Pharmacodynamic material basis and pharmacological mechanisms of Cortex Mori against diabetes mellitus.

ETHNOPHARMACOLOGICAL RELEVANCE: The application of Cortex Mori (CM) in the treatment of diabetes mellitus (DM) has been extensively documented in traditional medicine. In recent years, the chemical composition of CM has been gradually unraveled, and its therapeutic mechanism in treating DM, diabetic nephropathy, diabetic cardiomyopathy, and other related conditions has been highlighted in successive reports. However, there is no systematic study on the treatment of DM based on the chemical composition of CM. AIM OF THE STUDY: This study was conducted to systematically explore the hypoglycemic activity mechanism of CM based on its chemical composition. METHODS: The material basis of Cortex Mori extract (CME) was investigated through qualitative analyses based on liquid chromatography-mass spectrometry (LC-MS). The possible acting mechanism was simulated using network pharmacology and validated in streptozotocin (STZ) + high fat diet (HFD)-induced diabetic rats and glucosamine-induced IR-HepG2 model with the assistance of molecular docking techniques. RESULTS: A total of 39 compounds were identified in CME by the LC-MS-based qualitative analysis. In diabetic rats, it was demonstrated that CME significantly ameliorated insulin resistance, blood lipid levels, and liver injury. The network pharmacology analysis predicted five major targets, including AKT1, PI3K, FoxO1, Gsk-3ß, and PPARγ. Additionally, three key compounds (resveratrol, protocatechuic acid, and kaempferol) were selected based on their predicted contributions. The experimental results revealed that CME, resveratrol, protocatechuic acid, and kaempferol could promote the expression of AKT1, PI3K, and PPARγ, while inhibiting the expression of FoxO1 and Gsk-3ß. The molecular docking results indicated a strong binding affinity between resveratrol/kaempferol and their respective targets. CONCLUSIONS: CME contains a substantial amount of prenylated flavonoids, which may be the focal point of research on the efficacy of CM in the treatment of DM. Besides, CME is effective in controlling blood glucose and insulin resistance, improving lipid levels, and mitigating liver injury in patients with DM. Relevant mechanisms may be associated with the activation of the PI3K/Akt pathway, the inhibition of the expression of FoxO1 and Gsk-3ß, and the enhancement of PPARγ activity. This study represents the first report on the role of CME in the treatment of DM through regulating PPARγ, FoxO1, and Gsk-3ß.

Organic acid and aromatic compounds create distinctive flavor in the blackening process of jujube.

Previous studies demonstrated jujube blackening effectively increased cyclic adenosine phosphate and triterpene acid levels, improving its nutritional value. However, compositional changes during this process require further elucidation. The objective aimed to analyze compositional transformations during this process with SEM, TPA, UPLC-MS, E-nose. Results showed decreased hardness, springiness, and chewiness coupled with increased gumminess over blackening durations. Untargeted omics analysis revealed increases of 2-aminooctadec-8-ene-1,3,4-trioland carbendazim. Targeted organic acid analysis showed initial citric acid accumulation (1481.62 to 1645.78 mg/kg) in the first 24 h, then declines to 1072.96 mg/kg. Meanwhile, oxalic and lactic acids steadily rose, peaking at 96-120 h before slightly decreasing. E-nose analysis implied alterations in organic sulfide aromatics engendered the characteristic flavors. Organic acid fluctuations likely resulted from sugar biotransformation and thermal degradation. These comprehensive analyses demonstrate jujube blackening imparts a rich and unique flavor, providing theoretical support for investigating the mechanisms and products underlying this process.

CETSA and thermal proteome profiling strategies for target identification and drug discovery of natural products.

BACKGROUND: Monitoring target engagement at various stages of drug development is essential for natural product (NP)-based drug discovery and development. The cellular thermal shift assay (CETSA) developed in 2013 is a novel, broadly applicable, label-free biophysical assay based on the principle of ligand-induced thermal stabilization of target proteins, which enables direct assessment of drug-target engagement in physiologically relevant contexts, including intact cells, cell lysates and tissues. This review aims to provide an overview of the work principles of CETSA and its derivative strategies and their recent progress in protein target validation, target identification and drug lead discovery of NPs. METHODS: A literature-based survey was conducted using the Web of Science and PubMed databases. The required information was reviewed and discussed to highlight the important role of CETSA-derived strategies in NP studies. RESULTS: After nearly ten years of upgrading and evolution, CETSA has been mainly developed into three formats: classic Western blotting (WB)-CETSA for target validation, thermal proteome profiling (TPP, also known as MS-CETSA) for unbiased proteome-wide target identification, and high-throughput (HT)-CETSA for drug hit discovery and lead optimization. Importantly, the application possibilities of a variety of TPP approaches for the target discovery of bioactive NPs are highlighted and discussed, including TPP-temperature range (TPP-TR), TPP-compound concentration range (TPP-CCR), two-dimensional TPP (2D-TPP), cell surface-TPP (CS-TPP), simplified TPP (STPP), thermal stability shift-based fluorescence difference in 2D gel electrophoresis (TS-FITGE) and precipitate supported TPP (PSTPP). In addition, the key advantages, limitations and future outlook of CETSA strategies for NP studies are discussed. CONCLUSION: The accumulation of CETSA-based data can significantly accelerate the elucidation of the mechanism of action and drug lead discovery of NPs, and provide strong evidence for NP treatment against certain diseases. The CETSA strategy will certainly bring a great return far beyond the initial investment and open up more possibilities for future NP-based drug research and development.

Prospects for the application of traditional Chinese medicine network pharmacology in food science research.

There has always been a particular difficulty with in-depth research on the mechanisms of food nutrition and bioactivity. The main function of food is to meet the nutritional needs of the human body, rather than to exert a therapeutic effect. Its relatively modest biological activity makes it difficult to study from the perspective of general pharmacological models. With the popularity of functional foods and the concept of dietary therapy, and the development of information and multi-omics technology in food research, research into these mechanisms is moving towards a more microscopic future. Network pharmacology has accumulated nearly 20 years of research experience in traditional Chinese medicine (TCM), and there has been no shortage of work from this perspective on the medicinal functions of food. Given the similarity between the concept of 'multi-component-multi-target' properties of food and TCM, we think that network pharmacology is applicable to the study of the complex mechanisms of food. Here we review the development of network pharmacology, summarize its application to 'medicine and food homology', and propose a methodology based on food characteristics for the first time, demonstrating its feasibility for food research. © 2023 Society of Chemical Industry.

A comprehensive review on the ethnobotany, phytochemistry, pharmacology and quality control of the genus Lycium in China.

The Lycium genus, perennial herbs of the Solanaceae family, has been an important source of medicines and nutrient supplements for thousands of years in China, where seven species and three varieties are cultivated. Among these, Lycium barbarum L. and Lycium chinense Mill., two "superfoods", together with Lycium ruthenicum Murr, have been extensively commercialized and studied for their health-related properties. The dried ripe fruits of the genus Lycium are well recognized as functional foods for the management of various ailments including waist and knee pain, tinnitus, impotence, spermatorrhea, blood deficiency and weak eyes since ancient times. Phytochemical studies have reported numerous chemical components in the Lycium genus, categorized as polysaccharides, carotenoids, polyphenols, phenolic acids, flavonoids, alkaloids and fatty acids, and its therapeutic roles in antioxidation, immunomodulation, antitumor treatment, hepatoprotection and neuroprotection have been further confirmed by modern pharmacological studies. As a multi-functional food, the quality control of Lycium fruits has also attracted attention internationally. Despite its popularity in research, limited systematic and comprehensive information has been provided on the Lycium genus. Therefore, herein, we provide an up-to-date review of the distribution, botanical features, phytochemistry, pharmacology and quality control of the Lycium genus in China, which will provide evidence for further in-depth exploration and comprehensive utilization of Lycium, especially its fruits and active ingredients in the healthcare field.

Improved antioxidant activity of rutin via lipase-mediated esterification with oleic acid.

BACKGROUND: Oxidation is a major problem for oils and fats, which can be mitigated by antioxidants. Rutin has excellent antioxidant activity, but its poor lipid solubility greatly limits its practical application. In this study, an efficient enzymatic synthesis route of lipophilic rutin ester was established using oleic acid as an acyl donor, and the antioxidant potential of rutin oleate was evaluated for the first time by proton (1 H) nuclear magnetic resonance (NMR) spectroscopy. RESULTS: The synthesized product was finally identified as rutin oleate by Fourier transform infrared, high-performance liquid chromatography-mass spectrometry, and 1 H, carbon-13, and DEPT-135 NMR analyses, and the acylation site was the 4‴-OH of the rhamnose group in the rutin molecule. The maximum conversion was over 93% after 48 h of reaction using Novozym 435 as catalyst under the best conditions among these tests. The conversion of rutin ester decreased with the increase of carbon chain length and the number of carbon-carbon double bonds of the fatty acid molecule. Most importantly, rutin oleate exhibited antioxidant capacity comparable to butylated hydroxytoluene and its counterparts (rutin and oleic acid) at low temperatures (60° C), but had a significant advantage at high temperatures (120° C). CONCLUSION: The antioxidant activity of rutin was significantly enhanced by lipase-mediated esterification with oleic acid. Therefore, rutin oleate could be further developed as a novel antioxidant for use in oil- and fat-based foods. © 2023 Society of Chemical Industry.

Exploring the underlying mechanisms on starch restricted swelling-induced reduction in digestion rate of buckwheat noodles.

To elucidate the slower digestion rate of buckwheat starch in noodles-matrix, the digestion kinetics of Tartary (TBN) and common (CBN) buckwheat starch reconstituted noodles as well as wheat starch reconstituted noodles (WSN) were compared using a simulated oral-gastric-intestinal in vitro digestion. The swelling degree of starch in cooked noodles can be expressed by quantitative analysis of microstructure. The digestion rate of WSN was 2.3-2.9 times higher as compared to CBN and TBN. The swelling degree of starch in CBN and TBN was restricted due to their denser structure, which led to the reduction of the contact area between starch molecules and amylase. Additionally, the stronger water retention ability and higher cohesiveness of CBN and TBN could hinder the water migration, and ultimately affect the accessibility of enzymes. These results demonstrated that the restricted swelling of starch in CBN and TBN during cooking was the important reason for their slower digestibility.

The genus Porana (Convolvulaceae) - A phytochemical and pharmacological review.

There are about 20 species of Porana Burm. f. worldwide in tropical and subtropical Asia, Africa and neighboring islands, Oceania, and the Americas. In China, India, and other places, this genus enjoys a wealth of experience in folk applications. Nevertheless, the chemical composition of only five species has been reported, and 59 compounds have been isolated and identified, including steroids, coumarins, flavonoids, quinic acid derivatives, and amides. Pharmacological studies revealed that extracts from this genus and their bioactive components exhibit anti-inflammatory, analgesic, antioxidant, anti-gout, anti-cancer, and anti-diabetic effects. Although this genus is abundant, the development of its pharmacological applications remains limited. This review will systematically summarize the traditional and current uses, chemical compositions, and pharmacological activities of various Porana species. Network analysis was introduced to compare and confirm its output with current research progress to explore the potential targets and pathways of chemical components in this genus. We hope to increase understanding of this genus's medicinal value and suggest directions for rational medicinal development.

Investigation of the active ingredients and pharmacological mechanisms of Porana sinensis Hemsl. Against rheumatoid arthritis using network pharmacology and experimental validation.

BACKGROUND: Porana sinensis Hemsl. has been widely used as a substitute for Erycibes Caulis to treat rheumatoid arthritis (RA) in traditional Chinese medicine (TCM). However, little is known about the active ingredients and pharmacological mechanisms that mediate the action of P. sinensis against RA. METHODS: The compounds contained in P. sinensis were analyzed by Q Exactive Focus mass spectrometer. The active constituents and pharmacological mechanism of P. sinensis against RA were clarified using a network pharmacology-based investigation. LPS-induced RAW 264.7 cells was used to verify anti-inflammatory effects of the active compounds screened by network pharmacology. Collagen-induced arthritis model was used to further investigate the mechanism of P. sinensis against RA. RESULTS: The potential components and targets of P. sinensis against RA were analyzed using network pharmacology, and five compounds, twenty-five targets, and eight pathways were identified. Experimental validation suggested that P. sinensis extract and five compounds (esculetin, umbelliferone, trans-N-feruloyltyramine, caffeic acid and scopolin) could inhibit the release of inflammatory mediators (NO, TNF-α, IL-1ß and IL-6) in LPS-induced RAW 264.7 cell. P. sinensis extract attenuated the severity, pathological changes, and release of cytokines (IL-6 and HIF-1α) during RA progression by regulating the PI3K/AKT and HIF-1 pathways. CONCLUSION: The study provides a basis for the application of P. sinensis against RA. Our findings may provide suggestions for developing P. sinensis into a substitute for Erycibes Caulis.

Rhein regulates redox-mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage-activated crosstalk.

BACKGROUND AND PURPOSE: Macrophage infiltration and activation is a critical step during acute colitis. Redox-mediated activation of NLRP3 inflammasomes in macrophages plays a critical role in mediating colonic inflammatory responses. Rhein isolated from the rhizome of rhubarb exhibits anti-inflammatory effects in various diseases. However, its role in regulating acute colonic inflammation is unexplored. Here, we investigated the protective mechanisms of rhein during acute gut inflammation and its regulation of macrophage activation. EXPERIMENTAL APPROACH: Inhibitory effects of rhein on NLRP3 inflammasomes were evaluated in activated macrophages and a mouse model of colitis. Expression of inflammatory mediators, inflammasome complex and redox-related signalling were analysed by ELISA, Western blots, immunofluorescence staining, and qRT-PCR. The phenotype of macrophages was assessed by flow cytometry. Colonic inflammation was evaluated by histological analysis. KEY RESULTS: Rhein significantly decreased IL-1ß secretion via NLRP3 inflammasomes by disturbing their assembly in macrophages. Rhein also activated the Nrf2-HO1-NQO1 pathway and inhibited expression of Nox2 subunits and translocation to regulate redox balance. Moreover, rhein attenuated inflammatory responses by mediating macrophage polarization from M1 to M2 phenotype. NF-κB, AP-1, and MAPK signalling were also involved in improving inflammatory conditions by rhein. In mice with acute intestinal inflammation, rhein treatment attenuated clinical features and reduced macrophage infiltration into damaged tissue to alleviate colonic inflammation. CONCLUSION AND IMPLICATIONS: Rhein regulated redox-mediated NLRP3 inflammasome activation to protect against acute colitis, by interfering with macrophage accumulation and polarization. These findings provide a promising strategy of novel compounds for regulating mucosal inflammation in gastrointestinal disorders.

The dietary supplement Rhodiola crenulata extract alleviates dextran sulfate sodium-induced colitis in mice through anti-inflammation, mediating gut barrier integrity and reshaping the gut microbiome.

Rhodiola species are edible medicinal plants, which have been traditionally used in both Asia and Europe as an adaptogen, a tonic, an anti-depressant and anti-inflammatory supplement. However, whether it presents a therapeutic effect on colitis or not remains unknown. The aim of this study is to investigate the protective effect of a Rhodiola crenulata extract (RCE) on mice with DSS-induced colitis. RCE significantly alleviated the pathological abnormalities in colitic mice, including the correspondingly increased colon length, ameliorated colonic injury and reduced pro-inflammatory factors. The protective effect was similar to that of the positive control, 5-aminosalicylic acid. The DSS-induced epithelial apoptosis and maintained intestinal barrier function were attenuated by RCE through the upregulation of the level of tight junction proteins such as ZO-1 and occludin. Notably, RCE prevented gut dysbiosis in colitic mice by restoring the microbial richness and diversity, and decreasing the abundance of Proteobacteria phylum and opportunistic pathogenic Parasutterella and Staphylococcus, as well as increasing the abundance of beneficial microbes in Lactobacillus and Bifidobacterium, which were closely correlated with its protective effect against colitis. Meanwhile, chemical characterization of RCE was performed by UPLC-HR-MS to explain its material basis. A total of 63 compounds were identified, while the content of two bioactive ingredients (salidroside, 1.81%; rosavin, 0.034%) was determined.

Chemical compositions, pharmacological activities, quality control studies of Erycibes plants, and the development of their substitutes.

Erycibes are members of the Convolvulaceae family, including more than 10 species worldwide that are distributed in tropical Asia. Some Erycibes species have long been used as traditional remedies for rheumatoid arthritis, fever, hepatitis, and liver injury in China and Thailand. A total of 152 compounds from Erycibes plants have been isolated and identified, categorized as flavonoids, coumarins, quinic acid derivatives, lignans, and alkaloids. Coumarins are the characteristic and active constituents of this species, including scopoletin and scopolin. Modern pharmacological studies have shown that the extracts and bioactive components of Erycibes plants exhibit several biological activities, including antiinflammatory, analgesic, hepatoprotective, anti-gout, antitumor, antioxidation, and other therapeutic effects. However, in recent years, due to destructive exploitation and utilization, some Erycibes plants' natural resources have become rare or endangered. Developing substitutes is a strategy to alleviate the pressure on those endangered medicinal plant resources. To provide a scientific basis for the development and protection of those threatened Erycibes species, this review summarized the current status of the chemical compositions, pharmacological activities, quality control studies, and the development of substitutes for Erycibes plants. In particular, the rationale for use of Porana sinensis currently on the market is discussed.

A Comprehensive Summary of the Knowledge on COVID-19 Treatment.

Currently, the world is challenged by the coronavirus disease 2019 (COVID-19) pandemic. Epidemiologists and researchers worldwide are invariably trying to understand and combat this precarious new disease. Scrutinizing available drug options and developing potential new drugs are urgent needs to subdue this pandemic. Several intervention strategies are being considered and handled worldwide with limited success, and many drug candidates are yet in the trial phase. Despite these limitations, the development of COVID-19 treatment strategies has been accelerated to improve the clinical outcome of patients with COVID-19, and some countries have efficiently kept it under control. Recently, the use of natural and traditional medicine has also set the trend in coronavirus treatment. This review aimed to discuss the prevailing COVID-19 treatment strategies available globally by examining their efficacy, potential mechanisms, limitations, and challenges in predicting a future potential treatment candidate and bridging them with the effective traditional Chinese medicine (TCM). The findings might enrich the knowledge on traditional alternative medication and its complementary role with Western medicine in managing the COVID-19 epidemic.

Review and Prospect of Tissue-agnostic Targeted Strategies in Anticancer Therapies.

Due to the increasing prevalence of cancer year by year, and the complexity and refractory nature of the disease itself, it is required to constantly innovate the development of new cancer treatment schemes. At the same time, the understanding of cancers has deepened, from the use of chemotherapy regimens with high toxicity and side effects, to the popularity of targeted drugs with specific targets, to precise treatments based on tumor characteristics rather than traditional anatomical location classification. In precision medicine, in the view of the specific cancer diseases and their biological characteristics, there is a great potential to develop tissue-agnostic targeted therapy with broad-spectrum anticancer significance. The present review has discussed tissue-agnostic targeted therapy based on the biological and genetic characteristics of cancers, expounded its theoretical basis and strategies for drug development. In addition, the feasible drug targets, FDA-approved drugs, as well as drug candidates in clinical trials have also been summarized. In conclusion, the "tissue-agnostic targeted therapy" is a breakthrough in anticancer therapies.

Anti-inflammatory activities of Sigesbeckia glabrescens Makino: combined in vitro and in silico investigations.

BACKGROUND: Sigesbeckia glabrescens Makino (SG) is one of the important plant origins of Sigesbeckiae herba and has been widely used for the treatment of chronic inflammatory diseases in China. However, the underlying anti-inflammatory mechanism of SG is rarely investigated and reported. There are more than 40 kinds of chemical constituents in SG, but the action of the bioactive compounds of SG is still unclear. Therefore, we aimed to systemically investigate the mechanisms behind the anti-inflammatory properties of SG by combining in vitro and in silico investigations. METHODS: Cytotoxicity was measured using the 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Nitric oxide (NO) release was detected using the Griess assay. The secretion of pro-inflammatory cytokines and the expression of relevant proteins were assessed using ELISA kits and Western blots, respectively. Molecular docking was performed and scored using AutoDock via a comparison with the molecular docking of N-acetyl-d-glucosamine (NAG). RESULTS: In lipopolysaccharides (LPS)-stimulated macrophages, SG significantly inhibited NO, MCP-1, and IL-6 secretion; iNOS expression; and NF-κB activation but did not significantly affect MAPK signalling (p38, ERK, and JNK). Moreover, the results from the molecular docking prediction suggested that over 10 compounds in SG could likely target TLR4, p105, and p65. CONCLUSIONS: These findings suggest that the anti-inflammatory effects of SG are highly related to the inactivation of NF-κB. Moreover, this study provides a novel approach to investigate the effects of herbal medicine using combined in vitro and in silico investigations.

The anti-inflammatory potential of Portulaca oleracea L. (purslane) extract by partial suppression on NF-κB and MAPK activation.

Portulaca oleracea L. (Purslane) has great potential as food and traditional drugs in several countries. The purpose of this study was to evaluate the anti-inflammatory effects of purslane extract on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Purslane extracts significantly reduced LPS-induced synthesis of NO in a dose-dependent manner, as well as the expression levels of iNOS and COX-2. The productions of TNF-α and IL-6 were also significantly reduced at the higher dose of 400 µg/ml. Meanwhile, the expression levels of P65, p-P65, p-MEK and p-IκB-α were inhibited dose-dependently. The nuclear translocation of P65 was partially prevented by the extract, which explained the inhibition of NF-κB pathway. In addition, three reported flavonoids, named luteolin, kaempferol and quercitrin, were identified in the extract, which might be responsible for its anti-inflammatory effects. Above all, our research has partially proved that purslane could be considered as a natural anti-inflammatory agent in further applications.

Chinese herb pair Paeoniae Radix Alba and Atractylodis Macrocephalae Rhizoma suppresses LPS-induced inflammatory response through inhibiting MAPK and NF-κB pathway.

BACKGROUND: The combination of Radix Paeoniae Alba (RPA) and Rhizoma Atractylodis Macrocephalae (RAM) has long been used as a classic herb pair for the treatment of gynecologic and gastrointestinal diseases, but the underlying mechanisms of the herb pair remain unknown. This study aims to explore the anti-inflammatory potentials of RPA-RAM herb pair and to elucidate the underlying mechanisms. METHODS: The bioactive parts of RPA-RAM were extracted and screened through the inhibitory effects against nitric oxide (NO) production. The effects of optimized RPA-RAM extracts (OPAE) on inflammation-associated mediators were investigated by Western blotting, real-time quantitative PCR (RT-qPCR), Enzyme-linked immunosorbent (ELISA) and immunofluorescence staining. RESULTS: OPAE potently suppressed the productions of NO, TNF-α, IL-6 and MCP-1 in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, concentration-dependently inhibited protein level of inducible nitric oxide synthase (iNOS), dramatically downregulated mRNA expression of iNOS, TNF-α, IL-6 and MCP-1. In addition, OPAE significantly prevented phosphorylation and degradation of inhibitory kappa Bα (IκBα) and subsequently restrained the nuclear translocation of NF-κB p65. Pretreatment with OPAE also attenuated the LPS-induced phosphorylation of ERK, JNK and p38. CONCLUSIONS: Our findings demonstrated that OPAE suppressed inflammatory responses in LPS-stimulated RAW 264.7 macrophages by decreasing critical molecules involved in MAPK and NF-κB pathway, suggesting that the herb pair could be a promising therapeutic candidate for inflammation-related diseases.

Rhodiola species: A comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study.

Rhodiola species, belonging to the family Crassulaceae, have long been used as an adaptogen, tonic, antidepressant, and antistress medicine or functional food in Asia and Europe. Due to the valuable application, the growing demand of Rhodiola species has led to a rapid decrease in resource content. This review aims to summarize the integrated research progress of seven mainstream Rhodiola species. We first outline both traditional and current use of Rhodiola for the treatment of various diseases. A detailed summary and comparison of chemical, pharmacological, toxicological, and clinical studies of various Rhodiola species highlight recent scientific advances and gaps, which gives insights into the understanding of Rhodiola application and would be helpful to improve the situation of biological resources and diversities of Rhodiola plants.

Metabolomics study of the anti-inflammatory effects of endogenous omega-3 polyunsaturated fatty acids.

Low-grade inflammation is usually defined as the chronic production and a low-grade state of inflammatory factors, it often does not have symptoms, and has been associated with neurodegenerative disease, obesity, and diabetes. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are the precursors of many anti-inflammatory metabolites, such as resolvins and neuroprotectins. It is of interest to study the metabolic profile of endogenous n-3 PUFAs in low-grade inflammatory conditions. To evaluate the protective effects of endogenous n-3 PUFAs on low-grade inflammation with the metabolomics approach, we fed fat-1 mice with an n-6 PUFAs rich diet for a long time to induce a low-grade inflammatory condition. Multi-analysis techniques, including structural analysis using quadrupole time-of-flight mass spectrometry with MSE mode, were applied in untargeted metabolomics to search for meaningful metabolites with significant variance in fat-1 mice under low-grade inflammation. Following the untargeted metabolomics screening, several meaningful metabolites were selected which were associated with anti-inflammatory effects generated from endogenous n-3 PUFAs for further analysis. The results revealed that the purine metabolism, fatty acid metabolism and oxidative stress response pathways through insulin resistance were involved in anti-inflammatory mechanisms of n-3 PUFA in low-grade inflammatory conditions. For the first time, this study explored the highlighted pathways as contributors to the anti-inflammatory effects of endogenous n-3 PUFAs in low-grade inflammatory conditions.

Gambogic acid sensitizes breast cancer cells to TRAIL-induced apoptosis by promoting the crosstalk of extrinsic and intrinsic apoptotic signalings.

Due to the ability of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to induce cancer cell apoptosis selectively, TRAIL has attracted significant interest in the treatment of cancer. However, although TRAIL triggers apoptosis in a broad range of cancer cells, most primary cancers are often intrinsically TRAIL-resistant, or can acquire resistance after TRAIL treatment, evocating new strategies to overcome TRAIL resistance. Gambogic acid (GA), an active constituent of Garcinia Hanburyi (Teng Huang in Chinese), has been applied for thousands of years for medicinal uses, however, the potential effect of GA in combating cancer resistance remains poorly investigated. In this study, we found that GA could increase the sensitivity of breast cancer cells to TRAIL and enhance TRAIL-induced apoptosis. GA cooperated with TRAIL to decrease the levels of anti-apoptotic proteins and activate Bid (BH3 interacting-domain death agonist) to promote the crosstalk of extrinsic and intrinsic apoptotic signaling, rather than increasing the expression of TRAIL receptors DR4 and DR5. These findings may open a new window in the treatment of breast cancer using TRAIL in combination with GA.