Natural terpenoids with anti-inflammatory activities: Potential leads for anti-inflammatory drug discovery.

Natural products are mainly secondary metabolites produced by plants, microorganisms, and animals, which are still abundant in modern drug discovery. Terpenoids are the most diverse group of natural products, attracting extensive attention owing to their various biological activities. This manuscript reviewed the chemical structures, anti-inflammatory activities, and mechanisms of action of 281 terpenoid natural products reported from 2010 to the present. Their biological targets and both in vitro and in vivo screening models were also surveyed and statistically summarized. This review will provide potential anti-inflammatory lead compounds and helpful information to researchers engaged in natural products and anti-inflammatory drug discovery.

Discovery of small-molecule compounds and natural products against Parkinson's disease: Pathological mechanism and structural modification.

Parkinson's disease (PD) is the second common neurodegenerative disease characterized by movement disorder. The symptoms of PD harm both the physical and mental health of patients. However, the current treatment strategies for PD only alleviate the symptoms but cannot recover the degenerative process of dopaminergic neurons. Therefore, it is necessary to develop novel and safe drugs for the treatment of PD. In this review, we comprehensively summarized the detailed pathological mechanisms and potential drugable targets of PD. The approved anti-PD drugs in clinical use and the drug candidates under clinical trials were also listed. More importantly, the compounds in the drug discovery phase with in vivo anti-PD activities in the recent two decades (2000-2020) were summarized. The structure-activity relationships (SARs) were also analyzed. Additionally, we predicted all the reviewed compounds' blood-brain barrier (BBB) permeability and statistically analyzed their pharmacological targets and in vivo anti-PD testing models. It is hoped that this review can provide practical information for researchers in the field of anti-PD drug discovery and promote their research work.

HDAC1/MAO-B dual inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids.

A series of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer's disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC50 = 99.0 nM; HDAC1, IC50 = 21.4 nM) and excellent MAO selectively (MAO-A, IC50 = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aß1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer's disease.

N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease.

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09-22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 µM, hMAO-A IC50 = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood-brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.

Discovery of natural anti-inflammatory alkaloids: Potential leads for the drug discovery for the treatment of inflammation.

Inflammation is an adaptive response of the immune system to tissue malfunction or homeostatic imbalance. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently applied to treat varieties of inflammatory diseases but are associated with gastrointestinal, cardiovascular, and kidney side effects. Developing more effective and less toxic agents remain a challenge for pharmaceutical chemist due to the complexity of the different inflammatory processes. Alkaloids are widely distributed in plants with diverse anti-inflammatory activities, providing various potential lead compounds or candidates for the design and discovery of new anti-inflammatory drug candidates. Therefore, re-examining the anti-inflammatory alkaloid natural products is advisable, bringing more opportunities. In this review, we summarized and described the recent advances of natural alkaloids with anti-inflammatory activities and possible mechanisms in the period from 2009 to 2020. It is hoped that this review of anti-inflammatory alkaloids can provide new ideas for researchers engaged in the related fields and potential lead compounds for the discovery of anti-inflammatory drugs.

Numerical methods for low-dose EDS tomography.

Energy-dispersive X-ray spectroscopic (EDS) tomography is a powerful three-dimensional (3D) imaging technique for characterizing the chemical composition and structure of nanomaterials. However, the accuracy and resolution are typically hampered by the limited number of tilt images that can be measured and the low signal-to-noise ratios (SNRs) of the energy-resolved tilt images. Various sophisticated reconstruction algorithms have been proposed for specific types of samples and imaging conditions, yet deciding on which algorithm to use for each new case remains a complex problem. In this paper, we propose to tailor the reconstruction algorithm for EDS tomography in three aspects: (1) model the reconstruction problem based on an accurate assumption of the data statistics; (2) regularize the reconstruction to incorporate prior knowledge; (3) apply bimodal tomography to augment the EDS data with a high-SNR modality. Methods for the three aspects can be combined in one reconstruction procedure as three modules. Therefore, a reconstruction algorithm can be constructed as a 'recipe'. We also provide guidelines for preparing the recipe based on conditions and assumptions for the data. We investigate the effects of different recipes on both simulated data and real experimental data. The results show that the preferred recipe depends on both acquisition conditions and sample properties, and that the image quality can be enhanced using a properly tailored recipe.

EDS tomographic reconstruction regularized by total nuclear variation joined with HAADF-STEM tomography.

Energy-dispersive X-ray spectroscopy (EDS) tomography is an advanced technique to characterize compositional information for nanostructures in three dimensions (3D). However, the application is hindered by the poor image quality caused by the low signal-to-noise ratios and the limited number of tilts, which are fundamentally limited by the insufficient number of X-ray counts. In this paper, we explore how to make accurate EDS reconstructions from such data. We propose to augment EDS tomography by joining with it a more accurate high-angle annular dark-field STEM (HAADF-STEM) tomographic reconstruction, for which usually a larger number of tilt images are feasible. This augmentation is realized through total nuclear variation (TNV) regularization, which encourages the joint EDS and HAADF reconstructions to have not only sparse gradients but also common edges and parallel (or antiparallel) gradients. Our experiments show that reconstruction images are more accurate compared to the non-regularized and the total variation regularized reconstructions, even when the number of tilts is small or the X-ray counts are low.

Automatic correction of nonlinear damping effects in HAADF-STEM tomography for nanomaterials of discrete compositions.

HAADF-STEM tomography is a common technique for characterizing the three-dimensional morphology of nanomaterials. In conventional tomographic reconstruction algorithms, the image intensity is assumed to be a linear projection of a physical property of the specimen. However, this assumption of linearity is not completely valid due to the nonlinear damping of signal intensities. The nonlinear damping effects increase w.r.t the specimen thickness and lead to so-called "cupping artifacts", due to a mismatch with the linear model used in the reconstruction algorithm. Moreover, nonlinear damping effects can strongly limit the applicability of advanced reconstruction approaches such as Total Variation Minimization and discrete tomography. In this paper, we propose an algorithm for automatically correcting the nonlinear effects and the subsequent cupping artifacts. It is applicable to samples in which chemical compositions can be segmented based on image gray levels. The correction is realized by iteratively estimating the nonlinear relationship between projection intensity and sample thickness, based on which the projections are linearized. The correction and reconstruction algorithms are tested on simulated and experimental data.

A bimodal tomographic reconstruction technique combining EDS-STEM and HAADF-STEM.

A three-dimensional (3D) chemical characterization of nanomaterials can be obtained using tomography based on high angle annular dark field (HAADF) scanning transmission electron microscopy (STEM) or energy dispersive X-ray spectroscopy (EDS) STEM. These two complementary techniques have both advantages and disadvantages. The Z-contrast images have good image quality but lack robustness in the compositional analysis, while the elemental maps give more element-specific information, but at a low signal-to-noise ratio and a longer exposure time. Our aim is to combine these two types of complementary information in one single tomographic reconstruction process. Therefore, an imaging model is proposed combining both HAADF-STEM and EDS-STEM. Based on this model, the elemental distributions can be reconstructed using both types of information simultaneously during the reconstruction process. The performance of the new technique is evaluated using simulated data and real experimental data. The results demonstrate that combining two imaging modalities leads to tomographic reconstructions with suppressed noise and enhanced contrast.

Three dimensional mapping of Fe dopants in ceria nanocrystals using direct spectroscopic electron tomography.

Electron tomography is a powerful technique for the 3D characterization of the morphology of nanostructures. Nevertheless, resolving the chemical composition of complex nanostructures in 3D remains challenging and the number of studies in which electron energy loss spectroscopy (EELS) is combined with tomography is limited. During the last decade, dedicated reconstruction algorithms have been developed for HAADF-STEM tomography using prior knowledge about the investigated sample. Here, we will use the prior knowledge that the experimental spectrum of each reconstructed voxel is a linear combination of a well-known set of references spectra in a so-called direct spectroscopic tomography technique. Based on a simulation experiment, it is shown that this technique provides superior results in comparison to conventional reconstruction methods for spectroscopic data, especially for spectrum images containing a relatively low signal to noise ratio. Next, this technique is used to investigate the spatial distribution of Fe dopants in Fe:Ceria nanoparticles in 3D. It is shown that the presence of the Fe2+ dopants is correlated with a reduction of the Ce atoms from Ce4+ towards Ce3+. In addition, it is demonstrated that most of the Fe dopants are located near the voids inside the nanoparticle.

Dirac directional emission in anisotropic zero refractive index photonic crystals.

A certain class of photonic crystals with conical dispersion is known to behave as isotropic zero-refractive-index medium. However, the discrete building blocks in such photonic crystals are limited to construct multidirectional devices, even for high-symmetric photonic crystals. Here, we show multidirectional emission from low-symmetric photonic crystals with semi-Dirac dispersion at the zone center. We demonstrate that such low-symmetric photonic crystal can be considered as an effective anisotropic zero-refractive-index medium, as long as there is only one propagation mode near Dirac frequency. Four kinds of Dirac multidirectional emitters are achieved with the channel numbers of five, seven, eleven, and thirteen, respectively. Spatial power combination for such kind of Dirac directional emitter is also verified even when multiple sources are randomly placed in the anisotropic zero-refractive-index photonic crystal.

Conical dispersion and effective zero refractive index in photonic quasicrystals.

It is recognized that for a certain class of periodic photonic crystals, conical dispersion can be related to a zero-refractive index. It is not obvious whether such a notion can be extended to a noncrystalline system. We show that certain photonic quasicrystalline approximants have conical dispersions at the zone center with a triply degenerate state at the Dirac frequency, which is the necessary condition to qualify as a zero-refractive-index medium. The states in the conical dispersions are extended and have a nearly constant phase. Experimental characterizations of finite-sized samples show evidence that the photonic quasicrystals do behave as a near zero-refractive-index material around the Dirac frequency.

Effect of minocycline on cerebral ischemia-reperfusion injury.

Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-reperfusion (22.5 mg/kg, initially 45 mg/kg) at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein expression.

Chloride channel blocker 4,4-diisothiocyanatostilbene-2,2'-disulfonic acid inhibits nitric oxide-induced apoptosis in cultured rat hippocampal neurons.

Apoptosis in cultured rat hippocampal neurons was induced using the nitric oxide donor 3-morpholinosydnonimine, and cells were treated with the chloride channel blocker, 4,4-diisothiocyanatostilbene-2,2'-disulfonic acid. Results showed that the survival rate of neurons was significantly increased after treatment with 4,4-diisothiocyanatostilbene-2,2'-disulfonic acid, and the rate of apoptosis decreased. In addition, the expression of the apoptosis-related proteins poly(adenosine diphosphate-ribose)polymerase-1 and apoptosis-inducing factor were significantly reduced. Our experimental findings indicate that the chloride channel blocker 4,4-diisothiocyanatostilbene-2,2'-disulfonic acid can antagonize apoptotic cell death of hippocampal neurons by inhibiting the expression of the apoptosis-related proteins poly(adenosine diphosphate-ribose)polymerase-1 and apoptosis-inducing factor.

ClC-3 chloride channel in hippocampal neuronal apoptosis.

Over-production of nitric oxide is pathogenic for neuronal apoptosis around the ischemic area fol-lowing ischemic brain injury. In this study, an apoptotic model in rat hippocampal neurons was tablished by 0.5 mmol/L 3-morpholinosyndnomine (SIN-1), a nitric oxide donor. The models were then cultured with 0.1 mmol/L of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; the chloride channel blocker) for 18 hours. Neuronal survival was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis was assayed by Hoechst 33342-labeled neuronal DNA fluorescence staining. Western blot analysis and immunoche-nescence staining were applied to determine the changes of activated caspase-3 and CIC-3 channel proteins. Real-time PCR was used to detect the mRNA expression of CIC-3. The results showed that SIN-1 reduced the neuronal survival rate, induced neuronal apoptosis, and promoted ClC-3 chloride channel protein and mRNA expression in the apoptotic neurons. DIDS reversed the effect of SIN-1. Our findings indicate that the increased activities of the ClC-3 chloride channel may be involved in hippocampal neuronal apoptosis induced by nitric oxide.

Effects of minocycline on learning and memory of mice following ischemic-hypoxic cerebral injuries.

An ischemic-hypoxic animal model was established using right common carotid artery occlusions and inhalation of low concentrations of oxygen in mice. At 10 days after the ischemic-hypoxic injuries, saline-treated mice exhibited significantly prolonged escape latencies in water-maze tests and significantly shorter memory latencies and more mistakes in step-down tests. In contrast, mice treated with 5 mg/kg minocycline exhibited significant reversals of each of these effects compared with the saline-treated control mice. Moreover, we found that minocycline can relieve brain water content and morphological changes in mice following ischemic-hypoxic cerebral injuries. Accordingly, our findings indicate that minocycline provides some protections against the deleterious effects of these injuries in mice.