Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug de...Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.展开更多
The Janus kinases(JAKs)are a family of intracellular tyrosine kinases that play an essential role in many basic biological processes,such as apoptosis and inflammation.Thus any dysfunction of the proteins in this path...The Janus kinases(JAKs)are a family of intracellular tyrosine kinases that play an essential role in many basic biological processes,such as apoptosis and inflammation.Thus any dysfunction of the proteins in this pathway may lead to a variety of diseases,including cancer and diseases that affect the immune system,such as severe combined immune deficient(SCID).Marine biological resources have become an important source in new drug research and development due to their diversity,complexity and speciality.In this study,Marine alkaloid Neobacillamide A was isolated from the greedy and stubborn sponge symbiotic Bacillus atrophicus C89 in the South China Sea.Totally 24 novel marine alkaloid Neobacillamide A derivatives were designed and synthesized,which were evaluated for their inhibitory activity against JAK/STAT signaling pathway and their cytotoxicity to A549 cells.Compounds 13c,13o,14d,14g and 14h showed potent JAK/STAT inhibition capability(concentration of 25μmol L^(-1),all inhibitory potencies were above 60%),especially compound 14g exhibited superior JAK/STAT inhibition effect(89.70%inhibition).In addition,all these compounds with a concentration of 25μmol L^(-1)displayed weak or no cytotoxicity to A549 cells,which means that these Neobacillamide A derivatives with JAK/STAT inhibition capability may have potential anti-inflammatory function.展开更多
The marine biopharmaceutical industry(MBI)has been considered as an important part of the blue economy.The high-quality development of this industry depends on the high-level coordinated development of technological i...The marine biopharmaceutical industry(MBI)has been considered as an important part of the blue economy.The high-quality development of this industry depends on the high-level coordinated development of technological innovation system(TIS).In the present study,the coupling mechanism of industrial innovation input subsystem and innovation output subsystem was analyzed for the first time.On this basis,the development level and coupling coordination level of TIS in China’s MBI during 2008-2018 were empirically evaluated with the capacity coupling coordination model.Then,the obstacle factors were diagnosed and recognized with the obstacle model.The results showed that the innovation input index fluctuated at a low level in China’s MBI.The innovation output index has basically maintained a growth trend,whereas the quality of development was not high.Although the coupling coordination level of TIS showed a positive change as mild disordered→primary coordinated→well-coordinated,the development type of innovation system has changed from the lagging output of innovation into the lagging input of innovation.Insufficient input of innovation factors remained the main obstacle to the improvement of coordination level.Based on the above analysis,suggestions were put forward from the perspectives of policy and fund guarantees to improve the coupling coordination level in China’s MBI.展开更多
A new extracellular κ-carrageenase, namely CgkP, 34.0 kDa in molecular weight, was purified from Pseudoalteromonas sp. QY203. CgkP showed relatively high activity at acidities ranging from pH6.0 to pH9.0 and temperat...A new extracellular κ-carrageenase, namely CgkP, 34.0 kDa in molecular weight, was purified from Pseudoalteromonas sp. QY203. CgkP showed relatively high activity at acidities ranging from pH6.0 to pH9.0 and temperatures ranging from 30℃ to 50℃ with the highest activity at 45℃ and pH7.2. Sodium chloride increased its activity markedly, and KC1 increased its activity slightly. The divalent and trivalent metal ions including Cu^2＋, Ni^2＋, Zn^2＋, Mn^2＋, Al^3＋ and Fe^3＋ significantly inhibited its activity, while Mg^2＋ did not. CgkP remained 70% of original activity after being incubated at 40℃ for 48h, and remained 80% of the activity after being incubated at 45℃ for 1 h. It exhibited endo-κ-carrageenase activity, mainly depolymerizing the κ-carrageenan into disaccharide and tetrasaccharide. CgkP was more thermostable than most of previously reported κ-carrageenases with a potential of being used in industry.展开更多
An excess of reactive oxygen species（ROS）leads to a variety of chronic health problems.As potent antioxidants,marine bioactive extracts containing oligosaccharides and peptides have been extensively studied.Recently...An excess of reactive oxygen species（ROS）leads to a variety of chronic health problems.As potent antioxidants,marine bioactive extracts containing oligosaccharides and peptides have been extensively studied.Recently,there is a growing interest in protein-polysaccharide complexes because of their potential uses in pharmaceutical and food industries.However,only few studies are available on the antioxidant activities of such complexes,in terms of their ROS scavenging capability.In this study,we combined and superoxide radicals,and to evaluate the influences on the activities of superoxide dismutase（SOD）,glutathione peroxidase（GSH-Px）and the level of malondialdehyde（MDA）in UV-induced photoaging models.The results indicated that the antioxidant activities of all the complexes were stronger than those of their individual components.Among the 11 complexes tested,two complexes,namely MA1000＋CP and κ-ca3000＋CP,turned out to be highly effective antioxidants.Although the detailed mechanisms of this improved scavenging ability are not fully understood,this work provides insights into the design of highly efficient peptide-oligosaccharide complexes for potential applications in pharmaceutical,cosmetics and food industries.展开更多
kappa-carrageenan oligosaccharides exhibit various biological activities. Enzymatic degradation by kappa-carrageenase is safe and controllable. Therefore, kappa-carrageenases have captured more and more attentions. In...kappa-carrageenan oligosaccharides exhibit various biological activities. Enzymatic degradation by kappa-carrageenase is safe and controllable. Therefore, kappa-carrageenases have captured more and more attentions. In this study, a kappa-carrageenase encoding gene, cgkX, was cloned from Pseudoalteromonas sp. QY203 with degenerate and inverse PCR. It comprised an ORF of 1194 bp in length, encoding a protein with 397 amino acid residues. CgkX is a new member of glycoside hydrolase family 16. The deduced amino acid sequence shared a high similarity with CgkX of Pseudoalteromonas kappa-carrageenase; however, the recombinant CgkX showed different biochemical characteristics. The recombinant enzyme was most active at pH 7.0 and 55A degrees C in the presence of 300 mmol L-1 NaCl. It was stable in a broad range of acidity ranging from pH 3.0 to pH 10.0 when temperature was below 40A degrees C. More than 80% of its activity was maintained after being incubated at pH 3.6-10.0 and 4A degrees C for 24 h. CgkX retained more than 90% of activity after being incubated at 40A degrees C for 1 h. EDTA and SDS (1 mmol L-1) did not inhibit its activity. CgkX hydrolyzed kappa-carrageenan into disaccharide and tetrasaccharide as an endo-cleaver. All these characteristics demonstrated that CgkX is applicable to both kappa-carrageenan oligosaccharide production and kappa-carrageenase structure-function research.展开更多
The synthesis of a marine cytotoxic cyclic depsipeptide obyanamide has been accomplished. The key steps include assembling liner pentapeptide via Yamaguchi esterification and HATU-promoted ring closing. The structure ...The synthesis of a marine cytotoxic cyclic depsipeptide obyanamide has been accomplished. The key steps include assembling liner pentapeptide via Yamaguchi esterification and HATU-promoted ring closing. The structure of the synthetic sample was identified by ^1H and ^13C NMR, H-H COSY, HMQC, HMBC, and HRESIMS, but appears to be different from that of the marine natural product.展开更多
The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellari...The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellarin-like phenolic pyrrole compounds, which can inhibit hypoxia-induced HIF-1 activation. Many pyrrole-derived lamellarin-like alkaloids show potent MDR reversing activity. In this study, five permethylated derivatives of neolamellarin A were synthesized with their MDR reversing activity studied in order to identify new MDR reversal agents. A convergent strategy was adopted to synthesize the permethylated derivatives of neolamellarin A. Pyrrole was first converted into a corresponding N-trisisopropylsilyl （TIPS）-substituted derivative, then through iodination afforded 3,4-diiodinated pyrrole compound. The key intermediate, 3,4-disubstituent-lH-pyrrole, was obtained through desilylation of 3,4-disubstituent-l-TIPS pyrrole, which was prepared from 3,4-diiodinated pyrrole derivative and aryl boronic acid ester through Suzuki cross-coupling reaction between them. Then, the intermediate, 3,4-disubstituent-lH-pyrrole, reacted with fresh phenylacetyl chloride under n-BuLi/THF condition afforded the target compounds. Finally, we obtained five novel pyrrolic com- pounds, permethylated derivatives ofneolamellarin A 16a-e, in 30%-37% yield through five step reactions. The bioactivity testing of these compounds are in process.展开更多
A new phenolic compound, 6-(2-acetyl-3,5-dihydroxybenzyl)-4-hydroxy-3-methyl-2H-pyran-2-one(1), along with other six known phenolic derivatives(2-7), were isolated from the mangrove rhizosphere fungus Penicillium jant...A new phenolic compound, 6-(2-acetyl-3,5-dihydroxybenzyl)-4-hydroxy-3-methyl-2H-pyran-2-one(1), along with other six known phenolic derivatives(2-7), were isolated from the mangrove rhizosphere fungus Penicillium janthinellum HK1-6 cultured in potato dextrose broth medium containing 30 g L^(-1) of natural sea salt. The structure of the new compound(1) was elucidated by comprehensive analysis of spectroscopic data including 1D and 2D NMR spectra. The proposed biosynthetic pathway of compound 1 was also studied in this research. Interestingly, a brominated phenolic derivative, aryl bromide(compound 8), was obtained from this fungal strain cultured in medium containing 30 g L^-1 of NaBr instead of natural sea salt. Compound 8 is proposed as a new natural product and formed through bromination of compound 7 when the fungus was cultured with NaBr. The neuroprotective effect of compound 1 on oxygen-glucose deprivation(OGD)-induced injury was investigated in rat spinal cord astrocytes. MTT assay demonstrated that compound 1 can attenuate OGD-induced cell viability loss in rat spinal cord astrocytes.展开更多
Hyrtiosulawesine was isolated from Indonesian specimens of the marine sponges Hyrtios erectus and H.reticulatu in 2002.We report here the first total synthesis of hyrtiosulawesine using an efficient and convenient syn...Hyrtiosulawesine was isolated from Indonesian specimens of the marine sponges Hyrtios erectus and H.reticulatu in 2002.We report here the first total synthesis of hyrtiosulawesine using an efficient and convenient synthetic strategy which could be widely used in the synthesis of otherβ-carboline compounds.All structures of new compounds were confirmed by 1H NMR,13C NMR and HRMS.展开更多
Due to their structural diversity and variety of biological activities, marine natural products have been the subject of extensive study. These compounds, especially phospholipid polycyclic aromatic hydrocarbons, have...Due to their structural diversity and variety of biological activities, marine natural products have been the subject of extensive study. These compounds, especially phospholipid polycyclic aromatic hydrocarbons, have a wide range of pharmacological applications, including embedded DNA and central nervous system, anti-tumor, anti-virus, anti-parasite, anti-bacterial, and antithrombotic effects. Unfortunately, the insufficient drug sources have limited the development of these compounds. In this study, we isolated salinpostin compounds from a fermentation solution of marine-derived Salinospora sp., which has a common bicyclic enol-phosphotriester core framework, as well as potent and selective antimalarial activities against P. falciparum with EC_(50)=50 nmolL^(-1). The chemical synthesis of these compounds in greater quantities is necessary for their use in bioactivity studies. Thus we explored a short route with high yields and mild reaction conditions, which can generate combinatorial libraries for drug discovery and lead optimization. We developed a new total synthesis method for six cyclic enol-phosphotriester salinipotin compounds and their diastereomers. For the total synthesis of cyclipostin P, we prepared cyclic enol-phosphotriester salinipostin compounds in 10 steps from a readily accessible starting material, 1,3-dihydroxyacetone, and obtained an overall yield of 1.29%. We fully characterized these compounds by proton nuclear magnetic resonance(~1H-NMR), carbon-13 NMR(^(13)C-NMR), and high-resolution mass spectrometry(HRMS) analyses, and found they coincide absolutely with the same compounds reported previously.展开更多
A mutant (GQQ-M6) of a Sponge-Derived streptomyces sp. GQQ-10 obtained by UV-induced mutation was used for producing prodiginines (PGs). Single factor experiments and orthogonal array design (OAD) methods were employe...A mutant (GQQ-M6) of a Sponge-Derived streptomyces sp. GQQ-10 obtained by UV-induced mutation was used for producing prodiginines (PGs). Single factor experiments and orthogonal array design (OAD) methods were employed for medium optimization. In the single factor method, the effects of soluble starch, glucose, soybean flour, yeast extract and sodium acetate on PGs production were investigated individually. In the subsequent OAD experiments, the concentrations of these 5 key nutritional components combined with salinity were further adjusted. The mutant strain GQQ-M6 gave a 2.2-fold higher PGs production than that of the parent strain; OAD experiments offered a PGs yield of 61mg L-1, which was 10 times higher than that of the initial GQQ-10 strain under the original cultivation mode.展开更多
A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces...A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces.A3 and stachyose(internal standard)were separated by a BEH amide column at 65℃under the mobile phase of 10 mmol L^(-1)ammonium ace-tate-acetonitrile(42:58,v/v)with 350µLmin-1.The acquisition of transitions was carried out in multiple reaction monitoring(MRM)pattern operating with positive ionization at m/z 509.16>329.15 for A3 and m/z 689.15>527.11 for stachyose.The linearity ranges of A3 were 10 to 5000nmolL^(-1)for plasma,20 to 10000nmolL^(-1)for tissues,and 40 to 20000nmolL^(-1)for urine and feces.The accuracy and precision ranged from 90.9%to 111.6%and 0.7%to 10.1%,respectively.The stability was between 86.1%and 102.5%.The extraction recovery was consistent and reproducible.The matrix effect ranged from 1.5%to 11.4%.The pharmacokinetic,tissue dis-tribution,and excretion studies were successfully conducted with the validated method.Results showed that A3 could be absorbed by rats,and the absolute bioavailability was 6.7%.Furthermore,it was rapidly distributed in rat tissues and mainly eliminated via feces excretion(67.0%)after oral administration.For intravenous bolus,85.5%was recovered,and renal excretion was the primary path-way(77.6%)for cumulative recovery.展开更多
The application of chondroitinase requires consideration of the complex microenvironment of the target.Our previous research reported a marine-derived sodium dodecyl sulfate(SDS)-resistant chondroitinase VhChlABC.This...The application of chondroitinase requires consideration of the complex microenvironment of the target.Our previous research reported a marine-derived sodium dodecyl sulfate(SDS)-resistant chondroitinase VhChlABC.This study further investigated the mechanism of VhChlABC resistance to SDS.Focusing on the hydrophobic cluster on its strong hydrophilic surface,it was found that the reduction of hydrophobicity of surface residues Ala181,Met182,Met183,Ala184,Val185,and Ile305 significantly reduced the SDS resistance and stability.Molecular dynamics(MD)simulation and molecular docking analysis showed that I305G had more conformational flexibility around residue 305 than wild type(WT),which was more conducive to SDS insertion and binding.The affinity of A181G,M182A,M183A,V185A and I305G to SDS was significantly higher than that of WT.In conclusion,the surface hydrophobic microenvironment composed of six residues was the structural basis for SDS resistance.This feature could prevent the binding of SDS and the destruction of hydrophobic packaging by increasing the rigid conformation of protein and reducing the binding force of SDS-protein.The study provides a new idea for the rational design of SDS-resistant proteins and may further promote chondroitinase research in the targeted therapy of lung diseases under the pressure of pulmonary surfactant.展开更多
In order to determine the role of alginate-derived oligosaccharides (ADO) in drought stress resistance of tomato (Ly-copersicon esculentum Miller) seedlings, the leaves were exposed to different concentrations of ADO ...In order to determine the role of alginate-derived oligosaccharides (ADO) in drought stress resistance of tomato (Ly-copersicon esculentum Miller) seedlings, the leaves were exposed to different concentrations of ADO (0.05%, 0.10%, 0.20%, 0.30% and 0.50%) after drought stress was simulated by exposing the roots to 0.6 molL-1 PEG-6000 solution for 6 h. Changes in biomass, electrolyte leakage and malondialdehyde (MDA), free proline, total soluble sugars (TSS) and abscisic acid (ABA), the enzyme activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and phenylalanine ammonia-lyase (PAL) were measured to investigate the effects of ADO treatment. The results showed that the treatment with an ADO concentration of 0.20% exhibited the highest performance of drought stress resistance in the tomato seedlings by decreasing the electrolyte leakage and the concentration of MDA, increasing the contents of free proline, TSS and ABA, and increasing the activities of CAT, SOD, POD and PAL after treatment with ADO. It is suggested that changes in electrolyte leakage, MDA, osmotic solutes, ABA, anti-oxidative enzyme and PAL activities were responsible for the increased drought stress resistance in tomato seedlings. To our best knowledge, this is the first report of the effect of ADO treatment on enhancing the drought stress resistance of tomato seedlings.展开更多
A new compound, （S）-2, 4-dihydroxy-1-butyl （4-hydroxy） benzoate （1）, and a known compound, fructigenines A （2）, were isolated from fungus Penicillium auratiogriseum derived from sponge Mycale plumose, by bioas...A new compound, （S）-2, 4-dihydroxy-1-butyl （4-hydroxy） benzoate （1）, and a known compound, fructigenines A （2）, were isolated from fungus Penicillium auratiogriseum derived from sponge Mycale plumose, by bioassay-guided fractionation. Their structures were established by spectroscopic and chemical methods. Both compounds show.ed cytotoxic activity against tsFT210 cells.展开更多
Cultivation of an endophytic fungus Aspergillus niger EN-13 that was isolated from the inner tissue of the marine brown alga Colpomenia sinuosa resulted in the characterization of a new naphthoquinoneimine derivative,...Cultivation of an endophytic fungus Aspergillus niger EN-13 that was isolated from the inner tissue of the marine brown alga Colpomenia sinuosa resulted in the characterization of a new naphthoquinoneimine derivative, namely, 5,7-dihydroxy-2-[1-（4- methoxy-6-oxo-6H-pyran-2-yl）-2-phenylethylamino]-[ 1,4]naphthoquinone. The structure of the new compound was established on the basis of various NMR spectroscopic analyses including 2D NMR techniques, El-MS, and HR-ESI-MS. This compound displayed moderate antifungal activity.展开更多
Three new aspochalsins（R-T）（1-3） were isolated from the marine-derived fungus Spicaria elegans.Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR techniques,an...Three new aspochalsins（R-T）（1-3） were isolated from the marine-derived fungus Spicaria elegans.Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR techniques,and HR-ESI-MS.展开更多
Three polysaccharides （EW, EH and EA） were prepared from a red alga Eucheuma denticulatum by sequential extraction with cold water, hot water and sodium hydroxide water solution. Their monosaccharide compositions, r...Three polysaccharides （EW, EH and EA） were prepared from a red alga Eucheuma denticulatum by sequential extraction with cold water, hot water and sodium hydroxide water solution. Their monosaccharide compositions, relative molecular mass and structural characterization were determined by gas chromatography, high performance liquid chromatography, fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy methods. EW was hybrid l/k/v-carrageenan （701/17k/13v-car- rabiose）, EH was mainly t-carrageenan, and EA was mainly α-1,4-Glucan （88%） but mixed with small amount of t-carrageenan （12%）. The relative molecular mass ofEW, EH and EA was 480, 580 and 510kDa, respectively. The anti-influenza A （H1N1） virus activity of these three polysaccharides was evaluated using the Madin-Darby canine kidney cells model. EW showed good anti-H1N1 virus activity, its ICso was 276.5 μg mL-1, and the inhibition rate to H1N1 virus was 52% when its concentration was 250 μgmL-1. The ICs0 of t-carrageenan EH was 366.4 μgmL1, whereas EA showed lower anti-H1N1 virus activity （IC50〉430μgmL-1）. Available data obtained give positive evidence that the hybrid carrageenan EW from Eueheuma denticulatum can be used as potential anti-H1N1 virus inhibitor in future.展开更多
Seaweed Complex Preparation （SCP） is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and dige...Seaweed Complex Preparation （SCP） is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and digestive cancer. However, little infor- mation is available about the pharmacodynamic basis. The antitumor, immunomodulatory and free radical scavenging effects of SCP were evaluated in this study. Transplanted tumor in vivo method was used to determine the antitumor effect. The effects on spleno- cyte proliferation and phagocytosis of macrophages in tumor-bearing mice were measured by the MTT method and the phagocytizing cock red blood cell （CRBC） method respectively. The scavenging activities of SCP on DPPH and hydroxyl radicals in vitro were investigated. It was found that the medium-dose and high-dose of SCP could significantly inhibit the growth of transplanted hepatic tumor of murine hepatocarcinoma cell line H22, and promote proliferation of splenocytes and phagocytosis of macrophages. SCP possessed noticeable scavenging activities on DPPH and hydroxyl radicals. The antiturnor effects of SCP might be achieved by im- proving immune system and scavenging free radicals, which is in accordance with the viewpoint of traditional Chinese medicine in promoting the body resistance and eliminating pathogenic factors for cancer treatment.展开更多
基金supported by the Shandong Province Special Fund ‘Frontier Technology and Free Exploration’ from Laoshan Laboratory (No. 8-01)the National Natural Science Foundation of China (No. 42376116)+3 种基金the Special Funds of Shandong Province for Qingdao National Laboratory of Marine Science and Technology (No. 2022QN LM030003)the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University (No. CMEMR2023-B16)the National Key Research and Development Program of China (No. 2022YFC2601305)the Innovation Center for Academicians of Hainan Province, and the Fundamental Research Funds for the Central Universities (No. 202461059)
文摘Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.
基金financial supports granted by the National Natural Science Foundation of China(Nos.82073759 and 82003583)the Fund of Greater Bay Area Institute of Precision Medicine(Guangzhou)(No.IPM2021C009)the National Science and Technology Major Project for Significant New Drugs Development(No.2018ZX09735004)。
文摘The Janus kinases(JAKs)are a family of intracellular tyrosine kinases that play an essential role in many basic biological processes,such as apoptosis and inflammation.Thus any dysfunction of the proteins in this pathway may lead to a variety of diseases,including cancer and diseases that affect the immune system,such as severe combined immune deficient(SCID).Marine biological resources have become an important source in new drug research and development due to their diversity,complexity and speciality.In this study,Marine alkaloid Neobacillamide A was isolated from the greedy and stubborn sponge symbiotic Bacillus atrophicus C89 in the South China Sea.Totally 24 novel marine alkaloid Neobacillamide A derivatives were designed and synthesized,which were evaluated for their inhibitory activity against JAK/STAT signaling pathway and their cytotoxicity to A549 cells.Compounds 13c,13o,14d,14g and 14h showed potent JAK/STAT inhibition capability(concentration of 25μmol L^(-1),all inhibitory potencies were above 60%),especially compound 14g exhibited superior JAK/STAT inhibition effect(89.70%inhibition).In addition,all these compounds with a concentration of 25μmol L^(-1)displayed weak or no cytotoxicity to A549 cells,which means that these Neobacillamide A derivatives with JAK/STAT inhibition capability may have potential anti-inflammatory function.
基金supported by the National Natural Science Foundation of China(Nos.42176126,42076221)the Department of Marine Strategic Planning and Economy,Ministry of Natural Resources of China,and Marine Development Research Society of China(No.CAMA201817).
文摘The marine biopharmaceutical industry(MBI)has been considered as an important part of the blue economy.The high-quality development of this industry depends on the high-level coordinated development of technological innovation system(TIS).In the present study,the coupling mechanism of industrial innovation input subsystem and innovation output subsystem was analyzed for the first time.On this basis,the development level and coupling coordination level of TIS in China’s MBI during 2008-2018 were empirically evaluated with the capacity coupling coordination model.Then,the obstacle factors were diagnosed and recognized with the obstacle model.The results showed that the innovation input index fluctuated at a low level in China’s MBI.The innovation output index has basically maintained a growth trend,whereas the quality of development was not high.Although the coupling coordination level of TIS showed a positive change as mild disordered→primary coordinated→well-coordinated,the development type of innovation system has changed from the lagging output of innovation into the lagging input of innovation.Insufficient input of innovation factors remained the main obstacle to the improvement of coordination level.Based on the above analysis,suggestions were put forward from the perspectives of policy and fund guarantees to improve the coupling coordination level in China’s MBI.
基金supported by National Science Foundation of China (31000361 and 31070712)Program for Changjiang Scholars and Innovative Research Team in University (IRT0944)+1 种基金Special Fund for Marine Scientific Research in the Public Interest (201005024)the Fundamental Research Funds for the Central Universities(201013008)
文摘A new extracellular κ-carrageenase, namely CgkP, 34.0 kDa in molecular weight, was purified from Pseudoalteromonas sp. QY203. CgkP showed relatively high activity at acidities ranging from pH6.0 to pH9.0 and temperatures ranging from 30℃ to 50℃ with the highest activity at 45℃ and pH7.2. Sodium chloride increased its activity markedly, and KC1 increased its activity slightly. The divalent and trivalent metal ions including Cu^2＋, Ni^2＋, Zn^2＋, Mn^2＋, Al^3＋ and Fe^3＋ significantly inhibited its activity, while Mg^2＋ did not. CgkP remained 70% of original activity after being incubated at 40℃ for 48h, and remained 80% of the activity after being incubated at 45℃ for 1 h. It exhibited endo-κ-carrageenase activity, mainly depolymerizing the κ-carrageenan into disaccharide and tetrasaccharide. CgkP was more thermostable than most of previously reported κ-carrageenases with a potential of being used in industry.
基金funded by the National High Technology Research and Development Program of China 863 Program Grant (2001AA620405)
文摘An excess of reactive oxygen species（ROS）leads to a variety of chronic health problems.As potent antioxidants,marine bioactive extracts containing oligosaccharides and peptides have been extensively studied.Recently,there is a growing interest in protein-polysaccharide complexes because of their potential uses in pharmaceutical and food industries.However,only few studies are available on the antioxidant activities of such complexes,in terms of their ROS scavenging capability.In this study,we combined and superoxide radicals,and to evaluate the influences on the activities of superoxide dismutase（SOD）,glutathione peroxidase（GSH-Px）and the level of malondialdehyde（MDA）in UV-induced photoaging models.The results indicated that the antioxidant activities of all the complexes were stronger than those of their individual components.Among the 11 complexes tested,two complexes,namely MA1000＋CP and κ-ca3000＋CP,turned out to be highly effective antioxidants.Although the detailed mechanisms of this improved scavenging ability are not fully understood,this work provides insights into the design of highly efficient peptide-oligosaccharide complexes for potential applications in pharmaceutical,cosmetics and food industries.
基金supported by the National High-Tech R&D Program(No.2011AA090703)the National Natural Science Foundation of China(No.31070712)the Special Fund for Marine Scientific Research in the Public Interest(Nos.201105027 and 201005024)
文摘kappa-carrageenan oligosaccharides exhibit various biological activities. Enzymatic degradation by kappa-carrageenase is safe and controllable. Therefore, kappa-carrageenases have captured more and more attentions. In this study, a kappa-carrageenase encoding gene, cgkX, was cloned from Pseudoalteromonas sp. QY203 with degenerate and inverse PCR. It comprised an ORF of 1194 bp in length, encoding a protein with 397 amino acid residues. CgkX is a new member of glycoside hydrolase family 16. The deduced amino acid sequence shared a high similarity with CgkX of Pseudoalteromonas kappa-carrageenase; however, the recombinant CgkX showed different biochemical characteristics. The recombinant enzyme was most active at pH 7.0 and 55A degrees C in the presence of 300 mmol L-1 NaCl. It was stable in a broad range of acidity ranging from pH 3.0 to pH 10.0 when temperature was below 40A degrees C. More than 80% of its activity was maintained after being incubated at pH 3.6-10.0 and 4A degrees C for 24 h. CgkX retained more than 90% of activity after being incubated at 40A degrees C for 1 h. EDTA and SDS (1 mmol L-1) did not inhibit its activity. CgkX hydrolyzed kappa-carrageenan into disaccharide and tetrasaccharide as an endo-cleaver. All these characteristics demonstrated that CgkX is applicable to both kappa-carrageenan oligosaccharide production and kappa-carrageenase structure-function research.
基金the National Natural Science Foundation of China （30572245）.
文摘The synthesis of a marine cytotoxic cyclic depsipeptide obyanamide has been accomplished. The key steps include assembling liner pentapeptide via Yamaguchi esterification and HATU-promoted ring closing. The structure of the synthetic sample was identified by ^1H and ^13C NMR, H-H COSY, HMQC, HMBC, and HRESIMS, but appears to be different from that of the marine natural product.
基金supported by the National Natural Science Foundation of China (21171154 and 91129706)Special Fund for Marine Scientific Research in the Public Interest (01005024)
文摘The pyrrole-derived alkaloids with marine origin, especially their permethyl derivatives, have unique structures and promising biological activities. Marine natural product neolamellarins are a collection of lamellarin-like phenolic pyrrole compounds, which can inhibit hypoxia-induced HIF-1 activation. Many pyrrole-derived lamellarin-like alkaloids show potent MDR reversing activity. In this study, five permethylated derivatives of neolamellarin A were synthesized with their MDR reversing activity studied in order to identify new MDR reversal agents. A convergent strategy was adopted to synthesize the permethylated derivatives of neolamellarin A. Pyrrole was first converted into a corresponding N-trisisopropylsilyl （TIPS）-substituted derivative, then through iodination afforded 3,4-diiodinated pyrrole compound. The key intermediate, 3,4-disubstituent-lH-pyrrole, was obtained through desilylation of 3,4-disubstituent-l-TIPS pyrrole, which was prepared from 3,4-diiodinated pyrrole derivative and aryl boronic acid ester through Suzuki cross-coupling reaction between them. Then, the intermediate, 3,4-disubstituent-lH-pyrrole, reacted with fresh phenylacetyl chloride under n-BuLi/THF condition afforded the target compounds. Finally, we obtained five novel pyrrolic com- pounds, permethylated derivatives ofneolamellarin A 16a-e, in 30%-37% yield through five step reactions. The bioactivity testing of these compounds are in process.
基金supported by the National Natural Science Foundation of China (Nos.81703411, 41830535, U1606403)the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology (Qingdao) (No.2018SD KJ0406-5)+3 种基金the National Science and Technology Major Project for Significant New Drugs Development (No.2018 ZX09735-004)the Program of Open Studio for Druggability Research of Marine Natural Productthe Pilot National Laboratory for Marine Science and Technology (Qingdao, China)Taishan Scholars Program, China。
文摘A new phenolic compound, 6-(2-acetyl-3,5-dihydroxybenzyl)-4-hydroxy-3-methyl-2H-pyran-2-one(1), along with other six known phenolic derivatives(2-7), were isolated from the mangrove rhizosphere fungus Penicillium janthinellum HK1-6 cultured in potato dextrose broth medium containing 30 g L^(-1) of natural sea salt. The structure of the new compound(1) was elucidated by comprehensive analysis of spectroscopic data including 1D and 2D NMR spectra. The proposed biosynthetic pathway of compound 1 was also studied in this research. Interestingly, a brominated phenolic derivative, aryl bromide(compound 8), was obtained from this fungal strain cultured in medium containing 30 g L^-1 of NaBr instead of natural sea salt. Compound 8 is proposed as a new natural product and formed through bromination of compound 7 when the fungus was cultured with NaBr. The neuroprotective effect of compound 1 on oxygen-glucose deprivation(OGD)-induced injury was investigated in rat spinal cord astrocytes. MTT assay demonstrated that compound 1 can attenuate OGD-induced cell viability loss in rat spinal cord astrocytes.
基金financial support of Key International S&T Cooperation Projects of MOST(No. 2008DFA31040)
文摘Hyrtiosulawesine was isolated from Indonesian specimens of the marine sponges Hyrtios erectus and H.reticulatu in 2002.We report here the first total synthesis of hyrtiosulawesine using an efficient and convenient synthetic strategy which could be widely used in the synthesis of otherβ-carboline compounds.All structures of new compounds were confirmed by 1H NMR,13C NMR and HRMS.
基金supported by the National Natural Science Foundation of China (No. 81373322)the Innovation Project from Qingdao National Laboratory for Marine Science and Technology (No. 2015ASKJ02)the Taishan Scholar Project Fund of Shandong Province
文摘Due to their structural diversity and variety of biological activities, marine natural products have been the subject of extensive study. These compounds, especially phospholipid polycyclic aromatic hydrocarbons, have a wide range of pharmacological applications, including embedded DNA and central nervous system, anti-tumor, anti-virus, anti-parasite, anti-bacterial, and antithrombotic effects. Unfortunately, the insufficient drug sources have limited the development of these compounds. In this study, we isolated salinpostin compounds from a fermentation solution of marine-derived Salinospora sp., which has a common bicyclic enol-phosphotriester core framework, as well as potent and selective antimalarial activities against P. falciparum with EC_(50)=50 nmolL^(-1). The chemical synthesis of these compounds in greater quantities is necessary for their use in bioactivity studies. Thus we explored a short route with high yields and mild reaction conditions, which can generate combinatorial libraries for drug discovery and lead optimization. We developed a new total synthesis method for six cyclic enol-phosphotriester salinipotin compounds and their diastereomers. For the total synthesis of cyclipostin P, we prepared cyclic enol-phosphotriester salinipostin compounds in 10 steps from a readily accessible starting material, 1,3-dihydroxyacetone, and obtained an overall yield of 1.29%. We fully characterized these compounds by proton nuclear magnetic resonance(~1H-NMR), carbon-13 NMR(^(13)C-NMR), and high-resolution mass spectrometry(HRMS) analyses, and found they coincide absolutely with the same compounds reported previously.
基金supported by the National Natural Science Foundation of China (Nos.30973627 and 30772640)the public projects of the State Oceanic Administration (No.2010418022-3)+1 种基金the Program for Changjiang Scholars and Innovative Research Team in University (No.IRT0944)the Natural Science Fund of Shandong Province,P.R.China (No.ZR2009CZ016)
文摘A mutant (GQQ-M6) of a Sponge-Derived streptomyces sp. GQQ-10 obtained by UV-induced mutation was used for producing prodiginines (PGs). Single factor experiments and orthogonal array design (OAD) methods were employed for medium optimization. In the single factor method, the effects of soluble starch, glucose, soybean flour, yeast extract and sodium acetate on PGs production were investigated individually. In the subsequent OAD experiments, the concentrations of these 5 key nutritional components combined with salinity were further adjusted. The mutant strain GQQ-M6 gave a 2.2-fold higher PGs production than that of the parent strain; OAD experiments offered a PGs yield of 61mg L-1, which was 10 times higher than that of the initial GQQ-10 strain under the original cultivation mode.
基金funded by the Fundamental Research Funds for the Central Universities(Nos.201912008,201964019)the Natural Science Foundation of Shandong Province(No.ZR2019BC025).
文摘A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces.A3 and stachyose(internal standard)were separated by a BEH amide column at 65℃under the mobile phase of 10 mmol L^(-1)ammonium ace-tate-acetonitrile(42:58,v/v)with 350µLmin-1.The acquisition of transitions was carried out in multiple reaction monitoring(MRM)pattern operating with positive ionization at m/z 509.16>329.15 for A3 and m/z 689.15>527.11 for stachyose.The linearity ranges of A3 were 10 to 5000nmolL^(-1)for plasma,20 to 10000nmolL^(-1)for tissues,and 40 to 20000nmolL^(-1)for urine and feces.The accuracy and precision ranged from 90.9%to 111.6%and 0.7%to 10.1%,respectively.The stability was between 86.1%and 102.5%.The extraction recovery was consistent and reproducible.The matrix effect ranged from 1.5%to 11.4%.The pharmacokinetic,tissue dis-tribution,and excretion studies were successfully conducted with the validated method.Results showed that A3 could be absorbed by rats,and the absolute bioavailability was 6.7%.Furthermore,it was rapidly distributed in rat tissues and mainly eliminated via feces excretion(67.0%)after oral administration.For intravenous bolus,85.5%was recovered,and renal excretion was the primary path-way(77.6%)for cumulative recovery.
基金supported by Qingdao Marine Science and Technology Center(2022QNLM030003-1)Shandong Province Technology Innovation Guidance Program(2018YFC0311105)Shandong Provincial Natural Science Foundation(ZR2019ZD18).
文摘The application of chondroitinase requires consideration of the complex microenvironment of the target.Our previous research reported a marine-derived sodium dodecyl sulfate(SDS)-resistant chondroitinase VhChlABC.This study further investigated the mechanism of VhChlABC resistance to SDS.Focusing on the hydrophobic cluster on its strong hydrophilic surface,it was found that the reduction of hydrophobicity of surface residues Ala181,Met182,Met183,Ala184,Val185,and Ile305 significantly reduced the SDS resistance and stability.Molecular dynamics(MD)simulation and molecular docking analysis showed that I305G had more conformational flexibility around residue 305 than wild type(WT),which was more conducive to SDS insertion and binding.The affinity of A181G,M182A,M183A,V185A and I305G to SDS was significantly higher than that of WT.In conclusion,the surface hydrophobic microenvironment composed of six residues was the structural basis for SDS resistance.This feature could prevent the binding of SDS and the destruction of hydrophobic packaging by increasing the rigid conformation of protein and reducing the binding force of SDS-protein.The study provides a new idea for the rational design of SDS-resistant proteins and may further promote chondroitinase research in the targeted therapy of lung diseases under the pressure of pulmonary surfactant.
基金supported by the National Natural Science Foundation of China (No. 30771646)Shandong Province Independent Innovation Project with the title of ‘Industrialization development of several special seaweeds biological products using integrated technologies’
文摘In order to determine the role of alginate-derived oligosaccharides (ADO) in drought stress resistance of tomato (Ly-copersicon esculentum Miller) seedlings, the leaves were exposed to different concentrations of ADO (0.05%, 0.10%, 0.20%, 0.30% and 0.50%) after drought stress was simulated by exposing the roots to 0.6 molL-1 PEG-6000 solution for 6 h. Changes in biomass, electrolyte leakage and malondialdehyde (MDA), free proline, total soluble sugars (TSS) and abscisic acid (ABA), the enzyme activities of catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and phenylalanine ammonia-lyase (PAL) were measured to investigate the effects of ADO treatment. The results showed that the treatment with an ADO concentration of 0.20% exhibited the highest performance of drought stress resistance in the tomato seedlings by decreasing the electrolyte leakage and the concentration of MDA, increasing the contents of free proline, TSS and ABA, and increasing the activities of CAT, SOD, POD and PAL after treatment with ADO. It is suggested that changes in electrolyte leakage, MDA, osmotic solutes, ABA, anti-oxidative enzyme and PAL activities were responsible for the increased drought stress resistance in tomato seedlings. To our best knowledge, this is the first report of the effect of ADO treatment on enhancing the drought stress resistance of tomato seedlings.
文摘A new compound, （S）-2, 4-dihydroxy-1-butyl （4-hydroxy） benzoate （1）, and a known compound, fructigenines A （2）, were isolated from fungus Penicillium auratiogriseum derived from sponge Mycale plumose, by bioassay-guided fractionation. Their structures were established by spectroscopic and chemical methods. Both compounds show.ed cytotoxic activity against tsFT210 cells.
基金partially supported by the fund of Key Laboratory of Marine Drugs(0cean University of China),Ministry of Education[KLMD(0UC)2004]by the National Natural Science Foundation of China(No.30530080)+1 种基金A program supported by the Department of Science and Technology of Shandong Province(No.2006GG2205023)by the Guangdong Key Laboratory of Marine Materia Medica is also gratefully acknowledged.
文摘Cultivation of an endophytic fungus Aspergillus niger EN-13 that was isolated from the inner tissue of the marine brown alga Colpomenia sinuosa resulted in the characterization of a new naphthoquinoneimine derivative, namely, 5,7-dihydroxy-2-[1-（4- methoxy-6-oxo-6H-pyran-2-yl）-2-phenylethylamino]-[ 1,4]naphthoquinone. The structure of the new compound was established on the basis of various NMR spectroscopic analyses including 2D NMR techniques, El-MS, and HR-ESI-MS. This compound displayed moderate antifungal activity.
基金supported by the National Natural Science Foundation of China(No.30772640).
文摘Three new aspochalsins（R-T）（1-3） were isolated from the marine-derived fungus Spicaria elegans.Their structures were elucidated on the basis of comprehensive spectral analysis including 1D and 2D NMR techniques,and HR-ESI-MS.
基金supported by International Science and Technology Collaboration Program of China (2007DFA-30980)Program for Changjiang Scholars,Innovative Research Team in University (IRT0944)+1 种基金Natural Science Foundation of China (31070724)Special Fund for Marine Scientific Research in the Public Interest (201005024)
文摘Three polysaccharides （EW, EH and EA） were prepared from a red alga Eucheuma denticulatum by sequential extraction with cold water, hot water and sodium hydroxide water solution. Their monosaccharide compositions, relative molecular mass and structural characterization were determined by gas chromatography, high performance liquid chromatography, fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy methods. EW was hybrid l/k/v-carrageenan （701/17k/13v-car- rabiose）, EH was mainly t-carrageenan, and EA was mainly α-1,4-Glucan （88%） but mixed with small amount of t-carrageenan （12%）. The relative molecular mass ofEW, EH and EA was 480, 580 and 510kDa, respectively. The anti-influenza A （H1N1） virus activity of these three polysaccharides was evaluated using the Madin-Darby canine kidney cells model. EW showed good anti-H1N1 virus activity, its ICso was 276.5 μg mL-1, and the inhibition rate to H1N1 virus was 52% when its concentration was 250 μgmL-1. The ICs0 of t-carrageenan EH was 366.4 μgmL1, whereas EA showed lower anti-H1N1 virus activity （IC50〉430μgmL-1）. Available data obtained give positive evidence that the hybrid carrageenan EW from Eueheuma denticulatum can be used as potential anti-H1N1 virus inhibitor in future.
基金supported by the National Natural Science Foundation of China(No.30572314)the Basic Research Program of Science and Technology,Ministry of Science and Technology of China(No.2007FY210500)+1 种基金the Program of Chinese Offshore Investigation and Assessment,State Oceanic Administration of China(Nos.908-01-ST12,908-02-05-04)Science and Technology Program of Shandong Province,China(No.03BS109)
文摘Seaweed Complex Preparation （SCP） is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and digestive cancer. However, little infor- mation is available about the pharmacodynamic basis. The antitumor, immunomodulatory and free radical scavenging effects of SCP were evaluated in this study. Transplanted tumor in vivo method was used to determine the antitumor effect. The effects on spleno- cyte proliferation and phagocytosis of macrophages in tumor-bearing mice were measured by the MTT method and the phagocytizing cock red blood cell （CRBC） method respectively. The scavenging activities of SCP on DPPH and hydroxyl radicals in vitro were investigated. It was found that the medium-dose and high-dose of SCP could significantly inhibit the growth of transplanted hepatic tumor of murine hepatocarcinoma cell line H22, and promote proliferation of splenocytes and phagocytosis of macrophages. SCP possessed noticeable scavenging activities on DPPH and hydroxyl radicals. The antiturnor effects of SCP might be achieved by im- proving immune system and scavenging free radicals, which is in accordance with the viewpoint of traditional Chinese medicine in promoting the body resistance and eliminating pathogenic factors for cancer treatment.
