Exploring environment-specific regulation: Characterizing bacterioplankton community dynamics in a typical lake of Inner Mongolia, China.

Lakes serve as heterogeneous ecosystems with rich microbiota. Although previous studies on bacterioplankton have advanced our understanding, there are gaps in our knowledge concerning variations in the taxonomic composition and community assembly processes of bacterioplankton across different environment conditions. This study explored the spatial dynamics, assembly processes, and co-occurrence relationships among bacterioplankton communities in 35 surface water samples collected from Hulun Lake (a grassland-type lake), Wuliangsuhai Lake (an irrigated agricultural recession type lake), and Daihai Lake (an inland lake with mixed farming and grazing) in the Inner Mongolia Plateau, China. The results indicated a significant geographical distance decay pattern, with biomarkers (Proteobacteria and Bacteroidota) exhibiting differences in the contributions of different bacteria branches to the lakes. The relative abundance of Proteobacteria (42.23%) were high in Hulun Lake and Wuliangsuhai Lake. Despite Actinobacteriota was most dominant, Firmicutes accounted for approximately 17.07% in Daihai Lake, suggested the potential detection of anthropogenic impacts on bacteria within the agro-pastoral inland lake. Lake heterogeneity caused bacterioplankton responses to phosphorus, chlorophyll a, and salinity in Hulun Lake, Wuliangsuhai Lake, and Daihai Lake. Although bacterioplankton community assembly processes in irrigated agricultural recession type lake were more affected by dispersal limitation than those in grassland-type lake and inland lake with mixed farming and grazing (approximately 52.7% in Hulun Lake), dispersal limitation and undominated processes were key modes of bacterioplankton community assembly in three lakes. This suggested stochastic processes exerted a greater impact on bacterioplankton community assembly in a typical Inner Mongolia Lake than deterministic processes. Overall, the bacterioplankton communities displayed the potential for collaboration, with lowest connectivity observed in irrigated agricultural recession type lake, which reflected the complex dynamic patterns of aquatic bacteria in typical Inner Mongolia Plateau lakes. These findings enhanced our understanding of the interspecific relationships and assembly processes among microorganisms in lakes with distinct habitats.

Design, synthesis, and structure-activity relationship study of novel plinabulin derivatives as anti-tumor agents based on the co-crystal structure.

Plinabulin, a 2, 5-diketopiperazine-type tubulin inhibitor derived from marine natural products, is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and chemotherapy-induced neutropenia (CIN). To obtain novel 2, 5-diketopiperazine derivatives with higher biological activity, we designed and synthesized two series of 37 plinabulin derivatives at the C-ring, based on the co-crystal structure of compound 1 and tubulin. Their structures were characterized using NMR and HRMS. All compounds were screened in vitro using the lung cancer cell line NCI-H460 using the MTT method, and the compounds with better activity were further screened in BxPC-3 and HT-29 cells. The compounds 16c (IC50 = 2.0, NCI-H460; IC50 = 1.2 nM, BxPC-3; IC50 = 1.97 nM, HT-29) and 26r (IC50 = 0.96, NCI-H460; IC50 = 0.66 nM, BxPC-3; IC50 = 0.61 nM, HT-29) had the best activity. The cytotoxic activity of compound 26r against various tumor cell lines occurred at less than 1 nM.

Construction of a Soft Antifouling PAA/PSBMA Hydrogel Coating with High Toughness and Low Swelling through the Dynamic Coordination Bonding Provided by Al(OH)3 Nanoparticles.

Marine biofouling, resulting from the adhesion of marine organisms to ship surfaces, has long been a significant issue in the maritime industry. In this paper, we focused on utilizing soft and hydrophilic hydrogels as a potential approach for antifouling (AF) coatings. Acrylic acid (AA) with a polyelectrolyte effect and N-(3-sulfopropyl)-N-(methacryloxyethyl)-N,N-dimethylammonium betaine (SBMA) with an antipolyelectrolyte effect were selected as monomers. By adjusting the monomer ratio, we were able to create hydrogel coatings that exhibited low swelling ratio in both fresh water and seawater. The Al(OH)3 nanoparticle, as a physical cross-linker, provided better mechanical properties (higher tensile strength and larger elongation at break) than the chemical cross-linker through the dynamic coordination bonds and plentiful hydrogen bonds. Additionally, we incorporated trehalose into the hydrogel, enabling the repair of the hydrogel network through covalent-like hydrogen bonding. The zwitterion compound SBMA endowed the hydrogel with excellent AF performance. It was found that the highest SBMA content did not lead to the best antibacterial performance, as bacterial adhesion quantity was also influenced by the charge of the hydrogel. The hydrogel with appropriate SBMA content being close to electrical neutrality exhibits the strongest zwitterionic property of PSBMA chains, resulting in the best antibacterial adhesion performance. Furthermore, the pronounced hydrophilicity of SBMA enhanced the lubrication of the hydrogel surface, thereby reducing the friction resistance when applied to the hull surface during ship navigation.

Composition, interaction networks, and nitrogen metabolism patterns of bacterioplankton communities in a grassland type Lake: a case of Hulun Lake, China.

The composition of bacterial communities in freshwater ecosystems is influenced by numerous factors including environmental conditions and biological interactions. In grassland inland closed lakes, factors affecting lake ecosystems are either exogenous or endogenous, contributing to the formation of distinct habitats in the surface and bottom waters of the bacterial communities. However, the extent to which environmental factors selectively shape the bacterial communities in aquatic systems remains unclear. Therefore, we sampled the surface, middle, and bottom waters at 13 sampling points in each layer. High-throughput sequencing techniques were employed to examine the spatial heterogeneity of the bacterial community structure during summer in Hulun Lake, the largest grassland-type lake in Inner Mongolia, China, to determine the microbial community dynamics and symbiosis patterns under different habitat conditions. Our results revealed a decrease in the diversity and heterogeneity of the bacterioplankton community, influenced by changes in the environment from exogenous inputs to endogenous releases. Furthermore, this alteration in community structure was concomitant with enhanced co-occurrences among microorganisms in the bottom water layers. This finding suggests that endogenous release promotes heightened symbiotic interactions, thereby facilitating the development of more complex modular structures. Symbiotic networks in different layers were differentiated by key species, with the ecological clustering modules of these species demonstrating dissimilar environmental preferences. The microbial communities were highly habitat-specific, mimicking responses to total nitrogen (TN) in the surface layer, pH in the middle layer, and chemical oxygen demand (COD) in the bottom layer. Bacterioplankton functions were assessed using Tax4Fun, indicating exogenous inputs and endogenous release increased the relative abundance of genes with nitrogen-fixing and nitrification potential nitrogen metabolism functions in surface and bottom waters, respectively. With Planctomycetota and Proteobacteria phyla as potential key groups for regulating nitrogen metabolic processes, Proteobacteria may facilitate the depletion of nitrate in surface and bottom waters, while the close contact of surface waters with the atmosphere accelerated Planctomycetota-dominated nitrogen fixation into the lake. Our findings contribute to the understanding of vertical microbial diversity and its network patterns in grassland type lakes, underscoring the potential role of environmental factors (exogenous inputs and endogenous releases) in bacterioplankton community formation.

[Vertical Differences in Grassland Bacterial Community Structure During Non- Growing Season in Eastern Ulansuhai Basin].

Grassland is an important part of the regional ecosystem, and its micro ecological structures play key roles in the process of element migration and the evolution of ecological diversity systems. To discover the spatial difference of the grassland soil bacterial community, we collected five total soil samples at 30 cm depth and 60 cm depth in Eastern Ulansuhai Basin in early May (before the beginning of the new growing season, with a minimum influence of human activities and other factors). Based on 16S rRNA gene-based high-throughput sequencing technology, the vertical characteristic of the bacterial community was analyzed in detail. First, Actinobacteriota, Proteobacteria, Chloroflexi, Acidobacteriota, Gemmatimonadota, Planctomycetota, Methylomirabilota, and Crenarchacota all appeared in the 30 cm and 60 cm samples, with the relative contents all being higher than 1%. In addition, there were a total of six phyla, five genera, and eight OTUs in the 60 cm sample with relative contents higher than those in the 30 cm sample. As a result, the relative abundance changes in dominant bacterial phyla, genera, and even OTUs at different sample depths did not correspond to their contribution to the bacterial community structure. Second, because of the unique contribution to the bacterial community structure in 30 cm and 60 cm samples, the norank_f__norank_o__norank_c__norank_p__Armatimonadota and Candidatus_Xiphinematobacter could be utilized as key bacterial genera during ecological system analysis, belonging to the Armatimonadota and Verrucomicrobiota, respectively. Finally, the relative abundances of ko00190, ko00910, and ko01200 were all higher in 60 cm samples than those in 30 cm samples, which showed that through the increase in metabolic function abundance, the relative contents of C, N, and P elements in grassland soil had been reduced with the increase in depth. These results will provide references for further study on the spatial change of bacterial communities in typical grassland.

The spatial distribution and abundance of microplastics in lake waters and ice during ice-free and ice-covered periods.

Understanding the spatial distribution and characteristics of microplastics (MPs) in lake waters is essential to assessing and addressing lacustrine MP pollution. This study investigated how lake ice affects the abundance, spatial distribution, and characteristics (size, shape) of MPs in Lake Ulansuhai by analyzing samples collected at ten sites uniformly distributed throughout the lake during ice-free and ice-covered periods. The abundance of MPs ranged between 204 ± 28 and 1224 ± 185 n·L-1 in lake waters during the ice-free period, and from 34 ± 8 to 216 ± 21 n·L-1 and 269 ± 84 to 915 ± 117 n·L-1 in water and ice during the ice-covered period, respectively. During the ice-covered period, MPs were 2.74-8.14 times higher in the ice than in water beneath the ice. Ice formation decreased MP abundance in lake waters, in part, by incorporating a relatively high percentage of MPs into the ice mass during freezing and by inhibiting atmospheric MPs from reaching the lake waters. The abundance of MPs in the water during the ice-free period was 4.50-11.30 times greater than during the ice-covered period. Seasonal variations in MP shape also occurred; the proportion of fibrous MPs in water decreased during the ice-covered period. Variations in MP abundance were partly due to differences in sedimentation rates; the settling of fibrous MPs is slower, making it easier for them to be captured during the formation of surface ice. Spatially, MPs were uniformly distributed during the ice-free period, but exhibited a spatially distinct pattern during ice-covered periods, when MPs in lake waters were higher in the northeast and lower in the southwest portions of the lake. During the ice-free period, small MPs (0.05-0.5 mm) were more likely to move with currents in the lake, whereas water velocities were reduced by ice formation, allowing small MPs to accumulate near the lake inlet.

Conformation and energy investigation of microtubule longitudinal dynamic instability induced by natural products.

The natural products plinabulin, docetaxel, and vinblastine are microtubule targeting agents (MTAs). They have been used alone or in combination in cancer treatment. However, the exact nature of their effects on microtubule (MT) polymerization dynamics is poorly understood. To elucidate the longitudinal conformational and energetic changes during MT dynamics, a total of 140 ns molecular dynamic simulations combined with binding free energy calculations were performed on seven tubulin models. The results indicated that the drugs disrupted MT polymerization by altering both MT conformation and binding free energy of the neighboring tubulin subunits. The combination of plinabulin and docetaxel destabilized MT polymerization due to bending MT and weakening the polarity of tubulin polymerization. The new combination of docetaxel and vinblastine synergistically enhanced MT depolymerization and bending, while plinabulin and vinblastine had no synergistic inhibitory effects. The results were verified by the tubulin assembly assay. Our study obtained a comprehensive understanding of the action mechanisms of three natural drugs and their combinations on MT dynamic, provided theoretical guidance for new MTA combinations, and would promote the optimal use of MTA and contribute to developing new MTAs as anticancer agents.

Design and Synthesis of Novel Phenylahistin Derivatives Based on Co-Crystal Structures as Potent Microtubule Inhibitors for Anti-Cancer Therapy.

Phenylahistin is a naturally occurring marine product with a diketopiperazine structure that can bind to the colchicine site of microtubulin as a possible anticancer agent. To develop more potent microtubule inhibitors, novel phenylahistin derivatives were designed and synthesized based on the co-crystal complexes of phenylahistin derivatives and microtubulin. We established a focused library of imidazole-type molecules for the introduction of different groups to the C-ring and A-ring of phenylahistin. Structure-activity relationship studies indicated that appropriate hydrocarbon substituents and unsaturated alkenyl substituents at the 1-position of the imidazole group are important for improving the activity of such compounds. In addition, this study found that propylamine groups could maintain the activity of these compounds, as exemplified by compound 16d (IC50 = 5.38 nM, NCI-H460). Compound 15p (IC50 = 1.03 nM, NCI-H460) with an allyl group exhibited potent cytotoxic activity at the nanomolar level against human lung cancer cell lines. Immunofluorescence assay indicated that compound 15p could efficiently inhibited microtubule polymerization and induced a high expression of caspase-3. 15p also displayed good pharmacokinetic characteristics in vitro. Additionally, the growth of H22 transplanted tumors was significantly inhibited in BALB/c mice when 15p alone was administered at 4 mg/kg, and the tumor inhibition rate was as much as 65%. Importantly, the continuous administration of 15p resulted in a lower toxicity than that of docetaxel (10 mg/kg) and cyclophosphamide (20 mg/kg). Overall, the novel allyl-imidazole-diketopiperazine-type derivatives could be considered safe and effective potential agents for cancer treatment.

[Characteristics of Bacterial Community Structure in Wuliangsu Lake During an Irrigation Interval in Hetao Plain].

In order to study the bacterial community composition and corresponding function in Wuliangsu Lake at the end of the Hetao Plain during the irrigation gap period, lake samples were collected in September 2020, and the pH, TN, TP, DIP, DTP, NH4+-N, Chla, EC, SAL, and other indicators were analyzed. The 16S rRNA high-throughput sequencing method was used to explore the attached bacteria and bacterioplankton in 15 samples of the surface water in Wuliangsu Lake. The experimental results showed that:① the alpha diversity Chao and Shannon indices of attached bacteria were greater than that of bacterioplankton, but the median of Shannoneven index was the same. ② In each sampling point, the bacterioplankton of Proteobacteria and Actinobacteria in the top five dominant bacteria phyla were higher than that of attached bacteria, and the abundance of attached bacteria and bacterioplankton of Bacteroidota were staggered. On the contrary, the contents of attached bacteria of Verrucomicrobiota and Cyanobacteria were all higher than that of bacterioplankton. ③ Redundant analysis showed that pH had the most significant effect on dominant attached bacteria, and the effect of conductivity and salinity in dominant bacterioplankton was the most significant. ④ PICRUSt2 function prediction analysis showed that attached bacteria and planktonic bacteria had the strongest metabolic functions, showing abundant metabolic functions. There were 29 nitrogen-related effective KOs and 88 phosphorus-related effective KOs, with the greatest nitrogen-fixing function and strong inorganic phosphorus-dissolving function, and bacterioplankton played a greater role in the two functions.

Effects of handle height and load on the endurance time for simulated demolition tasks.

BACKGROUND: Manual demolition tasks are heavy physical demanding tasks which involve forceful exertion of sustained pushing. They result in muscle fatigue which could lead to musculoskeletal disorders. Assessments of maximum endurance time (MET) are essential in understanding the developing of muscle fatigue for these tasks. OBJECTIVE: The objectives of this study were to determine the effects of handle height and load conditions on the MET, and to establish MET models for the simulated demolition tasks. METHODS: Twenty three male participants performed simulated demolition tasks under three loads and three handle heights conditions until they could not do so any longer. Their METs and ratings of perceived exertion were recorded and analyzed. RESULTS: The results showed that both load and handle height were significant (p < 0.0001) factors affecting the MET. Regression models to predict the MET under handle height and load conditions were established. The mean absolute deviations of these models were between 1.91 and 4.84 min. CONCLUSION: The MET models established may be used to estimate the MET which may be adopted in work/rest arrangement for demolition tasks using a handheld demolition hammer.

Complete chloroplast genome sequence of Mucuna prurien and its phylogenetic position.

Mucuna pruriens is traditional medicinal plant originated in South Africa. We characterize the complete plastid genome of M. pruriens, which is a circular-mapping molecule 152,119 bp in length. The genome has a large single-copy region (LSC) of 78,258 bp and a small single-copy region (SSC) of 18,735 bp, respectively. Additionally, the overall GC content of the chloroplast genome was 35.37%. The genome contains 138 genes, including 96 protein-coding, 38 tRNA, and four rRNA genes. The gene content and structure are conserved compared to other species in the genus Glycine. The chloroplast genome and existing data were used to infer its phylogenetic position. The results showed that M. pruriens clustered together with Glycine max and G. soja. These findings provide potential genetic markers that can aid in understanding the genetic diversity of M. pruriens.

Novel Stachydrine-Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke.

As major active ingredients of the traditional Chinese medicine motherwort, stachydrine and leonurine were found to have protective effects against cerebral ischemia. However, their bioavailability in vivo was low, and their efficacy was unsatisfactory, which limited their further application. To solve these problems, the conjugates based on the structures of stachydrine and leonurine were designed and synthesized. SL06 was found to have neuronal cell survival improvement, neuronal apoptosis restraining, activation of superoxide dismutase (SOD) activity, and inhibition of lactic dehydrogenase (LDH), reactive oxygen species (ROS), malondialdehyde (MDA) in vitro. In vivo, the infarction size was significantly reduced by SL06 in the middle cerebral artery occlusion rat model. SL06 could also activate protein kinase B (AKT)/glycogen synthase kinase 3ß (GSK-3ß) activity and promoted the expression of antiapoptoticprotein Bcl-2. On the other hand, the expression of the apoptosis-associated protein cleaved caspase-3 would be inhibited as well. Thus, SL06 as the neuroprotective agent has potential for the treatment of cerebral ischemic stroke.

[Changes in the Bacterioplankton Community Between "Ice" and "Water" in the Frozen Dali Lake].

Bacteria are the key components of water ecosystems, and play important roles in material and energy cycle processes. To understand the changes in the bacterioplankton community in frozen lakes, we collected 15 "bottom ice" samples and 15 "surface water" samples under the ice sheet from Dali Lake, which is an inland closed lake in the Inner Mongolia Plateau. Combined with comparisons of the physicochemical proxies between "bottom ice" and "surface water" samples, the phylum community characteristics of the bacterioplankton were analyzed in detail. Although the bacterioplankton were mainly comprised of Proteobacteria, Actinobacteria, Cyanobacteria, Bacteroidetes, and 11 other phyla in the "bottom ice" and "surface water", the average relative abundances of the dominant planktonic bacteria were clearly different. For example, the average relative abundance of Proteobacteria was approximately 63.64% in the "bottom ice" samples, but decreased to approximately 26.75% in the surface water samples, which was visibly smaller than the relative abundance of Actinobacteria with an average value of approximately 39.10%. We concluded that the changes in the contents of nutrient elements and physicochemical proxies must be the primary factors influencing the changes in the bacterioplankton community in the frozen Dali Lake. The changes in the physicochemical proxies could have been responsible for the changes in the bacteria community in the "bottom ice" and "surface water". Otherwise, the different physiological characteristics of the planktonic bacteria phyla caused the different responses to the changes in the contents of the nutrient elements and physicochemical proxies in the frozen lake. For example, the major bacterioplankton phyla were mainly influenced by the changes in total phosphorus and dissolved total phosphorus in the "bottom ice" and by the changes in dissolved inorganic phosphorus and ammonia nitrogen in the "surface water". The results will provide basic data to analyze the lake ecological environment in Northern China.

Design, synthesis, and biological evaluation of novel stachydrine derivatives as potent neuroprotective agents for cerebral ischemic stroke.

Stachydrine is a natural product with multiple protective biological activities, including those involved in preventing cancer, ischemia, and cardiovascular disease. However, its use has been limited by low bioavailability and unsatisfactory efficacy. To address this problem, a series of stachydrine derivatives (A1/A2/A3/A4/B1/B2/B3/B4) were designed and synthesized, and biological studies were carried out in vitro and in vivo. When compared with stachydrine, Compound B1 exhibited better neuroprotective effects in vitro, and significantly reduced infarction size in the model of the middle cerebral artery occlusion rat model. Therefore, Compound B1 was selected for further research on ischemic stroke. Graphical abstract.

Structure-based design and synthesis of novel furan-diketopiperazine-type derivatives as potent microtubule inhibitors for treating cancer.

Plinabulin, a synthetic analog of the marine natural product "diketopiperazine phenylahistin," displayed depolymerization effects on microtubules and targeted the colchicine site, which has been moved into phase III clinical trials for the treatment of non-small cell lung cancer (NSCLC) and the prevention of chemotherapy-induced neutropenia (CIN). To develop more potent anti-microtubule and cytotoxic derivatives, the co-crystal complexes of plinabulin derivatives were summarized and analyzed. We performed further modifications of the tert-butyl moiety or C-ring of imidazole-type derivatives to build a library of molecules through the introduction of different groups for novel skeletons. Our structure-activity relationship study indicated that compounds 17o (IC50 = 14.0 nM, NCI-H460) and 17p (IC50 = 2.9 nM, NCI-H460) with furan groups exhibited potent cytotoxic activities at the nanomolar level against various human cancer cell lines. In particular, the 5-methyl or methoxymethyl substituent of furan group could replace the alkyl group of imidazole at the 5-position to maintain cytotoxic activity, contradicting previous reports that the tert-butyl moiety at the 5-position of imidazole was essential for the activity of such compounds. Immunofluorescence assay indicated that compounds 17o and 17p could efficiently inhibit microtubule polymerization. Overall, the novel furan-diketopiperazine-type derivatives could be considered as a potential scaffold for the development of anti-cancer drugs.

Combination of a novel microtubule inhibitor MBRI-001 and gemcitabine synergistically induces cell apoptosis by increasing DNA damage in pancreatic cancer cell lines.

Pancreatic cancer (PC) is a highly malignant cancer with poor prognosis. Although gemcitabine (GEM; 2',2'-difluoro-deoxycytidine) has been used as the first-line chemotherapeutic agent in PC treatment for decades, its limited efficacy remains a significant clinical issue, which may be resolved by GEM combination therapy. In this study, we aimed to investigate the anti-tumor effects of MBRI-001 in combination with GEM in BxPC-3 and MIA PaCa-2 human PC cell lines. In vitro and in vivo results indicate that MBRI-001 showed synergistic activity with GEM. GEM induced apoptosis by increasing DNA damage (phosphorylated core histone protein H2AX (γ-H2AX)), MBRI-001 activated mitochondrial-apoptotic pathway (cleaved poly-ADP ribose polymerase (PARP)). Thus, the combination of the two intensified both apoptosis and DNA damage and showed significantly superior anti-tumor activity compared to each agent alone. The adoption of combination of MBRI-001 with GEM may be beneficial as they act synergistically and thus, can be a potential therapeutic choice for improving the prognosis of PC patients in the future.

Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.

The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50 = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC50 = 26.2 nM) and similar to Compound 6b (IC50 = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.

Seahorse treatment improves depression-like behavior in mice exposed to CUMS through reducing inflammation/oxidants and restoring neurotransmitter and neurotrophin function.

ETHNOPHARMACOLOGICAL RELEVANCE: Seahorses (Hippocampus erectus), belonging to syngnathidae of syngnathiformes, are a traditional Chinese medicine for increasing and balancing vital energy within the body and brain, as well as calming mood and improving sleep. AIM OF THE STUDY: Based on the hypothesis of monoamine neurotransmitter deficiency, current antidepressant treatments, with many side effects, are ineffective. Thus, novel hypotheses, inflammation, oxidative stress and neurotrophin dysfunction were proposed. Since seahorses can modulate immune function, reduce oxidants and nourish brain function, it may effectively treat depression. Therefore, this study aimed to detect the predominant chemical characterization of seahorses and investigate the mechanism by which seahorses exert antidepressant effects by using a chronic unpredictable mild stress (CUMS)-induced model of depression. METHODS: Control and CUMS-exposed mice were fed normal or seahorse diet (0.018 g seahorses power) for 8-weeks. After behavioral tests, serum corticosterone, hippocampal expression of CD11b, glial fibrillary acidic protein (GFAP), and brain derived neurotrophic factor (BDNF), and the concentration of interleukin (IL)-1ß and monoamine neurotransmitters were measured, while amygdala IL-1ß and IL-10, anti-oxidative and oxidative enzyme were also studied. Then main phytoconstituents of seahorses was analyzed using liquid chromatography-mass spectrometry (LC-MS) methods. RESULTS: Compared to controls, sucrose preference, exploration in open field, social interaction, entry numbers into and times spent on the open arms of elevated plus maze were significantly decreased, while immobility times in forced-swimming was increased in CUMS mice. These changes were associated with significantly reduced levels of serotonin, noradrenaline and dopamine, also expressions of GFAP and BDNF. Moreover, CUMS elevated IL-1ß concentrations and reactive oxygen species (ROS), while decreased IL-10 concentration and anti-oxidative super oxide dismutase and glutathione peroxidase. Seahorse diet significantly reversed anxiety- and depression-like behaviors, which were correlated with reducing IL-1ß and ROS, but increasing neurotransmitter concentrations and BDNF expression. Several compounds were found in seahorses, including docosahexaenoic acid, eicosapentaenoic acid, bis(2-ethylheptyl) phthalate, chrysophanol, and hypoxanthine. CONCLUSION: Seahorses could attenuate the CUMS-induced anxiety- and depression-like behaviors by reducing oxidative stress and inflammation, and normalizing neurotransmitter and neurotrophin function, which are possibly due to the activities of one or more or mixture of these identified compounds.

Development of M10, myricetin-3-O-ß-d-lactose sodium salt, a derivative of myricetin as a potent agent of anti-chronic colonic inflammation.

Myricetin is a natural dietary flavonoid compound with multiple activities, such as anti-oxidant, anti-inflammatory, anti-carcinogenic and anti-proliferative effects. However, myricetin exhibited substantial limitations, such as poor water-solubility, and low stability in body when it was administrated by oral. To solve these problems, we designed and synthesized a series of derivatives based on the structure of myricetin. M10 was produced by adding a hydrophilic glycosylation group and then forming a sodium salt derivative, which exhibited excellent water-solubility (>100 mg/mL), and better stability in Wistar rat plasma and liver microsomes. In vivo study, M10 exhibited higher efficacy than myricetin and mesalazine in a dextran sulfate sodium (DSS) induced mice model with ulcerative colitis. In addition, M10 also exhibited high safety (LD50 > 5 g/kg) in mice. Based on these results, M10 could be developed as a potential therapeutic agent for treatment of ulcerative colitis.

Polymorphs, co-crystal structure and pharmacodynamics study of MBRI-001, a deuterium-substituted plinabulin derivative as a tubulin polymerization inhibitor.

MBRI-001, a deuterium-substituted plinabulin derivative, has been reported to have better pharmacokinetic and similar antitumor effects in comparison with plinabulin. In this approach, we further carried out its polymorphs, co-crystal structure of MBRI-001-tubulin and tubulin inhibition study. Among the different polymorphs, Form F (MBRI-001/H2O) was prepared and evaluated, which had better physical stability and suitable process for scale-up production. Co-crystal structure of MBRI-001-tubulin (PDB:5XI5) was prepared and analyzed. The result of tubulin polymerization assay demonstrated that MBRI-001 could inhibit tubulin polymerization which was similar as plinabulin. Subsequently, the anti-proliferative activities of plinabulin and MBRI-001 were evaluated against two different human lung cancer cell lines. In vivo study, MBRI-001 revealed similar antitumor inhibition in comparison with plinabulin in A549 xenograft tumor model. Therefore, we suggested that MBRI-001 could be developed as a promising anti-cancer agent in near future.