FFAR4 activation inhibits lung adenocarcinoma via blocking respiratory chain complex assembly associated mitochondrial metabolism.

Despite notable advancements in the investigation and management of lung adenocarcinoma (LUAD), the mortality rate for individuals afflicted with LUAD remains elevated, and attaining an accurate prognosis is challenging. LUAD exhibits intricate genetic and environmental components, and it is plausible that free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. The objective of this study is to ascertain whether a correlation exists between FFAR4, which functions as the primary receptor for dietary fatty acids, and various characteristics of LUAD, while also delving into the potential underlying mechanism. The findings of this study indicate a decrease in FFAR4 expression in LUAD, with a positive correlation (P < 0.01) between FFAR4 levels and overall patient survival (OS). Receiver operating characteristic (ROC) curve analysis demonstrated a significant diagnostic value [area under the curve (AUC) of 0.933] associated with FFAR4 expression. Functional investigations revealed that the FFAR4-specific agonist (TUG891) effectively suppressed cell proliferation and induced cell cycle arrest. Furthermore, FFAR4 activation resulted in significant metabolic shifts, including a decrease in oxygen consumption rate (OCR) and an increase in extracellular acidification rate (ECAR) in A549 cells. In detail, the activation of FFAR4 has been observed to impact the assembly process of the mitochondrial respiratory chain complex and the malate-aspartate shuttle process, resulting in a decrease in the transition of NAD+ to NADH and the inhibition of LUAD. These discoveries reveal a previously unrecognized function of FFAR4 in the negative regulation of mitochondrial metabolism and the inhibition of LUAD, indicating its potential as a promising therapeutic target for the treatment and diagnosis of LUAD.

Fully bio-based epoxy resins from lignin and epoxidized soybean oil: Rigid-flexible, tunable properties and high lignin content.

The application of epoxidized soybean oil (ESO) in thermosetting polymers is impeded by its unsatisfactory thermomechanical properties. Here, in order to address the limitation, technical lignin was modified by tung oil anhydride and then used as the hardener to compensate for the inherent flexibility defects of ESO thermosets (TLs). As the lignin content increased, a notable improvement in the activation energy of TLs was observed, attributed to the restraining effect of lignin's rigid structure on segmental relaxation. Concurrently, the tensile strength of TLs increased from 2.8 MPa to 34.0 MPa, concomitant with a decrease in elongation at break from 32.9 % to 8.0 %. Comparative analysis with TL-0 (devoid of lignin) demonstrated substantial enhancements in glass transition temperature, shape fixation ratio, and shape recovery ratio for TL-50 (comprising 50 wt% of lignin), elevating from 16.9 °C, 89.1 %, and 89.5 % to 118.6 °C, 94.0 %, and 99.3 %, respectively. These results unequivocally highlight the favorable dynamic mechanical and shape memory properties conferred upon TLs by lignin addition. While the introduction of lignin adversely affected thermal stability, a notable improvement in char yield (800 °C) was observed. Collectively, these findings underscore the potential of technical lignin as a promising bio-based curing agent for ESO.

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.

Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/- ) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4 ) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

Three new glycosides from the stems of Eurya chinensis R. Br.

Two new phenolic glycosides (1 and 2), one known analogue (3), along with a new diterpene glucoside (4) were obtained from ethanolic extract of the stems of Eurya chinensis R. Br. The structures of these isolated compounds were identified by extensive analysis of HRESIMS and NMR spectroscopic data. The cytotoxicities of these compounds were evaluated on MCF-7, A549, HepG2, CaCo2 and 5-8 F cell lines by MTT method, but no obvious activities were observed.

Three stilbenes from pigeon pea with promising anti-methicillin-resistant Staphylococcus aureus biofilm formation activity.

Cajaninstilbene acid (CSA), longistylin A (LLA), and longistylin C (LLC) are three characteristic stilbenes isolated from pigeon pea. The objective of this study was to evaluate the antibacterial activity of these stilbenes against Staphylococcus aureus and even methicillin-resistant Staphylococcus aureus (MRSA) and test the possibility of inhibiting biofilm formation. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of these stilbenes were evaluated. And the results showed that LLA was most effective against tested strains with MIC and MBC values of 1.56 µg/mL followed by LLC with MIC and MBC values of 3.12 µg/mL and 6.25 µg/mL as well as CSA with MIC and MBC values of 6.25 µg/mL and 6.25-12.5 µg/mL. Through growth curve and cytotoxicity analysis, the concentrations of these stilbenes were determined to be set at their respective 1/4 MIC in the follow-up research. In an anti-biofilm formation assay, these stilbenes were found to be effectively inhibited bacterial proliferation, biofilm formation, and key gene expressions related to the adhesion and virulence of MRSA. It is the first time that the anti-S. aureus and MRSA activities of the three stilbenes have been systematically reported. Conclusively, these findings provide insight into the anti-MRSA mechanism of stilbenes from pigeon pea, indicating these compounds may be used as antimicrobial agents or additives for food with health functions, and contribute to the development as well as application of pigeon pea in food science.

Euryachincoside, a Novel Phenolic Glycoside with Anti-Hepatic Fibrosis Activity from Eurya chinensis.

Eurya chinensis has been recorded as a folk medicine traditionally used for treatment of a variety of symptoms. However, the phytochemical and pharmacological investigations of this plant are still scarce. A novel phenolic glycoside named Euryachincoside (ECS) was isolated by chromatographic separation from E. chinensis, and its chemical structure was identified by analysis of HRMS and NMR data. Its anti-hepatic fibrosis effects were evaluated in both HSC-T6 (rat hepatic stellate cells) and carbon tetrachloride (CCl4)-induced mice with Silybin (SLB) as the positive control. In an in vitro study, ECS showed little cytotoxicity and inhibited transforming growth factor-beta (TGF-ß)-induced Collagen I (Col1) along with alpha-smooth muscle actin (α-SMA) expressions in HSC-T6. An in vivo study suggested ECS significantly ameliorated hepatic injury, secretions of inflammatory cytokines, and collagen depositions. Moreover, ECS markedly mediated Smad2/3, nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways both in vitro and vivo. These present findings confirmed that ECS is a novel phenolic glycoside from E. chinensis with promising curative effects on hepatic fibrosis, and its mechanisms may include decreasing extracellular matrix accumulation, reducing inflammation and attenuating free radicals via Smad2/3, NF-κB and Nrf2 signaling pathways, which may shed light on the exploration of more effective phenolic glycoside-based anti-fibrotic agents.

Two new withanolides from the whole plants of Physalis peruviana.

Two new withaphysalin-type withanolides (18-O-ethylwithaphysalin R and 5-O-ethylphysaminimin C, 1 and 2), along with twelve known withanolides (3-14), were purified and identified from Physalis peruviana L. The chemical structures of these new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All the obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7. Compound 7 was discovered to exhibit potent activity with an IC50 value of 3.51 µM and compounds 2, 6 and 14 showed weak cytotoxic effect.

Research on Current Drive System of Magnetorheological Damper Based on Fuzzy PI Control.

Magnetorheological dampers (MRD) are increasingly used in smart structural damping systems due to their good damping properties. In practical applications, as a nonlinear device, the parameters of the internal excitation coil of the magnetorheological damper will change during operation under the influence of the temperature and external environment, deteriorating the dynamic performance of the output current of the driver and reducing the damping effect of the system. Therefore, the current driver needs to be optimized for this phenomenon in order to ensure accurate current output. In this paper, a mathematical model of the buck circuit combined with the MRD equivalent circuit is established, and after analyzing the model, the parameters of the PI controller are rectified to lay the foundation for the design of the adaptive law. Then, with the help of the fuzzy control method, a fuzzy PI control strategy for MRD current driver is established, which enables the current driving system to adjust the control parameters adaptively when the MRD parameters change and ensure the accurate driving current output. The experimental results demonstrate that the fuzzy PI control strategy has a stronger robustness in the face of parameter changes of the control object compared with the traditional PI control at a system parameter change rate of 40%.

Peruranolides A-D, four new withanolides with potential antibacterial and cytotoxic activity from Physalis peruviana L.

BACKGROUND: Many drugs for anti-tumour have been developed, nevertheless, seeking new anticancer drug is the focus of ongoing investigation. Withanolides have been reported to possess potent antiproliferative activity. Literature findings revealed that a diversity of withanolides were obtained from Physalis peruviana, however, the antitumor activity of these bioactive compounds is still unclear. METHODS: The EtOAc fraction of P. peruviana were decolorized on Middle Chromatogram Isolated (MCI) Gel column, repeatedly subjected to column chromatography (CC) over sephadex LH-20, preparative High Performance Liquid Chromatography (HPLC) and silica gel to afford compounds. Their chemical structures of the new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All these obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7 by MTT assay, and in vitro antibacterial activity of the isolated compounds (1-7) were evaluated against E. coli, B. cereus and S. aureus. Results: Four new withanolides, including one withaphysalin-type withanolide (peruranolide A, 1), two 13,14-seco-withaphysalins (peruranolides B-C, 2-3), as well as one normal withanolide (peruranolide D, 4), were purified and separated from P. peruviana L.. Compound 5 was discovered to exhibit potent cytotoxic effect with an IC50 value of 3.51 µM. In vitro antibacterial activities, compounds 1-7 had no obvious inhibitory activity against E. coli, but had moderate inhibitory activities against B. cereus and S. aureus. CONCLUSIONS: Our findings might offer valuable clues for the utilization of withanolides as lead compounds for antineoplastic or antibacterial drug development.

Two new 7,20-epoxy-ent-kaurane diterpenoids from the aerial parts of Isodon serra.

Two new compounds (1 and 2), belonging to C-20 oxygenated ent-kauranes-type diterpenoids, were identified from the aerial parts of Isodon serra. Their structures were elucidated by extensive analysis of HRESI-MS and NMR spectroscopic data. Both these two compounds possess a common 7,20-epoxy-ent-kauranes skeleton with a hydroxyl group rarely occurring at C-13. Compounds 1 and 2 were evaluated for their cytotoxic activity against Hela-60 and HepG2 as well as the antibacterial activity against Staphylococcus aureus, Bacillus cereus and Escherichia coli.

Isolation and identification of a human intestinal bacterium capable of daidzein conversion.

Equol, which produced from daidzein (one of the principal isoflavones), is recognized to be the most resultful in stimulating an estrogenic and antioxidant response. The daidzein transformation was studied during fermentation of five growth media inoculated with feces from a healthy human, and a daidzein conversion strain was isolated. To enrich the bacterial population involved in daidzein metabolism in a complex mixture, fecal samples were treated with antibiotics. The improved propidium monoazide combined with the quantitative polymerase chain reaction (PMAxx-qPCR) assay showed that the ampicillin treatment of samples did result in a reduction of the total visible bacteria counts by 52.2% compared to the treatment without antibiotics. On this basis, the newly isolated rod-shaped, Gram-positive anaerobic bacterium, named strain Y11 (MN560033), was able to metabolize daidzein to equol under anaerobic conditions, with a conversion ratio (equol ratio: the amount of equol produced/amount of supplemented daizein) of 0.56 over 120 h. The 16S rRNA partial sequence of the strain Y11 exhibited 99.8% identity to that of Slackia equolifaciens strain DZE (NR116295). This study will provide new insights into the biotransformation of equol from daidzein by intestinal microbiota from the strain-level and explore the possibility of probiotic interventions.

Metabolomic profiling reveals serum L-pyroglutamic acid as a potential diagnostic biomarker for systemic lupus erythematosus.

OBJECTIVE: The spectrum of clinical manifestations and serological phenomena of SLE is heterogeneous among patients and even changes over time unpredictably in individual patients. For this reason, clinical diagnosis especially in complicated or atypical cases is often difficult or delayed leading to poor prognosis. Despite the medical progress nowadays in the understanding of SLE pathogenesis, disease-specific biomarkers for SLE remain an outstanding challenge. Therefore, we undertook this study to investigate potential biomarkers for SLE diagnosis. METHODS: Serum samples from 32 patients with SLE and 25 gender-matched healthy controls (HCs) were analysed by metabolic profiling based on liquid chromatography-tandem mass spectrometry metabolomics platform. The further validation for the potential biomarker was performed in an independent set consisting of 36 SLE patients and 30 HCs. RESULTS: The metabolite profiles of serum samples allowed differentiation of SLE patients from HCs. The levels of arachidonic acid, sphingomyelin (SM) 24:1, monoacylglycerol (MG) 17:0, lysophosphatidyl ethanolamine (lysoPE) 18:0, lysoPE 16:0, lysophosphatidyl choline (lysoPC) 20:0, lysoPC 18:0 and adenosine were significantly decreased in SLE patients, and the MG 20:2 and L-pyroglutamic acid were significantly increased in SLE group. In addition, L-pyroglutamic acid achieved an area under the receiver-operating characteristic curve of 0.955 with high sensitivity (97.22%) and specificity (83.33%) at the cut-off of 61.54 µM in the further targeted metabolism, indicating diagnostic potential. CONCLUSION: Serum metabolic profiling is differential between SLE patients and HCs and depicts increased L-pyroglutamic acid as a promising bitformatomarker for SLE.

Rosanortriterpenes A-B, Two Promising Agents from Rosa laevigata var. leiocapus, Alleviate Inflammatory Responses and Liver Fibrosis in In Vitro Cell Models.

Rosanortriterpenes A-B (RTA and RTB), two nortriterpenoids, are characteristic constituents in the fruits of Rosa laevigata var. leiocapus. However, pharmacological studies on these compounds are still scarce. In the present study, we aim to investigate the anti-inflammatory mechanisms associated with the effects of RTA-B in RAW264.7 macrophages and LO2 cells by detecting cell viabilities, nitric oxide (NO) production, tumour necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) production. Simultaneously, the anti-inflammatory action mechanisms of these two compounds were illustrated through western blot assay. Besides, the antihepatic fibrosis activities of these compounds have also been explored. The results demonstrated that RTA and RTB inhibited the production of NO, TNF-α, and IL-6 and suppressed liver fibrosis. RTA and RTB treatment also greatly inhibited the activation of NF-kappaB (NF-κB) pathway. Our study confirmed the promising anti-inflammatory and anti-liver fibrosis actions of RTA-B, suggesting that they might be developed as alternative and promising drugs for the treatment of hepatic inflammatory and fibrotic diseases.

Colonization Potential to Reconstitute a Microbe Community in Pseudo Germ-Free Mice After Fecal Microbe Transplant From Equol Producer.

Human intestinal microbiota plays a crucial role in the conversion of isoflavones into equol. Usually, human microbiota-associated (HMA) animal models are used, since it is difficult to establish the mechanism and causal relationship between equol and microbiota in human studies. Currently, several groups have successfully established HMA animal models that produce equol through germ-free mice or rats; however, the HMA model of producing equol through pseudo germ-free mice has not been established. The objective of this study is to establish an HMA mice model for equol production through pseudo germ-free mice, mimicking the gut microbiota of an adult human equol producer. First, a higher female equol producer was screened as a donor from 15 volunteers. Then, mice were exposed to vancomycin, neomycin sulfate, metronidazole, and ampicillin for 3 weeks to obtain pseudo germ-free mice. Finally, pseudo germ-free mice were inoculated with fecal microbiota of the equol producer for 3 weeks to establish HMA mice of producing equol. The results showed that (i) the ability to produce equol was partially transferred from the donor to the HMA mice. (ii) Most of the original intestinal microbiota of mice were eliminated after broad-spectrum antibiotic administration. (iii) The taxonomy data from HMA mice revealed similar taxa to the donor sample, and the species richness returned to the level close to the donor. (iv) The family Coriobacteriaceae and genera Collinsella were successfully transferred from the donor to HMA mice. In conclusion, the HMA mice model for equol production, based on pseudo germ-free mice, can replace the model established by germ-free mice. The model also provides a basis for studying microbiota during the conversion from isoflavones into equol.

Meta-analysis of the association between MBD4 Glu346Lys polymorphism and cancer risk.

OBJECTIVE: The purpose of this study was to systematically evaluate the association between methyl-CpG binding domain 4, DNA glycosylase (MBD4) Glu346Lys polymorphism and cancer risk. METHODS: A comprehensive document retrieval from the Chinese National Knowledge Infrastructure (CNKI), EMBASE, and PubMed databases was performed through 1 September 2019. The strength of the correlation was assessed using the pooled odds ratio (ORs) and 95% confidence interval (CIs). RESULTS: Five relevant studies were retrieved following screening, including 1804 cases and 2193 controls. We found no association between MBD4 Glu346Lys polymorphism and cancer risk under all genetic models. Nevertheless, a subgroup analysis based on country showed a strong association in the Chinese population. Under the recessive model, Chinese individuals with the Lys/Lys genotype had a higher risk of cancer (OR = 1.37, 95% CI = 1.11-1.70). CONCLUSION: Analysis of the MBD4 Glu346Lys polymorphism in different populations will help to elucidate the pathogenesis of cancer. The polymorphism can be utilized as a biomarker for cancer susceptibility among Chinese people.

Nanoplasmonically Engineered Interfaces on Amorphous TiO2 for Highly Efficient Photocatalysis in Hydrogen Evolution.

The nanoplasmonic metal-driven photocatalytic activity depends heavily on the spacing between metal nanoparticles (NPs) and semiconductors, and this work shows that ethylene glycol (EG) is an ideal candidate for interface spacer. Controlling the synthetic systems at pH 3, the composite of Ag NPs with EG-stabilized amorphous TiO2 (Ag/TiO2-3) was synthesized by the facile light-induced reduction. It is verified that EG spacers can set up suitable geometric arrangement in the composite: the twin hydroxyls act as stabilizers to bind Ag NPs and TiO2 together and the nonconductive alkyl chains consisting only of two CH2 are able to separate the two building blocks completely and also provide the shortest channels for an efficient transfer of radiation energies to reach TiO2. Employed as photocatalysts in hydrogen evolution under visible light, amorphous TiO2 hardly exhibits the catalytic activity due to high defect density, whereas Ag/TiO2-3 represents a remarkably high catalytic efficiency. The enhancement mechanism of the reaction rate is proposed by the analysis of the compositional, structural, and optical properties from a series of Ag/TiO2 composites.

New insight into the selective photocatalytic oxidation of RhB through a strategy of modulating radical generation.

Rhodamine B (RhB) has often been used as a model pollutant, but its photocatalytic mechanism is still controversial. Herein, Ag NPs were sandwiched between CdS QDs and amorphous-TiO2 (a-TiO2) with the intent to build a CdS/Ag/a-TiO2 catalyst with highly selective oxidation activity. When rhodamine B (RhB) was used as the model organic compound, the CdS/Ag/a-TiO2 composite can not only modulate radical generation but also improve the conversion ratio of RhB to rhodamine 110 (Rh-110) to as high as 82% at 80 min during the visible-light irradiation. A series of the radical scavenging experiments revealed that CdS/Ag/a-TiO2 composites could modulate the effects of hydroxyl radicals (·OH) and superoxide anion radicals (·O2 -) at different reaction stages so that the overoxidation of RhB and Rh-110 were repressed. Therefore, the transient state protection mechanism of selective oxidation of RhB was proposed to explain the reaction selectivity for Rh-110. Although the effects of both ·O2 - and ·OH are important during the photocatalytic selective oxidation of RhB, it is shown that the selective oxidation of RhB would be performed when the effect of ·O2 - is bigger than the ·OH, if not, RhB would be oxidized unselectively. Meanwhile, this may provide a new strategy for modulating radical generation in the photocatalysis of water phases.

Phospholipid-Tween 80 mixed micelles as an intravenous delivery carrier for paclitaxel.

A novel mixed micelle made of Tween 80 and soybean phospholipids (S80) was prepared and used as the delivery system for paclitaxel (PTX), with the purpose of improving the stability, therapeutic index, and security of PTX in comparison with Taxol® injection. The micelle size, morphological features, dilution stability, and critical micelle concentration (CMC) were measured. The in vitro antitumor activity, pharmacokinetics, and hemolysis effect of the optimal PTX-loaded mixed micelles (PTX-M) were evaluated and compared with Taxol®. The results showed that PTX-M was more stable than Taxol® upon dilution. PTX-M had a higher antitumor efficacy against HeLa and A549 cells than that of Taxol®. The plasma AUC of PTX-M was 1.3-fold higher than that of Taxol® and the hemolysis test revealed that PTX-M was safe for intravenous injection. In conclusion, PTX-M had a higher dilution stability and antitumor efficacy than Taxol®, but significantly reduced the toxicity while improving the bioavailability of PTX. Therefore, Tween 80-S80 mixed micelles could be a promising drug carrier for intravenous administration of PTX.