Compound 14c displayed most promising inhibitory potency with IC50 values of 3.08–9.94 µM against tested CVBs 2–6 strains and satisfactory SI value of 34.3 on CVB3, better than that of BBR. Also, 14c could inhibit CVB3 replication through down-regulating the expression of VP1 protein and VP1 RNA. The mechanism revealed that 14c could suppress host components JNK-MAPK, ERK-MAPK and p38-MAPK activation. Therefore, BBR derivatives were considered to be a new class of anti-CVB agents with an advantage of broad-spectrum anti-CVB potency.

Lysosome has a crucial role in clearance of endocytosed pathogens from the cell. Small molecules that can boost lysosome function and bactericidal ability to cope with subsequent infection are urgently needed. Here, we report that MPB, a novel berberine derivative, induced lysosome-based degradation and clearance of methicillin-resistant Staphylococcus aureus and enteroinvasive Escherichia coli in macrophages. MPB caused nuclear translocation of transcription factor EB (TFEB), which boosted expression of lysosome genes. TFEB silencing repressed the MPB-mediated enhancements in degradation and bacterial eradication. MPB switched on TFEB nuclear translocation by coupling 2 parallel signaling pathways. MPB-triggered JNK activation led to 14-3-3δ being released from TFEB, which, in turn, caused TFEB nuclear translocation. In addition, MPB induced AMPK activation and subsequent inhibition of mechanistic target of rapamycin activity, which also contributed to TFEB nuclear translocation. Importantly, genetical or pharmaceutical inhibition of TGF-β-activated kinase 1 (TAK1) reduced MPB action remarkably. MPB acted through TAK1 at lysine 158 to activate JNK and AMPK and, thus, induced TFEB-dependent bactericidal activity in macrophages. Therefore, our study reveals a novel mechanism by which MPB controls JNK and AMPK phosphorylation cascades to activate lysosomal function and bactericidal activity via TAK1 K158-dependent manner, which may offer insight into novel therapeutic strategies to control bacterial infection.-Liu, X., Zhang, N., Liu, Y., Liu, L., Zeng, Q., Yin, M., Wang, Y., Song, D., Deng, H. MPB, a novel berberine derivative, enhances lysosomal and bactericidal properties via TGF-β-activated kinase 1-dependent activation of the transcription factor EB.

[Image: see text] 8-Acetoxycycloberberine (2) with a unique skeleton was first identified to display a potent activity profile against Gram-positive bacteria, especially methicillin-resistant S. aureus (MRSA) with minimum inhibitory concentration (MIC) values of 1–8 μg/mL, suggesting a possible novel mechanism of action against bacteria. Taking 2 as the lead, 23 new 8-substituted cycloberberine (CBBR) derivatives including ether, amine, and amide were synthesized and evaluated for their antibacterial effect. The structure–activity relationship revealed that the introduction of a suitable substituent at the 8-position could greatly enhance the potency against MRSA. Among them, compounds 5d and 9e demonstrated equally effective anti-MRSA potency as lead 2, with an advantage of having a more stable pharmacokinetics feature. A preliminary mechanism study indicated that compound 9e acted upon bacteria partly through catalyzing the cleavage of bacterial DNA. Therefore, we consider that 8-substituted CBBR derivatives constitute a promising class of antibacterial agents in the treatment of MRSA infections.