Neuroprotective azaphilones from a deep-sea derived fungus Penicillium sp. SCSIO41030.

Ten azaphilones including one pair of new epimers and three new ones, penineulones A-E (1-5) with the same structural core of angular deflectin, were obtained from a deep-sea derived Penicillium sp. SCSIO41030 fermented on a liquid medium. Their structures including absolute configurations were elucidated using chiral-phase HPLC analysis, extensive NMR spectroscopic and HRESIMS data, ECD and NMR calculations, and by comparing NMR data with literature data. Biological assays showed that the azaphilones possessed no antitumor and anti-viral (HSV-1/2) activities at concentrations of 5.0 µM and 20 µM, respectively. In addition, azaphilones 8 and 9 showed neuroprotective effects against Aß25-35-induced neurotoxicity in primary cultured cortical neurons at a concentration of 10 µM. Azaphilones 8 and 9 dramatically promoted axonal regrowth against Aß25-35-induced axonal atrophy. Our study indicated that azaphilones could be promising lead compounds for neuroprotection.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 µM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Two New Isocoumarins Isolated from the Marine-Sponge-Derived Fungus Setosphaeria sp. SCSIO41009.

Two new dihydroisocoumarins, exserolides L and M (1 and 2), along with six known compounds (3-8) were isolated from the extract of the marine-sponge-derived fungus Setosphaeria sp. SCSIO41009. Their structures were established by spectroscopic analyses. The absolute configurations of two new compounds were determined by modified Mosher's method and ECD data. Compounds 1 and 4 showed significant antiviral activities against A/Puerto Rico/8/34 H274Y (H1 N1) with IC50 values of 4.07±0.76 µM and 20.06±4.85 µM, respectively.

Effects of secukinumab combined with tretinoin on metabolism, liver enzymes, and inflammatory factors in patients with moderate to severe psoriasis vulgaris.

Introduction: Psoriasis is a T cell-mediated polygenic chronic inflammatory disease. Interleukin (IL)-17A plays a major role in psoriasis pathogenesis. Secukinumab is a high-affinity human monoclonal antibody against IL-17A. Aim: This article explored efficacy and safety of secukinumab plus tretinoin in moderate to severe psoriasis (MSP) vulgaris, and assessed metabolism, liver function, and inflammation. Material and methods: A total of 135 patients diagnosed with moderate or severe psoriasis vulgaris were enrolled and randomized into three groups at a 1 : 1 : 1 ratio, receiving treatment with rretinoin, secukinumab, or combination therapy for a duration of 16 weeks. Psoriasis area and severity index (PASI) scores, serum T lymphocyte subsets, glucose, lipid, and uric acid (UA) metabolism, liver enzymes, and inflammatory factors (IFs) were measured. Results: Following the therapy, subjects had decreased PASI scores, increased serum CD3+, CD4+, and CD4+/CD8+, decreased serum CD8+, and decreased serum UA and IL-2, IL-6, IL-23, interferon-γ (IFN-γ), and tumor necrosis factor (TNF)-α (p < 0.05). Total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, apolipoproteins A1, B, fasting blood glucose, alanine transaminase, aspartate transaminase, and alkaline phosphatase had no obvious differences among the subjects (p > 0.05). As against the Tretinoin and the Secukinumab groups, the PASI score was visiblysmaller, the changes in serum T lymphocyte subsets were more obvious, and serum UA and IFs were lower in the Combination group following the therapy (p < 0.05). Conclusions: Secukinumab combined with tretinoin is more effective in MSP vulgaris, which can visibly reduce inflammatory response without affecting glucose and lipid metabolism and liver function.

Tanzawaic Acid Derivatives from the Marine-Derived Penicillium steckii as Inhibitors of RANKL-Induced Osteoclastogenesis.

Seven new tanzawaic acid derivatives, steckwaic acids E-K (1-7), and one new benzene derivate (8), together with seven known tanzawaic acid analogues (9-16) were isolated from the marine algicolous fungus Penicillium steckii SCSIO 41040. The structures and absolute configurations of these new compounds (1-8) were determined by spectroscopic analyses, X-ray diffraction, and comparison of ECD spectra to calculations. Compounds 2, 10, and 15 inhibited lipopolysaccharide (LPS)-induced nuclear factor kappa-B (NF-κB) with IC50 values of 10.4, 18.6, and 15.2 µM, respectively. Compound 2 could suppress the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophage cells (BMMCs). To the best of our knowledge, this is the first report of osteoclastogenesis inhibitory activity for tanzawaic acid derivatives.

Structurally various p-terphenyls with neuraminidase inhibitory from a sponge derived fungus Aspergillus sp. SCSIO41315.

Guided by Global Natural Products Social molecular networking, 14 new p-terphenyl derivatives, asperterphenyls A-N (1-14), together with 20 known p-terphenyl derivatives (15-34), were obtained from a sponge derived fungus Aspergillus sp. SCSIO41315. Among them, new compounds 2-8 and 15-17 were ten pairs of enantiomers. Comprehensive methods such as chiral-phase HPLC analysis, ECD calculations and X-ray diffraction analysis were applied to determine the absolute configurations. Asperterphenyls B (2) and C (3) represented the first reported natural p-terphenyl derivatives possessing a dicarboxylic acid system. Asperterphenyl A (1) displayed neuraminidase inhibitory activity with an IC50 value of 1.77 ± 0.53 µM and could efficiently inhibit infection of multiple strains of H1N1 with IC50 values from 0.67 ± 0.28 to 1.48 ± 0.60 µM through decreasing viral plaque formation in a dose-dependent manner, which suggested that asperterphenyl A (1) might be exploited as a potential antiviral compound in the pharmaceutical fields.

Secondary Metabolites from the Coral-Derived Fungus Aspergillus austwickii SCSIO41227 with Pancreatic Lipase and Neuraminidase Inhibitory Activities.

The coral-derived fungus Aspergillus austwickii SCSIO41227 from Beibu Gulf yielded four previously uncharacterized compounds, namely asperpentenones B-E (1-4), along with twelve known compounds (5-16). Their structures were elucidated using HRESIMS and NMR (1H and 13C NMR, HSQC, HMBC), among which the stereo-structure of compounds 1-3 was determined by calculated ECD. Furthermore, compounds 1-16 were evaluated in terms of their enzyme (acetylcholinesterase (AChE), pancreatic lipase (PL), and neuraminidase (NA)) inhibitory activities. These bioassay results revealed that compounds 2 and 14 exerted noticeable NA inhibitory effects, with IC50 values of 31.28 and 73.64 µM, respectively. In addition, compound 3 exhibited a weak inhibitory effect against PL. Furthermore, these compounds showed the potential of inhibiting enzymes in silico docking analysis to demonstrate the interactions between compounds and proteins.

Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines.

Based on the marine natural products piperafizine B, XR334, and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (1, 2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives 6, 8-12, and 14 had moderate to good anticancer capacities, with IC50 values ranging from 0.7 to 8.9 µM. Among them, compound 11, with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3 and 6 positions of 2,5-DKP ring, respectively, displayed good inhibitory activities toward both A549 (IC50 = 1.2 µM) and Hela (IC50 = 0.7 µM) cancer cells. It could also induce apoptosis and obviously block cell cycle progression in the G2/M phases in both cells at 1.0 µM. The electron-withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and XR334, these semi-N-alkylated derivatives have high liposolubilities (>1.0 mg mL-1). Compound 11 can be further developed, aiming at the discovery of a novel anticancer candidate.

New Fusarin Derivatives from the Marine Algicolous Fungus Penicillium steckii SCSIO41040.

Five new fusarin derivatives, steckfusarins A-E (1-5), and two known natural products (6, 7), were isolated and identified from the marine algicolous fungus Penicillium steckii SCSIO 41040. The new compounds, including absolute configurations, were determined by spectroscopic analyses and calculated electronic circular dichroism (ECD). All new compounds were evaluated for their antioxidant, antibacterial, antifungal, antiviral, cytotoxic, anti-inflammatory, antioxidant, cholesterol-lowering, acetyl cholinesterase (AChE) enzyme and 6-phosphofructo-2-kinase (PFKFB3) and phosphatidylinositol-3-kinase (PI3K) inhibitory activities. The biological evaluation results revealed that compound 1 exhibited radical scavenging activity against 2,2-diphenyl-1-picrylhydrazylhydrate (DPPH), with an IC50 value of 74.5 µg/mL. In addition, compound 1 also showed weak anti-inflammatory activity at a concentration of 20 µM.

Liver Protection of a Low-Polarity Fraction from Ficus pandurata Hance, Prepared by Supercritical CO2 Fluid Extraction, on CCl4-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Ferroptosis Mediated by Strengthened Antioxidation.

Ficus pandurata Hance (FPH) is a Chinese herbal medicine widely used for health care. This study was designed to investigate the alleviation efficacy of the low-polarity ingredients of FPH (FPHLP), prepared by supercritical CO2 fluid extraction technology, against CCl4-induced acute liver injury (ALI) in mice and uncover its underlying mechanism. The results showed that FPHLP had a good antioxidative effect determined by the DPPH free radical scavenging activity test and T-AOC assay. The in vivo study showed that FPHLP dose-dependently protected against liver damage via detection of ALT, AST, and LDH levels and changes in liver histopathology. The antioxidative stress properties of FPHLP suppressed ALI by increasing levels of GSH, Nrf2, HO-1, and Trx-1 and reducing levels of ROS and MDA and the expression of Keap1. FPHLP significantly reduced the level of Fe2+ and expression of TfR1, xCT/SLC7A11, and Bcl2, while increasing the expression of GPX4, FTH1, cleaved PARP, Bax, and cleaved caspase 3. The results demonstrated that FPHLP protected mouse liver from injury induced by CCl4 via suppression of apoptosis and ferroptosis. This study suggests that FPHLP can be used for liver damage protection in humans, which strongly supports its traditional use as a herbal medicine.

Topological flowers and spider webs in 3D vector fields.

Topological structures currently are of special interest in the integration of singular optics and topological photonics. In this article, the topological flowers and spider webs, which got less attention comparing to the lemon-, star- structures of the same category, are investigated in 3D vector fields. We show that by strongly focusing higher-order singular beams, both the spin density (SD) vectors and the polarization states of the transverse fields on the focal plane exhibit flowers and spider webs structures in topology with 2|m - 1| folds/sectors (m is the beam order), and the topological structures of the SD vectors are demonstrated to have a 90°/|m - 1| rotation. On the other hand, the topological theory also needs to be developed according to the rapid growth of topological photonics. Here, by defining a 'relative topological charge', we have observed and analyzed the topological reactions of the loops (composed of SD singularities) rather than the 'point-type' singularities in conventional reactions. More specially, the 'radial index' and 'azimuthal index' are proposed to characterize the topological features of the flowers and spider webs, and have been verified that the 'radial index' is peculiar to 3D vector fields and proportional to 1/|m - 1| in general. Our work provides a way to describe the topological behaviors of groups of singularities and supplies new parameters for measuring the topological patterns in 3D vector fields, which will rich the topological theory and may have applications in topological photonics.

Cryopreservation of stool samples altered the microbial viability quantitively and compositionally.

Stool is the most commonly used sample for gut microbiota analysis in humans and animals. Cryopreservation of stool at - 80 °C is a feasible and simple method in clinics and researches, especially in large-scale cohort studies. However, the viability of bacteria in stool after freezing has yet well-demonstrated quantitatively and compositionally. This study determined the viable microbiota of samples under cryopreservation at - 80 °C, relative to fresh samples and that stored at ambient. Stool samples were collected from three healthy adults. Propidium monoazide treatment combined with quantitative PCR and 16S rRNA gene sequencing was performed to target viable microbiota. After freezing, the number of viable bacteria decreased, though inter-individual difference existed. Notably, the alpha diversity of viable microbiota after freezing did not change significantly, while its composition changed. Freezing significantly reduced the viable bacteria in Gram-negative genera of Bacteroidetes and Firmicutes, and proportionally increased Gram-positive bacteria in genera of Actinobacteria and Firmicutes, including Bifidobacterium, Collinsella and Blautia, implying that the cell envelope structure associated with the bacterial sensitivity to freezing. On the contrary, the room temperature storage not only decreased the number of viable bacteria, but also decreased the microbial alpha diversity, and remarkably enriched facultative anaerobes of Escherichia-Shigella, Enterococcus and Lactococcus, some of which are opportunistic pathogens. Our findings suggested that changes in viable microbiota in stool samples caused by cryopreservation should be paid enough attention for downstream utilization.

Orbital angular momentum spectrum of pin-like optical vortex beams in turbulent atmosphere.

The analytical formula of the probability density of a single orbital angular momentum (OAM) mode for pin-like optical vortex beams (POVBs) in turbulent atmosphere is derived. Its OAM spectrum in the receiving plane is obtained by the numerical calculation. For comparison, the OAM spectrum of commonly Gaussian vortex beams is showed, too. Those results show that POVBs show good performance on resisting the cross talk of the OAM mode induced by the turbulence in some cases, such as smaller radius of the receiving aperture, longer propagation distance, and stronger turbulence. Our finding has application in free-space optical communication based on the OAM mode.

Deep-Sea Natural Products from Extreme Environments: Cold Seeps and Hydrothermal Vents.

The deep sea has been proven to be a great treasure for structurally unique and biologically active natural products in the last two decades. Cold seeps and hydrothermal vents, as typical representatives of deep-sea extreme environments, have attracted more and more attention. This review mainly summarizes the natural products of marine animals, marine fungi, and marine bacteria derived from deep-sea cold seeps and hydrothermal vents as well as their biological activities. In general, there were 182 compounds reported, citing 132 references and covering the literature from the first report in 1984 up to March 2022. The sources of the compounds are represented by the genera Aspergillus sp., Penicillium sp., Streptomyces sp., and so on. It is worth mentioning that 90 of the 182 compounds are new and that almost 60% of the reported structures exhibited diverse bioactivities, which became attractive targets for relevant organic synthetic and biosynthetic studies.

Asperbenzophenone A and Versicolamide C, New Fungal Metabolites from the Soft Coral Derived Aspergillus sp. SCSIO 41036.

Two new compounds, asperbenzophenone A (1) and versicolamide C (5), together with fifteen known compounds were isolated from a soft coral derived fungus Aspergillus sp. SCSIO 41036. Their structures were elucidated by spectroscopic methods, ECD analysis, and by a comparison with data from the literature. In bioassay, compound 8 showed significant inhibitory activity against lipopolysaccharide-inducted nitric oxide (NO) in RAW264.7 cells at the concentration of 10 µM. Additionally, the anti-acetylcholinesterase activity assay showed that 14 exhibited weak inhibition with an IC50 value of 157.8 µM.

New Diterpene and Indole Alkaloid Analogs from the Streptomyces malaysiensis SCSIO 41397.

One new cyclooctatin-type diterpenoid, 15-hydroxycyclooctatin (1), and one new indole alkaloid, streptoprenylindole D (3), along with 9 known compounds, were isolated from the Streptomyces malaysiensis SCSIO 41397. Their structures were established on the basis of spectroscopic analysis, optical rotation, and by a comparison with data from the literature. All isolated compounds were evaluated for their antibacterial (MRSA), antitumor (22Rv1 and PC-3) and antiviral (HSV-1/2) activities. According to the analysis of biological gene clusters in the whole genome, we preliminarily locate the gene clusters related to the synthesis of 15-hydroxycyclooctatin (1).

Citrinin and α-pyrone derivatives with pancreatic lipase inhibitory activities from Penicillium sp. SCSIO 41302.

One new citrinin monomer derivative (1), and two new natural products α-pyrone analogues (2a and 2b), were isolated from the sponge derived fungus Penicillium sp. SCSIO 41302. Their structures were determined by extensive spectroscopic analysis, chiral-phase HPLC analysis, modified Mosher's method, ECD calculations, and X-ray single-crystal diffraction. Bioactivity screening showed that compounds 2b and 8 exhibited obvious inhibitory activities against pancreatic lipase and acetyl cholinesterase with IC50 values of 48.5 and 4.8 µM, respectively, which indicated that different chiral center between enantiomers (2a and 2b) might result in different biological activities (IC50 value against PL for 2a >100 µg/ml).

Diversified Chaetoglobosins from the Marine-Derived Fungus Emericellopsis sp. SCSIO41202.

Two undescribed cytochalasins, emeriglobosins A (1) and B (2), together with nine previously reported analogues (3-11) and two known tetramic acid derivatives (12, 13) were isolated from the solid culture of Emericellopsis sp. SCSIO41202. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis and the calculated ECD. Some of the isolated compounds were evaluated for their cytotoxicity and enzyme inhibitory activity against acetylcholinesterase (AChE) in vitro. Among them, 8 showed potent AChE inhibitory activity, with an IC50 value of 1.31 µM, and 5 showed significant cytotoxicity against PC-3 cells, with an IC50 value of 2.32 µM.

Dual Action of Acidic Microenvironment on the Enrichment of the Active Metabolite of Disulfiram in Tumor Tissues.

Disulfiram, an antialcoholism drug, could potentially be repurposed as an anticancer drug because of the formation of copper(II) diethyldithiocarbamate (CuET) from dithiocarb (DTC, a reduced metabolite of disulfiram) and Cu2+ CuET exhibited preferential distribution to tumor tissues. This study investigated the mechanism of CuET accumulation in tumor tissues by employing MDA-MB-231 human breast cancer cells. The concentration of CuET in cells treated with DTC and Cu2+ in acidic culture medium (pH 6.8) was significantly higher than that of the control group (pH 7.4). Subsequently, the effects of pH on the uptake of DTC, Cu2+, and CuET were investigated separately. The acidic environment significantly increased the uptake rate of DTC and Cu2+ but had no effect on CuET. MDA-MB-231 cells overexpressing copper transporter hCTR1 were constructed to evaluate its intermediate role in CuET accumulation. After treatment with CuCl2 followed by DTC for 15 minutes, the levels of CuET and Cu2+ in hCTR1-overexpressed cells were 2.5 times as much as those of vector group. In the tumors of cancer xenograft models constructed by hCTR1-MDA-MB-231 cells, the concentrations of CuET and Cu were also significantly higher than those of control group. In conclusion, the acidic microenvironment of tumors can promote the enrichment of CuET in tumors through dual action. On the one hand, it can promote transmembrane transport of DTC by converting ionic DTC into molecular state. On the other hand, it enhances Cu2+ uptake by activating hCTR1, which ultimately leads to the enrichment of CuET. SIGNIFICANCE STATEMENT: Increasing evidence suggests that the antitumor activity of disulfiram is related to the formation of a copper(II) diethyldithiocarbamate (CuET) of its reducing metabolite dithiocarb with copper(II) ion, which is preferentially distributed in tumor tissues. We showed that the acidic microenvironment, a common feature of many solid tumor tissues, could promote intracellular CuET accumulation through dual action without changing CuET uptake. This result is helpful for the formulation of clinical dosage regimens of disulfiram in cancer treatment.

p-Terphenyls as Anti-HSV-1/2 Agents from a Deep-Sea-Derived Penicillium sp.

Guided by Global Natural Products Social molecular networking, two p-terphenyl derivatives and one 4,5-diphenyl-2-pyrone analogue, peniterphenyls A-C (1-3), together with five known p-terphenyl derivatives (4-8) and sulochrin (9), were obtained from a deep-sea-derived Penicillium sp. SCSIO41030. Their structures were elucidated using extensive NMR spectroscopic and HRESIMS data and by comparing the information with literature data. Peniterphenyl B (2) represented the first reported natural product possessing a 4,5-diphenyl-substituted 2-pyrone derivative. The p-terphenyl derivatives displayed inhibitory activities against HSV-1/2 with EC50 values ranging from 1.4 ± 0.6 to 9.3 ± 3.7 µM in Vero cells, which showed that they possessed antiviral activities with low cytotoxicity, superior to the current clinical drug acyclovir (EC50 3.6 ± 0.7 µM). Peniterphenyl A (1) inhibited HSV-1/2 virus entry into cells and may block HSV-1/2 infection through direct interaction with virus envelope glycoprotein D to interfere with virus adsorption and membrane fusion, and thus differs from the nucleoside analogues such as acyclovir. Our study indicated peniterphenyl A (1) could be a promising lead compound against HSV-1/2.