Carneusones A-F, Benzophenone Derivatives from Sponge-Derived Fungus Aspergillus carneus GXIMD00543.

Six benzophenone derivatives, carneusones A-F (1-6), along with seven known compounds (7-13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC50 values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 µM, while 11 showed potent effect with an EC50 value of 2.9 ± 0.1 µM.

Identification and bioactivity evaluation of miliusanes from Miliusa sinensis.

Miliusanes are a class of anticancer lead molecules belonging to meroterpenoids with an 18-carbon skeleton isolated from Miliusa plants. A phytochemical study of the plant M. sinensis was carried out to discover new miliusanes with diverse structural features in order to better understand their structure-activity relationship. As a result, 20 compounds including 12 new ones (7-14 and 17-20) belonging to two sub-classes of miliusanes were isolated and identified from the twigs and leaves of this plant. Their structures, including absolute configurations, were determined by spectroscopic analyses and electronic circular dichroism. The absolute stereochemistry of miliusane structures has also been confirmed for the first time through the single crystal X-ray diffraction analysis of miliusol (1). Bioactivity evaluation showed that some of the miliusane isolates potently inhibit cell growth of several human derived cancer cell lines with IC50 values ranging from 0.52 to 23.5 µM. Compound 11 demonstrated more potent cytotoxic activity than the known miliusol (1) in stomach cancer cells though its structure contains an unconjugated 1, 4-diketone system, which added a new structure-activity feature to miliusanes. The preliminary mechanism of action studies revealed that they could be a class of dual cell migration inhibitor and senescence inducer.

Plant-derived lignans as potential antiviral agents: a systematic review.

Medicinal plants are one of the most important sources of antiviral agents and lead compounds. Lignans are a large class of natural compounds comprising two phenyl propane units. Many of them have demonstrated biological activities, and some of them have even been developed as therapeutic drugs. In this review, 630 lignans, including those obtained from medicinal plants and their chemical derivatives, were systematically reviewed for their antiviral activity and mechanism of action. The compounds discussed herein were published in articles between 1998 and 2020. The articles were identified using both database searches (e.g., Web of Science, Pub Med and Scifinder) using key words such as: antiviral activity, antiviral effects, lignans, HBV, HCV, HIV, HPV, HSV, JEV, SARS-CoV, RSV and influenza A virus, and directed searches of scholarly publisher's websites including ACS, Elsevier, Springer, Thieme, and Wiley. The compounds were classified on their structural characteristics as 1) arylnaphthalene lignans, 2) aryltetralin lignans, 3) dibenzylbutyrolactone lignans, 4) dibenzylbutane lignans, 5) tetrahydrofuranoid and tetrahydrofurofuranoid lignans, 6) benzofuran lignans, 7) neolignans, 8) dibenzocyclooctadiene lignans and homolignans, and 9) norlignans and other lignoids. Details on isolation and antiviral activities of the most active compounds within each class of lignan are discussed in detail, as are studies of synthetic lignans that provide structure-activity relationship information.

Stable Axially Chiral Isomers of Arylnaphthalene Lignan Glycosides with Antiviral Potential Discovered from Justicia procumbens.

Arylnaphthalene lignans (ANLs) were known to have axial chirality due to the biphenyl skeleton with hindered rotation at the single bond. However, the stable ANL atropisomers have not been isolated from nature until the present study. Phytochemical separation of the methanol extract of the stems and barks of Justicia procumbens led to the isolation of 11 ANL glycosides including four pairs of new atropisomers with stable confirmations at room temperature. Their structures were deduced from elucidation of the extensive spectral data, and their absolute configurations were determined by the circular dichroism, electronic circular dichroism, and X-ray methods as well as the total synthesis of one pair of the atropisomers. The ANL compounds were evaluated for their antiviral potential, and it was found that they displayed great antiviral activity discrepancy between a pair of atropisomers due to the geometric orientation. The 1'P-oriented atropisomers showed much more significant antiviral potency than their corresponding 1'M-oriented counterparts. The biological activity discrepancy caused by the axial chirality will not only inspire synthetic design of novel ANL atropisomers to enrich the structural diversity, but also provide important hints to direct the synthetic approaches toward the antiviral drug development of ANL compounds.

1,3-Benzodioxole-based fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

A series of target compounds 1,3-benzodioxole-based fibrate derivatives were designed and synthesized. All the target compounds were preliminarily evaluated by hyperlipidemia mice induced by Triton WR-1339, in which compound 12 displayed a greater anti-hyperlipidemia activity than other compounds as well as positive drug fenofibrate (FF). 12 showed a significant reduction of plasma lipids, such as triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterin (LDL-C), in high fat diet (HFD) induced hyperlipidemic mice. In addition, hepatic transaminases (AST and ALT) were ameliorated after administration of 12, in particular the AST, and the histopathological examination showed that 12 improved the hepatic lipid accumulation. The expression of PPAR-α involved in lipids metabolism was up-regulated in the liver tissues of 12-treated group. Other significant activity such as antioxidant, and anti-inflammation was confirmed and reinforced the effects of 12 as a potential hypolipidemia and hepatoprotective agent.

3,4-Dihydroxyphenethyl nitrate with nitric oxide releasing, antioxidant, hypoglycemic and hypolipidemic effects.

Nitric oxide (NO) dysfunction, oxidative stress, and dyslipidemia are main risk factors associated with the pathophysiology of diabetic complications. In this study, 3,4-dihydroxyphenethyl nitrate (HT-ONO2) was designed, synthesized and evaluated, which incorporated hydroxytyrosol (HT) and nitrate. HT-ONO2 significantly exhibited hypoglycemic activity after oral administration to diabetic mice induced by streptozocin (STZ). HT-ONO2 also potently decreased plasma triglyceride (TG), total cholesterol (TC) in hyperlipidemia mice induced by Triton WR 1339. Meanwhile, HT-ONO2 displayed NO-releasing and antioxidant activity both in diabetic and hyperlipidemia mice and in vitro. Moreover, HT-ONO2 shown definite vasodilation and α-glucosidase inhibition activity in vitro. The results suggested that the hybrid hydroxytyrosol-based nitrate with NO supplement, antioxidant, hypoglycemia and hypolipidemia provided a potential multi-target agent to ameliorate the diabetes mellitus and its complications.

New citrinin derivatives from the deep-sea-derived fungus Cladosporium sp. SCSIO z015.

During the course of our search for novel bioactive compounds from marine fungi, four new citrinin derivatives, cladosporins A-D (1-4) were isolated from a culture broth of the deep-sea-derived fungus Cladosporium sp. SCSIO z015. Their complete structural assignments were elucidated by the extensive spectroscopic investigation. The absolute configurations of 1-3 were established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compounds 1-4 showed weak toxicity towards brine shrine naupalii with LC50 values of 72.0, 81.7, 49.9 and 81.4 µM, respectively. And 4 also showed significant antioxidant activity against ɑ,α-diphenyl-picrylhydrazyl (DPPH) radicals with an IC50 value of 16.4 µM.

Anti-HIV lignans from Justicia procumbens.

Twenty-one lignans including three new ones (1, 2 and 13) were isolated from Justicia procumbens. The chemical structures of the new lignans were determined by spectroscopic means including 1D and 2D NMR analysis. These compounds were evaluated for their cytotoxic and anti-HIV activities. The new secoisolariciresinol dimethyl ether acetate (13) exhibited anti-HIV-1 activity with an IC50 value of 5.27 µmol·L-1 and a selective index (SI) value of 2.2. The known arylnaphthalene lignan procumbenoside A (3) and diphyllin (8) demonstrated inhibitory activity against HIV-1 with IC50 values of 4.95 (SI > 6.2) and 0.38 µmol·L-1 (SI = 5.3), respectively.

In Vitro and in Vivo Antitumor Effects of Plant-Derived Miliusanes and Their Induction of Cellular Senescence.

Our earliest phytochemical separation of Miliusa sinensis aided us in the isolation of a class of unique miliusanes, which were demonstrated as anticancer lead molecules. In the present study, we isolated 19 miliusanes (1-19), including 11 novel ones (5 and 10-19) from another Miliusa plant ( M. balansae), and synthesized additional derivatives to elucidate the structure-activity relationship of miliusanes. When extrapolated to various carcinoma xenograft mouse models, miliusol (1) and its derivatives 20, 26, and 27 (7.5-40 mg/kg) were demonstrated with tumor inhibitory efficacy comparable or even superior to the mainstay chemotherapeutics paclitaxel or fluorouracil. To gain a molecular insight into their anticancer mechanism, 1-3 (GI50 0.03-4.79) were administered to a wide spectrum of human cancer cell lines, including those with specific drug resistance. We further revealed that the antiproliferative properties of miliusanes in carcinoma cells were highly associated with the p21-dependent induction of cellular senescence.

Combined magnetic porous molecularly imprinted polymers and deep eutectic solvents for efficient and selective extraction of aristolochic acid I and II from rat urine.

Aristolochia and related plants contain nephrotoxins and mutagens in the form of aristolochic acids (AAs). However, there is still lack of a fast and specific method for monitoring AAs in biological samples. Herein, we synthesized a hybrid magnetic mesoporous carbon-molecularly imprinted polymers (MMC@MIPs) as a novel magnetic solid-phase extraction (MSPE) adsorbent for selective recognition of aristolochic acid I and II from rat urine samples. The choline chloride/glycol-based deep eutectic solvent (DES) and indomethacin were used as the eluent and dummy template molecule accordingly. The morphology, structure property and surface groups of the prepared materials were investigated in sequence, and the optimum conditions of the MMC@MIPs-MSPE procedure were also optimized well. Results showed that the proposed method had a relatively satisfactory recovery (86.7-94.3%), with low standard deviation (<4.85%) and acceptable correlation coefficients (0.991-0.996). Overall, this work not only provides an inexpensive and eco-friendly method to fabricate MMC@MIPs, but also develops a highly promising approach for the detection of aristolochic acid I and II in biological samples.

Hybrid-type carbon microcoil-chitosan composite for selective extraction of aristolochic acid I from Aristolochiaceae medicinal plants.

Aristolochic acid I is a nephrotoxic compound widely existing in many kinds of traditional Chinese medicines, especially in Aristolochiaceae medicinal plants. In this study, chitosan modified carbon microcoils were designed and prepared for the selective separation of aristolochic acid I from medicinal herbs. Successful modification of carbon microcoils was confirmed by scanning electron microscopy, Fourier-transfer infrared spectroscopy, elemental analysis, X-ray photoelectron spectroscopy, and thermogravimetric analyses. The effects of adsorption conditions were investigated and it was determined that the adsorption of aristolochic acid I was controlled by pH. Adsorption isotherms, kinetics, and selectivity tests were performed to evaluate the adsorption capacity and selectivity of the modified carbon microcoils. The chitosan modified carbon microcoils exhibited excellent binding ability (77.72 mg g-1) and satisfactory selectivity. Finally, this material was used in solid phase extraction combined with HPLC to enrich and detect aristolochic acid I from medicinal plants. The detector response for aristolochic acid I was linear from 0.5 to 150 mg L-1, and the recoveries of aristolochic acid I ranged from 73.61 to 77.73% with the relative standard deviations of less than 5%. Thus, chitosan modified carbon microcoils were ideal adsorbents for the selective extraction of aristolochic acid I from Aristolochiaceae plants.

Antimalarial Activity of Plant Metabolites.

Malaria, as a major global health problem, continues to affect a large number of people each year, especially those in developing countries. Effective drug discovery is still one of the main efforts to control malaria. As natural products are still considered as a key source for discovery and development of therapeutic agents, we have evaluated more than 2000 plant extracts against Plasmodium falciparum. As a result, we discovered dozens of plant leads that displayed antimalarial activity. Our phytochemical study of some of these plant extracts led to the identification of several potent antimalarial compounds. The prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002) reported structures of plant-derived compounds with antiplasmodial activity and covered literature up to the year 2000. As a continuation of this effort, the present review covers the antimalarial compounds isolated from plants, including marine plants, reported in the literature from 2001 to the end of 2017. During the span of the last 17 years, 175 antiplasmodial compounds were discovered from plants. These active compounds are organized in our review article according to their plant families. In addition, we also include ethnobotanical information of the antimalarial plants discussed.

Screening of Anti-Biofilm Compounds from Marine-Derived Fungi and the Effects of Secalonic Acid D on Staphylococcus aureus Biofilm.

Biofilm formation of Staphylococcus aureus is one of its mechanisms of drug resistance. Antibiofilm screening of 106 compounds from marine-derived fungi displayed that 12 compounds inhibited S. aureus biofilm formation by >50% at the concentration of 100 µg/ml, and only secalonic acid D (SAD) and B inhibited by >90% at 6.25 µg/ml without inhibiting cell growth after 24-h incubation. Meanwhile, it was found that the double bond between C-1 and C-10 of citrinin derivatives and the C-C connection position of two chromone monomers may be important for their anti-biofilm activities. Moreover, SAD slightly facilitated biofilm eradication and influenced its architecture. Furthermore, SAD slowed the cell growth rate in the preceding 18-h incubation and differentially regulated transcriptional expression of several genes, such as agr, isaA, icaA, and icaD, associated with biofilm formation in planktonic and biofilm cells, which may be the reason for the anti-biofilm activity of SAD. Finally, SAD acted synergistically against S. aureus growth and biofilm formation with other antibiotics. These findings indicated that various natural products from marine-derived fungi, such as SAD, could be used as a potential biofilm inhibitor against S. aureus.

Ultraviolet A Enhances Cathepsin L Expression and Activity via JNK Pathway in Human Dermal Fibroblasts.

BACKGROUND: Cathepsin L (CatL) is a cysteine protease with strong matrix degradation activity that contributes to photoaging. Mannose phosphate-independent sorting pathways mediate ultraviolet A (UVA)-induced alternate trafficking of CatL. Little is known about signaling pathways involved in the regulation of UVA-induced CatL expression and activity. This study aims to investigate whether a single UVA irradiation affects CatL expression and activity and whether mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) pathway is involved in the regulation of UVA-induced CatL expression and activity in human dermal fibroblasts (HDFs). METHODS: Primary HDFs were exposed to UVA. Cell proliferation was determined by a cell counting kit. UVA-induced CatL production and activity were studied with quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and fluorimetric assay in cell lysates collected on three consecutive days after irradiation. Time courses of UVA-activated JNK and p38MAPK signaling were examined by Western blotting. Effects of MAPK inhibitors and knockdown of Jun and Fos on UVA-induced CatL expression and activity were investigated by RT-PCR, Western blotting, and fluorimetric assay. Data were analyzed by one-way analysis of variance. RESULTS: UVA significantly increased CatL gene expression, protein abundance, and enzymatic activity for three consecutive days after irradiation (F = 83.11, 56.14, and 71.19, respectively; all P < 0.05). Further investigation demonstrated phosphorylation of JNK and p38MAPK activated by UVA. Importantly, inactivation of JNK pathway significantly decreased UVA-induced CatL expression and activity, which were not affected by p38MAPK inhibition. Moreover, knockdown of Jun and Fos significantly attenuated basal and UVA-induced CatL expression and activity. CONCLUSIONS: UVA enhances CatL production and activity in HDFs, probably by activating JNK and downstreaming AP-1. These findings provide a new possible molecular approach for antiphotoaging therapy.

Oxalicumone A, a new dihydrothiophene-condensed sulfur chromone induces apoptosis in leukemia cells through endoplasmic reticulum stress pathway.

Oxalicumone A (POA1), a novel dihydrothiophene-condensed sulfur chromone isolated from the marine fungus Penicillium oxalicum SCSGAF 0023, showed cytotoxicity against several cancer cells previously. In this study, its anti-cancer activity and underlying mechanism of this action were investigated in leukemia cells like KG-1a, HL60, U937, and K562. The results showed that POA1 inhibited dose-/time-dependently cell growth and induced apoptosis in leukemia cells. Also, POA1 caused cleavages of caspase-3, 8, 9 and PARP1, loss of mitochondrial membrane potential, up-regulations of phosphorylated p38 and JNK, and activation of endoplasmic reticulum stress (ER stress). Furthermore, 4-PBA (an ER stress inhibitor) but not SP600125 and SB203580 (JNK and p38 inhibitor, respectively) could largely inhibit POA1-induced growth suppression. Additionally, 4-PBA obstructed mitochondrial depolarization and cleavage of PARP1. These data suggested that ER stress pathway might be an important mediator in POA1-induced apoptosis. In conclusion, POA1 may have antitumor effects in leukemia cells through the induction of ER stress pathway.

An HPLC method for the determination of a novel anti-hypertension agent 6,7-dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl)quinazolin-4(3H)-one in rat plasma: application to pharmacokinetic study.

6,7-dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl) quinazolin-4(3H)-one (DFMQ-19), a novel analogue of 3-benzylquinazolin-4(3H)-ones, may be considered as a drug candidate for the treatment of hypertension. The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatography to determine the DFMQ-19 in plasma and demonstrate its application in pharmacokinetic study. Separation of DFMQ-19 and I.S (structural analog of DFMQ-19) was performed using Shim-Pack VP-ODS column and a mixture of acetonitrile and water as mobile phase. The HPLC method was validated according to the ICH guidelines. The limit of detection and lower limit of quantitation were 0.05 µg/ml and 0.1 µg/ml respectively. The recovery rate of DFMQ-19 from blood samples was >81% of the spiked amount. The RSD of the intra- and inter-day precisions was within 7.5%, and RE of accuracy was between -14.4% and 4.5%. This method was successfully applied to the pharmacokinetic study after administration of DFMQ-19. The pharmacokinetic parameters, such as half-life (t1/2 ), mean residence time (MRT), maximum concentration (Cmax ) were determined. Based on these pharmacokinetic parameters, the oral bioavailability of DFMQ-19 was calculated to be 13.42% in rat. This article is protected by copyright. All rights reserved. HIGHLIGHTS: HPLC method was validated to quantify DFMQ-19 in rat plasma I.S is one of the structural analogs of the analyte The HPLC method was validated according to the ICH guidelines The oral bioavailability of DFMQ-19 was 13.42% in rat.

Nahuoic Acids B-E, Polyhydroxy Polyketides from the Marine-Derived Streptomyces sp. SCSGAA 0027.

Four new polyol polyketides containing a decalin ring, nahuoic acids B-E (1-4), together with a known analogue, nahuoic acid A (5), possessing an unprecedented carbon skeleton, were isolated from a culture broth of the marine-derived Streptomyces sp. SCSGAA 0027. Their structures were determined by detailed analysis of spectroscopic data and chemical transformations including acetonide formation and Mosher's ester method. Compounds 1-5 showed weak antibiofilm activity against Shewanella onedensis MR-1 biofilm. This is the first series of analogues of the novel selective SETD8 inhibitor nahuoic acid A.

Antifouling Compounds from the Marine-Derived Fungus Aspergillus terreus SCSGAF0162.

A new cyclic tetrapeptide, asperterrestide B (1), and 11 known compounds (2-12) were isolated from a marine-derived fungus Aspergillus terreus SCSGAF0162. The structure of 1 was elucidated by spectroscopic analysis, and the absolute configuration of 1 was determined by Mosher ester and Marfey's methods. Compounds 4, 6, and 8 had potent antifouling activity against larvae of the barnacle Balanus amphitrite, with EC50 values of 17.1 ± 1.2, 11.6 ± 0.6, and 17.1 ± 0.8 µg x mL(-1), respectively.

Territrem and butyrolactone derivatives from a marine-derived fungus Aspergillus terreus.

Seventeen lactones including eight territrem derivatives (1-8) and nine butyrolactone derivatives (9-17) were isolated from a marine-derived fungus Aspergillus terreus SCSGAF0162 under solid-state fermentation of rice. Compounds 1-3 and 9-10 were new, and their structures were elucidated by spectroscopic analysis. The acetylcholinesterase inhibitory activity and antiviral activity of compounds 1-17 were evaluated. Among them, compounds 1 and 2 showed strong inhibitory activity against acetylcholinesterase with IC50 values of 4.2 ± 0.6, 4.5 ± 0.6 nM, respectively. This is the first time it has been reported that 3, 6, 10, 12 had evident antiviral activity towards HSV-1 with IC50 values of 16.4 ± 0.6, 6.34 ± 0.4, 21.8 ± 0.8 and 28.9 ± 0.8 µg·mL-1, respectively. Antifouling bioassay tests showed that compounds 1, 11, 12, 15 had potent antifouling activity with EC50 values of 12.9 ± 0.5, 22.1 ± 0.8, 7.4 ± 0.6, 16.1 ± 0.6 µg·mL-1 toward barnacle Balanus amphitrite larvae, respectively.

Insights into deep-sea sediment fungal communities from the East Indian Ocean using targeted environmental sequencing combined with traditional cultivation.

The fungal diversity in deep-sea environments has recently gained an increasing amount attention. Our knowledge and understanding of the true fungal diversity and the role it plays in deep-sea environments, however, is still limited. We investigated the fungal community structure in five sediments from a depth of ∼ 4000 m in the East India Ocean using a combination of targeted environmental sequencing and traditional cultivation. This approach resulted in the recovery of a total of 45 fungal operational taxonomic units (OTUs) and 20 culturable fungal phylotypes. This finding indicates that there is a great amount of fungal diversity in the deep-sea sediments collected in the East Indian Ocean. Three fungal OTUs and one culturable phylotype demonstrated high divergence (89%-97%) from the existing sequences in the GenBank. Moreover, 44.4% fungal OTUs and 30% culturable fungal phylotypes are new reports for deep-sea sediments. These results suggest that the deep-sea sediments from the East India Ocean can serve as habitats for new fungal communities compared with other deep-sea environments. In addition, different fungal community could be detected when using targeted environmental sequencing compared with traditional cultivation in this study, which suggests that a combination of targeted environmental sequencing or traditional cultivation alone. This study is the first to report new insights into the fungal communities in deep-sea sediments environmental sequencing and traditional cultivation will generate a more diverse fungal community in deep-sea environments than using either from the East Indian Ocean, which increases our knowledge and understanding of the fungal diversity in deep-sea environments.