Retrobisabolane A, a Novel Bisabolane-Derived Sesquiterpenoid Isolated from Deep-Sea-Derived Fungus Retroconis fusiformis MCCC 3A00792.

One novel bisabolane-derived sesquiterpenoid retrobisabolane A (1), featuring a methyl group location at the C-4 position instead of C-3 in the bisabolanes, and a known ester-substituted eremophilane-type sesquiterpenoid cryptosphaerolide (2), along with three known indole alkaloids (3-5) were discovered from the fermented cultures of a deep-sea-derived fungus Retroconis fusiformis MCCC 3A00792. The planar structure of new compound 1 was determined by extensive analysis of the NMR and HRESIMS spectra. The relative and absolute configurations of 1 were resolved by the coupling constant (J), calculation of ECD and NMR spectra, and the DP4+ probability analysis of the 1H and 13C NMR data. Interestingly, retrobisabolane A was the new subclass of bisabolanes bearing a methyl group linkage at C-4 instead of C-3 position. Three human cancer cell lines (Hela, AGS, and BIU-87) were subjected to evaluate the cytotoxic activities of compounds 1-5. As a result, compound 2 exhibited significant inhibitory activities against three cell lines with IC50 values ranging from 9.95 to 18.77 µM.

First-principles study of the effects of doping B, N, and O on the photoelectric properties of Cr adsorbed GaS.

CONTEXT: To lessen the impact of the dangerous metal Cr, this paper applies the first principles to investigate the adsorption behavior and photoelectric properties of GaS on Cr. The effects of doped GaS on Cr adsorption behavior are investigated with four GaS systems, which are pure, boron (B)-doped, nitrogen (N)-doped, and oxygen (O)-doped, in order to maximize the characteristics of GaS for use in novel sectors, to obtain understanding of the impact of doping on the electronic structure and optical properties of GaS adsorption of Cr, as well as to promote the development of the material. Four GaS adsorbed Cr systems, pure, B-doped, N-doped, and O-doped, are optimized, and the optimized results show that the stable adsorption position of Cr on both pure and doped GaS is the top position of Ga atoms, whereas doped elements B, N, and O can promote the adsorption of Cr on GaS, and the order of the strength of this promotion is B > N > O. METHOD: In this paper, molecular simulation calculations and analyses using the CASTEP module in the software Materials Studio are performed to simulate the structure optimization of GaS-adsorbed Cr materials doped with B, N, and O atoms by using the generalized gradient approximation (GGA) plane-wave pseudopotential approach [1] and the Perdew-Burke-Ernzerhof (PBE) generalized function [2]. From the convergence test, it is reasonable to set the K-point network to 4 × 4 × 1 and the truncation energy to 500 eV [3]. In this paper, a 3 × 3 × 1 supercell structure with 18 S atoms and 18 Ga atoms is selected. The convergence value of the iterative accuracy is 1.0e - 5 eV/atom, and all the atomic forces are less than 0.02 eV/Å. A vacuum layer of 16 Å is also set in the C direction to avoid interlayer interactions of GaS. First, we optimize the geometry of the model and then analyze the nature of the adsorption energy and electronic structure corresponding to the model.

Preclinical Pharmacology Characterization of Sovleplenib (HMPL-523), an Orally Available Syk Inhibitor.

Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase involved in the signal transduction in immune cells mainly. Its aberrant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibition of Syk is considered a reasonable approach to treat autoimmune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib, a novel, highly potent and selective, oral Syk inhibitor, in several rodent autoimmune disease models. Sovleplenib potently inhibited Syk activity in a recombinant enzymatic assay and Syk-dependent cellular functions in various immune cell lines and human whole blood in vitro. Furthermore, sovleplenib, by oral administration, demonstrated strong in vivo efficacies in murine models of immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and chronic graft-versus-host disease (cGVHD), and a rat model of collagen induced arthritis (CIA) respectively, in a dose-dependent manner. Collectively, these results clearly supported sovleplenib as a therapeutic agent in the treatment of autoimmune diseases. Sovleplenib is being globally developed for ITP (Phase III, NCT05029635, Phase Ib/II, NCT03951623), wAIHA (Phase II/III, NCT05535933) and B-cell lymphoma (Phase I, NCT02857998, NCT03779113). SIGNIFICANCE STATEMENT: Syk is a key mediator of signaling pathways downstream of a wide array of receptors important for immune functions, including the B cell receptor, immunoglobulin receptors bearing Fc receptors. Inhibition of Syk could provide a novel therapeutic approach for autoimmune diseases and hematologic malignancies. The manuscript describes the preclinical pharmacology characterization of sovleplenib, a novel Syk inhibitor, in enzymatic and cellular assays in vitro and several murine autoimmune disease models in vivo.

A rare imaging presentation with multisystemic clinicopathological features of Langerhans cell histiocytosis: Case report and literature review.

RATIONALE: Langerhans cell histiocytosis (LCH) is a kind of rare disease in which dendritic cells proliferate abnormally. It often occurs in children and can involve any tissue and organ. The affected sites usually include bone, skin, pituitary gland, and lungs, while the thyroid gland and external auditory canal are rarely observed. The perineal and labial involvement of this disease has not been reported yet. PATIENT CONCERNS: A 47-year-old female patient experienced a swelling of the anterior neck area without an obvious inducement. She noticed a quail egg-like mass on the left side, and the mass increased progressively within 3 months. The anterior neck area was found to be swollen, and some flaky red rashes were seen on the scalp and bilateral external auditory canals. DIAGNOSES: Imaging examination showed enlarged thyroid and cervical lymph nodes, multiple low-density nodules in the liver, and reduced signal in the posterior pituitary gland. The biopsy pathological result of the increased left cervical lymph node indicated that LCH was detected. INTERVENTIONS: VP regimen (vincristine, dexamethasone per os) and related supportive treatments were given as inducing chemotherapy for 6 weeks. OUTCOMES: After the second chemotherapy, the rash on the scalp and external auditory canal improved, and the neck mass was significantly reduced. After the third chemotherapy, the rash was mostly disappeared, while the neck lumps increased during chemotherapy. Thus, clatribine chemotherapy was recommended as the follow-up. LESSONS: Imaging examinations played an important role in the diagnosis and follow-up of the disease, especially 18F-FDG PET/CT, which could show multiple involving organs at the same time. When a patient suffering from diabetes insipidus, skin rash, or fever, has a high FDG uptake PET/CT result in multiple tissues and organs throughout the body, it is necessary to consider the possibility of LCH.

Ramulus Cinnamomi essential oil exerts an anti-inflammatory effect on RAW264.7 cells through N-acylethanolamine acid amidase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of Ramulus Cinnamomi essential oil (RCEO) have been confirmed, although the potential mechanisms by which RCEO exerts its anti-inflammatory effects have not been fully elucidated. AIM OF THE STUDY: To investigate whether N-acylethanolamine acid amidase (NAAA) mediates the anti-inflammatory effects of RCEO. MATERIALS AND METHODS: RCEO was extracted by steam distillation of Ramulus Cinnamomi, and NAAA activity was detected using HEK293 cells overexpressing NAAA. N-Palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), both of which are NAAA endogenous substrates, were detected by liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The anti-inflammatory effects of RCEO were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit. The nitric oxide (NO) in the cell supernatant was measured using the Griess method. The level of tumor necrosis factor-α (TNF-α) in the RAW264.7 cell supernatant was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The chemical composition of RCEO was assessed by gas chromatography-mass spectroscopy (GC-MS). The molecular docking study for (E)-cinnamaldehyde and NAAA was performed by using Discovery Studio 2019 software (DS2019). RESULTS: We established a cell model for evaluating NAAA activity, and we found that RCEO inhibited the NAAA activity with an IC50 of 5.64 ± 0.62 µg/mL. RCEO significantly elevated PEA and OEA levels in NAAA-overexpressing HEK293 cells, suggesting that RCEO might prevent the degradation of cellular PEA and OEA by inhibiting the NAAA activity in NAAA-overexpressing HEK293 cells. In addition, RCEO also decreased NO and TNF-α cytokines in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, the GC-MS assay revealed that more than 93 components were identified in RCEO, of which (E)-cinnamaldehyde accounted for 64.88%. Further experiments showed that (E)-cinnamaldehyde and O-methoxycinnamaldehyde inhibited NAAA activity with an IC50 of 3.21 ± 0.03 and 9.62 ± 0.30 µg/mL, respectively, which may represent key components of RCEO that inhibit NAAA activity. Meanwhile, docking assays revealed that (E)-cinnamaldehyde occupies the catalytic cavity of NAAA and engages in a hydrogen bond interaction with the TRP181 and hydrophobic-related interactions with LEU152 of human NAAA. CONCLUSIONS: RCEO showed anti-inflammatory effects by inhibiting NAAA activity and elevating cellular PEA and OEA levels in NAAA-overexpressing HEK293 cells. (E)-cinnamaldehyde and O-methoxycinnamaldehyde, two components in RCEO, were identified as the main contributors of the anti-inflammatory effects of RCEO by modulating cellular PEA levels through NAAA inhibition.

Phaeosphamides A and B, Cytotoxic Cyclodecadepsipeptides from the Mangrove-Derived Fungus Phaeosphaeriopsis sp. S296.

Chemical examination of the fermented broth of the mangrove-derived fungus Phaeosphaeriopsis sp. S296 resulted in the isolation of two new cyclodecadepsipeptides, namely phaeosphamides A (1) and B (2), as well as one known congener Sch 217048 (3). The structures of new metabolites, including absolute configurations, were established on the basis of extensive spectroscopic data analyses, chemical conversion, and Marfey's method. The 2-hydroxy-3-methylpentanoic acid (Hmp) moiety and pipecolic acid (Pip) unit in structures were rarely discovered in nature. Interestingly, compounds 1-3 are examples of peptides discovered from the fungal genus Phaeosphaeriopsis for the first time. All identified compounds were evaluated for their cytotoxicity against five tumor cell lines of AGS, BEL-7402, HepG2, B16, and BIU87. Among them, compound 1 showed inhibitory activities against these tumor cell lines with IC50 values ranging from 5.14 to 66.38 µM. A further mechanistic investigation found that 1 arrested AGS cells in the G2 phase and induced their apoptosis in a dose-dependent manner.

Phenolic Metabolites from a Deep-Sea-Derived Fungus Aspergillus puniceus A2 and Their Nrf2-Dependent Anti-Inflammatory Effects.

Four undescribed phenolic compounds, namely asperpropanols A-D (1-4), along with two known congeners 5 and 6, were isolated from Aspergillus puniceus A2, a deep-sea-derived fungus. The gross structures of the compounds were established by detailed analyses of the HRESIMS and NMR data, and their absolute configurations were resolved by modified Mosher's method and calculations of ECD data. Compounds 1-6 were found to have excellent anti-inflammatory effect on lipopolysaccharide (LPS)-induced RAW264.7 cells at 20 µM, evidenced by the reduced nitric oxide (NO), tumor necrosis factor α, and interleukin 6 production. Among them, 5 and 6 showed inhibitory effects on NO production comparable with the positive control (BAY11-7083 at 10 µM). Additionally, the LPS-induced mRNA expressions of inducible nitric oxide synthase and cyclooxygenase-2 were also decreased. Interestingly, mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was downregulated by LPS and recovered by 1-6, suggesting a vital role of Nrf2 in their effect. We further found that pharmacological inhibition of Nrf2 by ML385 largely abrogated the effects of 1-6 on RAW264.7 cells. Therefore, 1-6 may share a common anti-inflammatory mechanism via Nrf2 upregulation and activation.

Rigid, eco-friendly and superhydrophobic SiO2-Polyvinyl alcohol composite sponge for durable oil remediation.

Development of durable and eco-friendly adsorbents for oil remediation is in great demands. However, most of adsorbents were designed to pursue large capabilities while ignored their strength after adsorbing oil, which might cause secondary oil spilling during complex salvage process. Herein, an eco-friendly and superhydrophobic SiO2-modified polyvinyl alcohol composite (H-SiO2-G-PVA) sponge with extraordinary rigid structure after oil adsorption is designed for durable oil remediation. Through a two-step hydrolysis-condensation process including deposition of silica microparticles and introduction of hexadecyltrimethoxysilane (HDTMS), a superhydrophobic H-SiO2-G-PVA sponge has been successfully constructed. The sponge presents stable superhydrophobicity in various complex environments，therefore it efficiently adsorbs oil from water (up to 6 g g-1) and separate surfactant-stabilized water/oil emulsion with high efficiency (>99%). Noticeably, the H-SiO2-G-PVA sponge maintains tough strength (3.5 MPa) after oil adsorption, which ideally overcomes secondary oil spilling problem and endows the sponge with excellent recycling performances (>20 cycles). Meanwhile, the excellent biocompatibility of the sponge (high cell viability of 91.85%) ensures the potential for practical applications. This rigid, eco-friendly oil-adsorbing sponge that achieves stable superhydrophobicity and recyclability, fulfills the application needs for durable oil remediation.

Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/ß-catenin signalling via interaction with Gli1.

BACKGROUND AND PURPOSE: Portal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications. EXPERIMENTAL APPROACH: Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC-LX2 cells using real-time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation and site-directed mutagenesis. KEY RESULTS: Wnt/ß-catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo-independent Gli1 nuclear translocation followed by LARG-mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a-induced Gli1 nuclear translocation. Wnt/ß-catenin repressed transcription of Sufu dependent on ß-catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site-directed mutagenesis identified the ß-catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short-term liver-targeting ß-catenin deficiency or acute treatment with ß-catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long-term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation. CONCLUSION AND IMPLICATIONS: Interaction between Wnt/ß-catenin and Smo-independent Gli1 pathways promoted HSC contraction via TCF4-dependent transrepression of Sufu. HSC-specific inhibition of ß-catenin may have therapeutic benefits for cirrhotic portal hypertension.

Separation of saturated fatty acids from docosahexaenoic acid-rich algal oil by enzymatic ethanolysis in tandem with molecular distillation.

Algal oil, rich in docosahexaenoic acid (DHA) and an environmentally sustainable source of ω-3 fatty acids, is receiving increasing attention. In the present study, a novel approach combining ethanolysis with a 1,3-specific immobilized lipase (Lipozyme® TL IM) and molecular distillation was investigated to increase the DHA content of algal oil. Algal oil with a 45.94% DHA content was mixed with ethanol, pumped into a column filled with Lipozyme® TL IM, and then circulated for 4 hr at room temperature. The ethanol was then recycled by vacuum distillation. At an evaporator temperature of 150°C, the residue was separated by molecular distillation into a heavy component enriched with DHA glycerides (in the form of triglyceride (TG), diglyceride (DG), and monoglyceride (MG)) and a light component enriched with palmitic acid (PA) and DHA ethyl ester (EE). As a result, 76.55% of the DHA from the algal oil was present in the heavy component, whose DHA content was 70.27%. DHA-MG was collected in the heavy component mostly in the form of 1-MG. Lipozyme® TL IM appeared to specifically target PA rather than DHA at the sn-1(3) position. The Lipozyme® TL IM allowed 90.03% of the initial DHA yield to be retained after seven reaction cycles. Therefore, an eco-friendly and simple method for increasing the DHA content in algal oil has been developed.

Synthesis, biological activities, and docking studies of d-pantolactone derivatives as novel FAS inhibitors.

A novel series of fatty acid synthase (FAS) inhibitors with D-(-)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC50 values in the range of 13.68 ±â€¯1.52-33.19 ±â€¯1.39 µM, reference inhibitor C75 has IC50 value of 13.86 ±â€¯2.79 µM. Eight compounds (3c, 3d, 3e, 3f, 3j, 3m, 3q and 3r) also displayed inhibitory effect on lipid accumulation in human HepG2 cells. Additionally, the molecular docking study revealed that compound 3m having good inhibition activity against FAS and lipid accumulation also showed promising binding affinities with hFAS, while its binding model with hFAS (PDB ID: 4PIV) was different from that of reference compound C75.

EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity.

Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.

Risk Assessment in Chinese Hospitalized Patients Comparing the Padua and Caprini Scoring Algorithms.

The current venous thromboembolism (VTE) guidelines recommend all patients to be assessed for the risk of VTE using risk assessment models (RAMs). The study was to evaluate the performance of the Caprini and Padua RAMs among Chinese hospitalized patients. We reviewed data from 189 patients with deep venous thrombosis (DVT) and 201 non-DVT patients. Deep venous thrombosis risk factors were obtained from all patients. The sensitivity and specificity of the Caprini and Padua scores for all patients were calculated. The receiver operating curve (ROC) and the area under the ROC curve (AUC) were used to evaluate the performance of each score. We documented that age, acute infection, prothrombin time (PT), D-dimer, erythrocyte sedimentation rate, blood platelets, and anticoagulation were significantly associated with the occurrence of DVT (P < .05). These results were true for all medical and surgical patients group (G1), as well as the analysis of medical versus surgical patients (G2). Finally, analysis of the scores in patients with and without cancer was also done (G3). The Caprini has a higher sensitivity but a lower specificity than the Padua (P < .05). Caprini has a better predictive ability for the first 2 groups (P < .05). We found Caprini and Padua scores have a similar predictive value for patients with cancer (P > .05), while Caprini has a higher predictive ability for no cancer patients in G3 than Padua (P < .05). For Chinese hospitalized patients, Caprini has a higher sensitivity but a lower specificity than Padua. Overall, Caprini RAM has a better predictive ability than Padua RAM.

Ligand Activation of PPARγ by Ligustrazine Suppresses Pericyte Functions of Hepatic Stellate Cells via SMRT-Mediated Transrepression of HIF-1α.

Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl4 for evaluating ligustrazine's effects in vivo. Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl4-induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.

Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia.

Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats.

Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV-1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-κB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins.

Docosahexaenoic acid attenuates carbon tetrachloride-induced hepatic fibrosis in rats.

Fish oil containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has been reported to exert beneficial health effects, including hepatoprotection. However, the effect of DHA alone has not been well studied, and the mechanism is not fully understood. In the present study, we reported the protective effect of DHA on carbon tetrachloride (CCl4) induced hepatic fibrosis. Compared with the control group, the CCl4 group showed hepatic damage as evidenced by histological changes and elevation in serum transaminase activity, fibrosis, inflammation and oxidative stress levels. These pathophysiological changes were attenuated by chronic DHA supplementation. The anti-fibrotic effect of DHA was accompanied by reductions in gene and protein expression of α-smooth muscle actin (α-SMA), fibronectin, and collagen in the liver tissue. DHA also attenuated CCl4-induced elevation of lipid peroxidation (LPO) and decrease of glutathione (GSH)/oxidized GSH (GSSG) ratio. The upregulated inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6 by CCl4 were also ameliorated by DHA. Peroxisome proliferator-activated receptor (PPAR)-γ upregulation and type I and II receptors for transforming growth factor (TGF)-ß (Tß-RI and Tß-RII) and platelet-derived growth factor (PDGF)-ß receptor (PDGF-ßR) downregulation on both mRNA and protein levels were observed by DHA treatment compared to CCl4 group. Moreover, in vitro study showed that DHA inhibited HSC activation, being associated with elevating PPARγ level and reducing the phosphorylation levels of Smad2/3 and ERKs, which are downstream intermediates of TGFß and PDGF receptors, respectively. Taken together, the hepatoprotective, anti-inflammatory and anti-fibrotic effects of DHA appeared to be multifactorial. Further, one of the mechanisms of the anti-fibrotic effect of chronic DHA supplementation is probably through PPARγ signaling to interrupt TGFß/Smad and PDGF/ERK pathways in HSCs.

Preparation and antioxidant properties of selenium nanoparticles-loaded chitosan microspheres.

Selenium nanoparticles (SeNPs), as a special form of selenium (Se) supplement, have attracted worldwide attention due to their favorable properties and unique bioactivities. Herein, an eco-friendly and economic way to prepare stable SeNPs is introduced. SeNPs were synthesized in aqueous chitosan (CTS) and then embedded into CTS microspheres by spray-drying, forming selenium nanoparticles-loaded chitosan microspheres (SeNPs-M). The physicochemical properties including morphology, elemental state, size distribution and surface potential were investigated. Institute of Cancer Research mice were used as model animal to evaluate the bioactivities of SeNPs-M. Trigonal-phase SeNPs of ~35 nm were synthesized, and SeNPs-M physically embedding those SeNPs were successfully prepared. Amazingly, acute toxicity test indicated that SeNPs-M were much safer than selenite in terms of Se dose, with a LD50 of around 18-fold of that of selenite. In addition, SeNPs-M possessed powerful antioxidant activities, as evidenced by a dramatic increase of both Se retention and the levels of glutathione peroxidase, superoxide dismutase and catalase. The design of SeNPs-M can offer a new way for further development of SeNPs with a higher efficacy and better biosafety. Thus, SeNPs-M may be a potential candidate for further evaluation as an Se supplement with antioxidant properties and be used against Se deficiency in animals and human beings.

Intra-herb pharmacokinetics interaction between quercetin and isorhamentin.

AIM: Quercetin and isorhamnetin are common constituents of some herb extracts, such as extracts of gingko leaves and total flavones of Hippophae rhamnoides L. The intra-herb pharmacokinetics interactions between isorhamnetin and quercetin were investigated in the present study. METHODS: Human MDR1 cDNA transfected MDCKII cells were used to validate whether isorhamnein interacted with P-gp. Caco-2 transport assays and a randomized, 3-way crossover pharmacokinetics study in rats were used to investigate the pharmacokinetics interactions. HPLC was used to determine cell transport samples. The total plasma concentrations of quercetinand isorhamnetin were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) by treatment with beta-glucuronidase and sulfatase. RESULTS: The permeability ratio (absorptive permeability/secretive permeability) of isorhamnetin across human MDR1 cDNA transfected MDCKII cells, Caco-2 cells and wild-type MDCKII cells are 0.25+/-0.02, 0.74+/-0.05, and 1.41+/-0.06, respectively. This result proved the role of P-gp in the cell efflux of isorhamnetin. While co-transporting with each other across Caco-2 cells monolayer, the permeability ratio of isorhamnetin and quercetin increased by 4.3 and 2.2 times. After coadministration with each other to rats, the C(max), AUC(0-72 h), and AUC(0-infinity) of both isorhamnetin and quercetin significantly increased compared with single administration. CONCLUSION: The above results proved intra-herb pharmacokinetics interaction between quercetin and isorhamentin. P-gp might play an important role, whereas other drug efflux pumps, such as multi-drug resistance associate protein 2 and breast cancer resistance protein, might be involved. Accordingly, besides the drug-herb interactions, intra-herb interaction might be brought into view with the wide use of herbal-based remedies.

[Effect of resveratrol on chronic obstructive pulmonary disease in rats and its mechanism].

The purpose of this study is to establish COPD animal model by intra-tracheal instillation of bleomycin (BLM) once and exposure to cigarette smoke for continuous 27 d, and to observe the effects of the inhalation on the model. At the 29th day, blood samples were taken from cervical artery for blood-gas analysis and parameters of lung function were recorded. Bronchoalveolar lavage fluid (BALF) was collected to measure intercellular adhesion molecule-1 (ICAM-1) concentration. The results showed that atomization inhaled resveratrol could alleviate rat COPD lung injury accompanied by amelioration of pathological changes, increase the ratio of forced expiratory volume in 0.3 s (FEV0.3) and forced vital capacity (FVC), and decrease the ICAM-1 level in BALF. The ultimate reduction of inflammatory factors was involved, at least in part, in the mechanism of resveratrol effects.