Polyoxygenated cembrane-type diterpenes from the Hainan soft coral Lobophytum crassum as a promising source of anticancer agents with ErbB3 and ROR1 inhibitory potential.

A detailed chemical investigation of the Hainan soft coral Lobophytum crassum led to the identification of a class of polyoxygenated cembrane-type macrocyclic diterpenes (1-28), including three new flexible cembranoids, lobophycrasins E-G (2-4), and twenty-five known analogues. Their structures were elucidated by combining extensive spectroscopic data analysis, quantum mechanical-nuclear magnetic resonance (QM-NMR) methods, the modified Mosher's method, X-ray diffraction analysis, and comparison with data reported in the literature. Bioassays revealed that sixteen cembranoids inhibited the proliferation of H1975, MDA-MB231, A549, and H1299 cells. Among them, Compounds 10, 17, and 20 exhibited significant antiproliferative activities with IC50 values of 1.92-8.82 µM, which are very similar to that of the positive control doxorubicin. Molecular mechanistic studies showed that the antitumour activity of Compound 10 was closely related to regulation of the ROR1 and ErbB3 signalling pathways. This study may provide insight into the discovery and utilization of marine macrocyclic cembranoids as lead compounds for anticancer drugs.

Development and validation of Malaysian one stop crisis center service quality instrument (OSCC-Qual) for domestic violence management.

One Stop Crisis Center (OSCC) is a multi-sectorial center aimed to provide medical, social, legal, police and shelter services to survivors of domestic violence, rape, sexual assault, sodomy and child abuse. Although OSCCs have been established for almost three decades in different parts of the world including in Malaysia, there is a lack of a validated instrument to measure the service quality rendered in OSCCs. A validated instrument known as OSCC-Qual was developed using a 5-stage approach where (1) in stage 1, group discussions were conducted among all authors to identify potential items for the instrument; (2) in stage 2, content validation was performed by 13 experts using content validity index and modified kappa; (3) in stage 3, exploratory factor analysis was performed by 141 healthcare staff with experience in managing OSCC cases to validate the items as well as to identify the number of factors in the instrument; (4) in stage 4, confirmatory factor analysis was performed by 110 domestic violence survivors to ascertain the validity of the factors and items retained in stage 3 and (5) in stage 5, forward and backward translation into local Malay and Chinese languages was performed. Results: In stage 1, a total of 42 items were identified. No item was deleted in stage 2. In stage 3, a total of 7 factors (i.e., "information provision", "competency of staff", "professionalism", "supportive environment", "attitude of staff", "multi-sectorial coordination" and "tangibles") were identified. Four items were deleted due to poor factor loading. In stage 4, another 3 items were iteratively removed due to poor factor loading. Discriminant validity was good. Conclusion: With the availability of the 7-factor and 35-item OSCC-Qual instrument, it is hoped that the efficiency of OSCC in achieving its philosophical objectives after three decades of implementation can be unraveled and remedial actions can be taken, if necessary.

In Vitro Insights into the Role of 7,8-Epoxy-11-Sinulariolide Acetate Isolated from Soft Coral Sinularia siaesensis in the Potential Attenuation of Inflammation and Osteoclastogenesis.

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the process of bone remodeling. Excessive osteoclast differentiation plays a pivotal role in the pathogenesis of bone diseases such as rheumatoid arthritis and osteoporosis. In the present study, we examined whether 7,8-epoxy-11-sinulariolide acetate (Esa), a marine natural product present in soft coral Sinularia siaesensis, attenuates inflammation and osteoclastogenesis in vitro. The results indicated that Esa significantly inhibited lipopolysaccharide (LPS)-induced inflammation model of RAW264.7 cells and suppressed receptor activator for nuclear factor-κB ligand (RANKL)-triggered osteoclastogenesis. Esa significantly down-regulated the protein expression of iNOS, COX-2, and TNF-α by inhibiting the NF-κB/MAPK/PI3K pathways and reducing the release of reactive oxygen species (ROS) in RAW264.7 macrophages. Besides, Esa treatment significantly inhibited osteoclast differentiation and suppressed the expression of osteoclast-specific markers such as NFATC1, MMP-9, and CTSK proteins. These findings suggest that Esa may be a potential agent for the maintenance of bone homeostasis associated with inflammation.

Efficient Noncollinear Antiferromagnetic State Switching Induced by the Orbital Hall Effect in Chromium.

Recently, orbital Hall current has attracted attention as an alternative method to switch the magnetization of ferromagnets. Here we present our findings on electrical switching of the antiferromagnetic state in Mn3Sn/Cr, where despite the much smaller spin Hall angle of Cr, the switching current density is comparable to heavy metal-based heterostructures. However, the inverse process, i.e., spin-to-charge conversion in Cr-based heterostructures, is much less efficient than the Pt-based equivalents, as manifested in the 1 order of magnitude smaller terahertz emission intensity and spin current-induced magnetoresistance. These results in combination with the slow decay of terahertz emission against Cr thickness (diffusion length of ∼11 nm) suggest that the observed magnetic switching can be attributed to orbital current generation in Cr, followed by efficient conversion to spin current. Our work demonstrates the potential of light metals like Cr as efficient orbital/spin current sources for antiferromagnetic spintronics.

Pivotal Role of Geometry Regulation on O-O Bond Formation Mechanism of Bimetallic Water Oxidation Catalysts.

In this study, we highlight the impact of catalyst geometry on the formation of O-O bonds in Cu2 and Fe2 catalysts. A series of Cu2 complexes with diverse linkers are designed as electrocatalysts for water oxidation. Interestingly, the catalytic performance of these Cu2 complexes is enhanced as their molecular skeletons become more rigid, which contrasts with the behavior observed in our previous investigation with Fe2 analogs. Moreover, mechanistic studies reveal that the reactivity of the bridging O atom results in distinct pathways for O-O bond formation in Cu2 and Fe2 catalysts. In Cu2 systems, the coupling takes place between a terminal CuIII -OH and a bridging µ-O⋅ radical. Whereas in Fe2 systems, it involves the coupling of two terminal Fe-oxo entities. Furthermore, an in-depth structure-activity analysis uncovers the spatial geometric prerequisites for the coupling of the terminal OH with the bridging µ-O⋅ radical, ultimately leading to the O-O bond formation. Overall, this study emphasizes the critical role of precisely adjusting the spatial geometry of catalysts to align with the O-O bonding pathway.

The Effects of Pore Defects in π-Extended Pentadecabenzo[9]helicene.

The introduction of precise pore defects into nanocarbon structures results in the emergence of distinct physicochemical characteristics. However, there is a lack of research on non-planar chiral nanographene involving precise pore defects. Herein, we have developed two analogues to the π-extended pentadecabenzo[9]helicene (EP9H) containing embedded pore defects. Each molecules, namely extended dodecabenzo[7]helicene (ED7H; 1) or extended nonabenzo[5]helicene (EN5H; 2), exhibits dual-state emission. Significantly, the value of |glum| of 1 is exceptionally high at 1.41×10-2 in solution and BCPL as 254 M-1 cm-1. In PMMA film, |glum| of 1 is 8.56×10-3, and in powder film, it is 5.00×10-3. This study demonstrates that nanocarbon molecules with pore defects exhibit dual-state emission properties while maintaining quite good chiral luminescence properties. It was distinguished from the aggregation-caused quenching (ACQ) effect corresponding to the nanocarbon without embedded defect. Incorporating pore defects into chiral nanocarbon molecules also simplifies the synthesis process and enhances the solubility of the resulting product. These findings suggest that the introduction of pore defects can be a viable approach to improve nanocarbon molecules.

AHR/TET2/NT5E axis downregulation is associated with the risk of systemic lupus erythematosus and its progression.

The prognosis of systemic lupus erythematosus (SLE) is unpredictable. This study aimed to examine the regulatory mechanism of the AHR/TET2/NT5E pathway during SLE progression. The AHR, TET2 and NT5E expression levels were examined in T regulatory cells (Tregs) of patients with SLE. The correlation of AHR, TET2 or NT5E expression levels with the immunosuppressive functions of Tregs was analysed. In patients with SLE, the number of CD4+ IL2RA- FOXP3+ T cell subset was positively correlated with the SLE disease activity index value and negatively correlated with the AHR and TET2 expression levels in CD4+ IL2RA+ FOXP3+ Tregs. Transcriptional profiles of 79 patients with SLE obtained from the Gene Expression Omnibus database (GSE61635 dataset) revealed a significant positive correlation between the mRNA expression levels of AHR and TET2. In silico analysis predicted that the TET2 promoter comprises an AHR-binding site. Kynurenine (KYN) promoted the binding of AHR to the TET2 promoter in Tregs of patients with SLE and Jurkat T cell lines. Furthermore, NT5E expression was significantly downregulated in Tregs of patients with SLE, which can be attributed to the dysregulation of NT5E promoter methylation status induced by downregulated TET2 activity. Furthermore, the Treg immunosuppressive activity, which is mediated through the TET2 and A2AR-adenosine pathways, in the KYN-treated group was approximately two-fold higher than that in the control group. The AHR/TET2/NT5E axis mediates the Treg immunosuppressive activity. These findings provide novel insights for the development of therapeutic approaches for SLE and related autoimmune diseases.

Measurement of Hyperfine Structure and the Zemach Radius in

We investigate the 2^{3}S_{1}-2^{3}P_{J} (J=0, 1, 2) transitions in ^{6}Li^{+} using the optical Ramsey technique and achieve the most precise values of the hyperfine splittings of the 2^{3}S_{1} and 2^{3}P_{J} states, with smallest uncertainty of about 10 kHz. The present results reduce the uncertainties of previous experiments by a factor of 5 for the 2^{3}S_{1} state and a factor of 50 for the 2^{3}P_{J} states, and are in better agreement with theoretical values. Combining our measured hyperfine intervals of the 2^{3}S_{1} state with the latest quantum electrodynamic (QED) calculations, the improved Zemach radius of the ^{6}Li nucleus is determined to be 2.44(2) fm, with the uncertainty entirely due to the uncalculated QED effects of order mα^{7}. The result is in sharp disagreement with the value 3.71(16) fm determined from simple models of the nuclear charge and magnetization distribution. We call for a more definitive nuclear physics value of the ^{6}Li Zemach radius.

Amelioration of Cholesterol Rich diet-induced Impaired Cognition in AD Transgenic Mice by an LXR Agonist TO901317 Is Associated with the Activation of the LXR-ß-RXR-α-ABCA1 Transmembrane Transport System and Improving the Composition of Lipid Raft.

BACKGROUND: It has been reported that LXR agonist can inhibit Aß generation and alleviate Aß-induced various adverse reactions in vivo and in vitro experiments, but the mechanisms have not been clarified. The study aimed to observe the effect of LXR agonist TO901317 on the cognitive function of AD transgenic mice fed with cholesterol-rich diet (CRD), and to explore the possible mechanism. Methods: 32 male 6-month-old double transgenic AD mice were enrolled and randomly divided into 4 groups: control (normal diet) group, CRD treatment group, TO901317 treatment group and GSK2033 treatment group. After 3 month, Morris water maze was for the changes of spatial exploration and memory ability; ELISA was for detecting the production of Aß42 in the brain; the concentration of total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein (HDL) in serum were detected by cholesterol enzyme colorimetry; Finally, the expression of LXR-ß, RXR-α, ABCA1, caveolin-1, BACE1 and APP at protein level in the brains was measured by Western blotting. RESULTS: Compared with the control group, the learning, memory ability and spatial exploration ability of the mice were more significantly serious in the CRD group (P<0.05); The contents of TC and LDL in the serum and the production of Aß42 in the brains were significantly increased (P<0.05), but HDL was remarkably decreased (P<0.05); The protein levels of LXR-ß, RXR-α and ABCA1 were also significantly decreased (P<0.05); The expression of caveolin-1, APP and BACE1 were evidently increased (P<0.05). However, after treatment with TO901317, the impaired learning and memory and spatial exploration ability of the mice were significantly improved (P<0.05); The contents of TC and LDL in serum and the production of Aß42 in the brains were significantly decreased (P<0.05), but HLD was increased (P<0.05); The protein levels of LXR-ß, RXR-α, ABCA1were all significantly increased (P<0.05), while, the expression of caveolin-1, APP and BACE1 were all significantly decreased (P<0.05). All the changes were reversed by GSK2033 (P<0.05). CONCLUSIONS: TO901317 attenuated the more serious impairment of spatial exploration, learning and memory in transgenic AD mice induced by CRD, and the mechanism may be that TO901317 could activate the LXR-ß/RXR-α/ABCA1 transmembrane transport system, promote the cholesterol efflux, and decreased caveolin-1, APP and BACE1, further reduce Aß42 in the brains.

Four New Diterpenoids from the South China Sea Soft Coral Sinularia nanolobata and DFT-Based Structure Elucidation.

Three new cembranoids (1-3) and a new casbanoid (4), along with three known analogues (5-7), have been isolated from the soft coral Sinularia nanolobata collected off Ximao Island. The structures, including the absolute configurations of new compounds, were established using extensive spectroscopic data analysis, time-dependent density functional theory/electronic circular dichroism (TDDFT-ECD) calculations, and the comparison with spectroscopic data of known compounds. In the in vitro bioassay, compounds 1 and 5 exhibited moderate cytotoxic activities against human erythroleukemia (HEL) cell lines, with IC50 values of 37.1 and 42.4 µM, respectively.