Chemical Constituents and Anti-Angiogenic Principles from a Marine Algicolous Penicillium sumatraense SC29.

In this study, a marine brown alga Sargassum cristaefolium-derived fungal strain, Penicillium sumatraense SC29, was isolated and identified. Column chromatography of the extracts from liquid fermented products of the fungal strain was carried out and led to the isolation of six compounds. Their structures were elucidated by spectroscopic analysis and supported by single-crystal X-ray diffraction as four previously undescribed (R)-3-hydroxybutyric acid and glycolic acid derivatives, namely penisterines A (1) and C-E (3-5) and penisterine A methyl ether (2), isolated for the first time from natural resources, along with (R)-3-hydroxybutyric acid (6). Of these compounds identified, penisterine E (5) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. All the isolates were subjected to in vitro anti-angiogenic assays using a human endothelial progenitor cell (EPCs) platform. Among these, penisterine D (4) inhibited EPC growth, migration, and tube formation without any cytotoxic effect. Further, in in vivo bioassays, the percentages of angiogenesis of compound 3 on Tg (fli1:EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 µg/mL, respectively, and the percentages of angiogenesis of compound 4 were 52% and 41% as the treated concentration increased from 8.6 to 17.2 µg/mL, respectively. The anti-angiogenic activity of penisterine D (4) makes it an attractive candidate for further preclinical investigation.

11ß,20ß-Epoxybriaranes from the Gorgonian Coral Junceella fragilis (Ellisellidae).

Two 11,20-epoxybriaranes, including a known compound, juncenolide K (1), as well as a new metabolite, fragilide X (2), have been isolated from gorgonian Junceella fragilis collected off the waters of Taiwan. The absolute configuration of juncenolide K (1) was determined by single-crystal X-ray diffraction analysis for the first time in this study and the structure, including the absolute configuration of briarane 2 was established on the basis of spectroscopic analysis and compared with that of model compound 1. One aspect of the stereochemistry of the known compound 1 was revised. Briarane 2 was found to enhance the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) release from RAW 264.7 cells.

Asiatic acid exhibits antimetastatic activity in human prostate cancer cells by modulating the MZF-1/Elk-1/Snail signaling axis.

Prostate cancer metastasis is associated with poor prognosis and is difficult to treat clinically. Numerous studies have shown that Asiatic Acid (AA) has antibacterial, anti-inflammatory, and antioxidant effects. However, the effect of AA on prostate cancer metastasis is still unclear. This purpose of this study is to investigate the effect of AA on prostate cancer metastasis and to better understand its molecular mechanisms of action. Our results indicate that AA ≤ 30 µM did not influence cell viability and cell cycle distribution in PC3, 22Rv1 and DU145 cells. AA inhibited the migratory and invasive capabilities of three prostate cancer cells to be due to its effects on Snail, but did not have activity on Slug. We observed that AA inhibited the Myeloid zinc finger 1 (MZF-1) and ETS Like-1 (Elk-1) protein interaction and affected the complex's binding capacity to the Snail promoter region, ultimately blocking Snail transcription activity. Kinase cascade analysis revealed that phosphorylation of MEK3/6 and p38MAPK was inhibited by AA treatment. Moreover, knockdown of p38MAPK enhanced AA-suppressed protein levels of MZF-1, Elk-1, and Snail, suggesting that p38MAPK influences prostate cancer cell metastasis. These results provide promise for AA as a future candidate in the development of drug therapies to prevent or treat prostate cancer metastasis.

Meso-Dihydroguaiaretic Acid Ameliorates Acute Respiratory Distress Syndrome through Inhibiting Neutrophilic Inflammation and Scavenging Free Radical.

The pathogenesis of acute respiratory distress syndrome (ARDS) is very complex. Patients with ARDS still suffer high mortality rates. Infiltration and activation of neutrophils in lungs are critical pathogenic factors in ARDS. In this study, we demonstrate that meso-dihydroguaiaretic acid (MDGA), a natural lignan, inhibits inflammatory responses in human neutrophils and ameliorates ARDS in mice. MDGA inhibited superoxide anion generation and elastase release in various G-protein coupled receptor agonists-induced human neutrophils. However, MDGA did not alter superoxide anion generation and elastase activity in cell-free systems. These results suggest that the anti-inflammatory effects of MDGA are mediated by regulating cellular signals in human neutrophils. In consistent with this, MDGA suppressed phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in activated human neutrophils. Moreover, MDGA inhibited CD11b expression and adhesion in activated human neutrophils. Interestingly, MDGA reduced reactive oxygen species (ROS) generation but not superoxide anion generation in protein kinase C (PKC) activator-induced human neutrophils, suggesting that MDGA may also have ROS scavenging ability. Indeed, MDGA showed strong free radical scavenging activity in cell-free assays. Significantly, MDGA suppressed PKC-induced neutrophil extracellular trap formation. Additionally, treatment of MDGA attenuated neutrophil infiltration and lung damage on lipopolysaccharide-induced ARDS in mice. In conclusion, our results demonstrate that MDGA has anti-neutrophilic inflammatory effects and free-radical scavenging activity. We also suggest that MDGA has potential to serve as a lead for developing new therapeutics to treat ARDS.

Experiential ownership and body ownership are different phenomena.

Body ownership concerns what it is like to feel a body part or a full body as mine, and has become a prominent area of study. We propose that there is a closely related type of bodily self-consciousness largely neglected by researchers-experiential ownership. It refers to the sense that I am the one who is having a conscious experience. Are body ownership and experiential ownership actually the same phenomenon or are they genuinely different? In our experiments, the participant watched a rubber hand or someone else's body from the first-person perspective and was touched either synchronously or asynchronously. The main findings: (1) The sense of body ownership was hindered in the asynchronous conditions of both the body-part and the full-body experiments. However, a strong sense of experiential ownership was observed in those conditions. (2) We found the opposite when the participants' responses were measured after tactile stimulations had ceased for 5 s. In the synchronous conditions of another set of body-part and full-body experiments, only experiential ownership was blocked but not body ownership. These results demonstrate for the first time the double dissociation between body ownership and experiential ownership. Experiential ownership is indeed a distinct type of bodily self-consciousness.

Bletinib ameliorates neutrophilic inflammation and lung injury by inhibiting Src family kinase phosphorylation and activity.

BACKGROUND AND PURPOSE: Neutrophil overactivation is crucial in the pathogenesis of acute lung injury (ALI). Bletinib (3,3'-dihydroxy-2',6'-bis(p-hydroxybenzyl)-5-methoxybibenzyl), a natural bibenzyl, extracted from the Bletilla plant, exhibits anti-inflammatory, antibacterial, and antimitotic effects. In this study, we evaluated the therapeutic effects of bletinib in human neutrophilic inflammation and LPS-mediated ALI in mice. EXPERIMENTAL APPROACH: In human neutrophils activated with the formyl peptide (fMLP), we assessed integrin expression, superoxide anion production, degranulation, neutrophil extracellular trap (NET) formation, and adhesion through flow cytometry, spectrophotometry, and immunofluorescence microscopy. Immunoblotting was used to measure phosphorylation of Src family kinases (SFKs) and downstream proteins. Finally, a LPS-induced ALI model in male BALB/c mice was used to investigate the potential therapeutic effects of bletinib treatment. KEY RESULTS: In activated human neutrophils, bletinib reduced degranulation, respiratory burst, NET formation, adhesion, migration, and integrin expression; suppressed the enzymic activity of SFKs, including Src, Lyn, Fgr, and Hck; and inhibited the phosphorylation of SFKs as well as Vav and Bruton's tyrosine kinase (Btk). In mice with ALI, the pulmonary sections demonstrated considerable amelioration of prominent inflammatory changes, such as haemorrhage, pulmonary oedema, and neutrophil infiltration, after bletinib treatment. CONCLUSION AND IMPLICATIONS: Bletinib regulates neutrophilic inflammation by inhibiting the SFK-Btk-Vav pathway. Bletinib ameliorates LPS-induced ALI in mice. Further biochemical optimisation of bletinib may be a promising strategy for the development of novel therapeutic agents for inflammatory diseases.

Body-as-Subject in the Four-Hand Illusion.

In a recent study (Chen et al., 2018), we conducted a series of experiments that induced the "four-hand illusion": using a head-mounted display (HMD), the participant adopted the experimenter's first-person perspective (1PP) as if it was his/her own 1PP. The participant saw four hands via the HMD: the experimenter's two hands from the adopted 1PP and the subject's own two hands from the adopted third-person perspective (3PP). In the active four-hand condition, the participant tapped his/her index fingers, imitated by the experimenter. Once all four hands acted synchronously and received synchronous tactile stimulations at the same time, many participants felt as if they owned two more hands. In this paper, we argue that there is a philosophical implication of this novel illusion. According to Merleau-Ponty (1945/1962) and Legrand (2010), one can experience one's own body or body-part either as-object or as-subject but cannot experience it as both simultaneously, i.e., these two experiences are mutually exclusive. Call this view the Experiential Exclusion Thesis. We contend that a key component of the four-hand illusion-the subjective experience of the 1PP-hands that involved both "kinesthetic sense of movement" and "visual sense of movement" (the movement that the participant sees via the HMD)-provides an important counter-example against this thesis. We argue that it is possible for a healthy subject to experience the same body-part both as-subject and as-object simultaneously. Our goal is not to annihilate the distinction between body-as-object and body-as-subject, but to show that it is not as rigid as suggested by the phenomenologists.

Body ownership and the four-hand illusion.

Recent studies of the rubber hand illusion (RHI) have shown that the sense of body ownership is constrained by several factors and yet is still very flexible. However, exactly how flexible is our sense of body ownership? In this study, we address this issue by investigating the following question: is it possible that one may have the illusory experience of owning four hands? Under visual manipulation, the participant adopted the experimenter's first-person perspective (1PP) as if it was his/her own. Sitting face to face, the participant saw four hands-the experimenter's two hands from the adopted 1PP together with the subject's own two hands from the adopted third-person perspective (3PP). We found that: (1) the four-hand illusion did not occur in the passive four-hand condition. (2) In the active four-hand condition, the participants tapped their index fingers, imitated by the experimenter. When tactile stimulations were not provided, the key illusion was not induced, either. (3) Strikingly, once all four hands began to act with the same pattern and received synchronous tactile stimulations at the same time, many participants felt as if they had two more hands. These results show that the sense of body ownership is much more flexible than most researchers have suggested.

The Sense of 1PP-Location Contributes to Shaping the Perceived Self-location Together with the Sense of Body-Location.

Self-location-the sense of where I am in space-provides an experiential anchor for one's interaction with the environment. In the studies of full-body illusions, many researchers have defined self-location solely in terms of body-location-the subjective feeling of where my body is. Although this view is useful, there is an issue regarding whether it can fully accommodate the role of 1PP-location-the sense of where my first-person perspective is located in space. In this study, we investigate self-location by comparing body-location and 1PP-location: using a head-mounted display (HMD) and a stereo camera, the subjects watched their own body standing in front of them and received tactile stimulations. We manipulated their senses of body-location and 1PP-location in three different conditions: the participants standing still (Basic condition), asking them to move forward (Walking condition), and swiftly moving the stereo camera away from their body (Visual condition). In the Walking condition, the participants watched their body moving away from their 1PP. In the Visual condition, the scene seen via the HMD was systematically receding. Our data show that, under different manipulations of movement, the spatial unity between 1PP-location and body-location can be temporarily interrupted. Interestingly, we also observed a "double-body effect." We further suggest that it is better to consider body-location and 1PP-location as interrelated but distinct factors that jointly support the sense of self-location.

Honokiol suppresses formyl peptide-induced human neutrophil activation by blocking formyl peptide receptor 1.

Formyl peptide receptor 1 (FPR1) mediates bacterial and mitochondrial N-formyl peptides-induced neutrophil activation. Therefore, FPR1 is an important therapeutic target for drugs to treat septic or sterile inflammatory diseases. Honokiol, a major bioactive compound of Magnoliaceae plants, possesses several anti-inflammatory activities. Here, we show that honokiol exhibits an inhibitory effect on FPR1 binding in human neutrophils. Honokiol inhibited superoxide anion generation, reactive oxygen species formation, and elastase release in bacterial or mitochondrial N-formyl peptides (FPR1 agonists)-activated human neutrophils. Adhesion of FPR1-induced human neutrophils to cerebral endothelial cells was also reduced by honokiol. The receptor-binding results revealed that honokiol repressed FPR1-specific ligand N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein binding to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells. However, honokiol did not inhibit FPR2-specific ligand binding to FPR2 in human neutrophils. Furthermore, honokiol inhibited FPR1 agonist-induced calcium mobilization as well as phosphorylation of p38 MAPK, ERK, and JNK in human neutrophils. In conclusion, our data demonstrate that honokiol may have therapeutic potential for treating FPR1-mediated inflammatory diseases.

Body ownership and experiential ownership in the self-touching illusion.

We investigate two issues about the subjective experience of one's body: first, is the experience of owning a full-body fundamentally different from the experience of owning a body-part?Second, when I experience a bodily sensation, does it guarantee that I cannot be wrong about whether it is me who feels it? To address these issues, we conducted a series of experiments that combined the rubber hand illusion (RHI) and the "body swap illusion." The subject wore a head mounted display (HMD) connected with a stereo camera set on the experimenter's head. Sitting face to face, they used their right hand holding a paintbrush to brush each other's left hand. Through the HMD, the subject adopted the experimenter's first-person perspective (1PP) as if it was his/her own 1PP: the subject watched either the experimenter's hand from the adopted 1PP, and/or the subject's own hand from the adopted third-person perspective (3PP) in the opposite direction (180°), or the subject's full body from the adopted 3PP (180°, with or without face). The synchronous full-body conditions generate a "self-touching illusion": many participants felt that "I was brushing my own hand!" We found that (1) the sense of body-part ownership and the sense of full-body ownership are not fundamentally different from each other; and (2) our data present a strong case against the mainstream philosophical view called the immunity principle (IEM). We argue that it is possible for misrepresentation to occur in the subject's sense of "experiential ownership" (the sense that I am the one who is having this bodily experience). We discuss these findings and conclude that not only the sense of body ownership but also the sense of experiential ownership call for further interdisciplinary studies.

Neuroprotective mechanism of BNG-1 against focal cerebral ischemia: a neuroimaging and neurotrophin study.

BNG-1 is a herb complex used in traditional Chinese medicine to treat stroke. In this study, we attempted to identify the neuroprotective mechanism of BNG-1 by using neuroimaging and neurotrophin analyses of a stroke animal model. Rats were treated with either saline or BNG-1 for 7 d after 60-min middle cerebral artery occlusion by filament model. The temporal change of magnetic resonance (MR) imaging of brain was studied using a 7 Tesla MR imaging (MRI) system and the temporal expressions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in brain were analyzed before operation and at 4 h, 2 d, and 7 d after operation. Compared with the saline group, the BNG-1 group exhibited a smaller infarction volume in the cerebral cortex in T2 image from as early as 4 h to 7 d, less edema in the cortex in diffusion weighted image from 2 to 7 d, earlier reduction of postischemic hyperperfusion in both the cortex and striatum in perfusion image at 4 h, and earlier normalization of the ischemic pattern in the striatum in susceptibility weighted image at 2 d. NT-3 and BDNF levels were higher in the BNG-1 group than the saline group at 7 d. We concluded that the protective effect of BNG-1 against cerebral ischemic injury might act through improving cerebral hemodynamics and recovering neurotrophin generation.