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.

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.

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.

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.

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.

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.

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.

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.

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.