Efficient and Selective Extraction of Rhamnogalacturonan-I-Enriched Pectic Polysaccharides from Tartary Buckwheat Leaves Using Deep-Eutectic-Solvent-Based Techniques.

Tartary buckwheat green leaves are considered to be among the most important by-products in the buckwheat industry. Although Tartary buckwheat green leaves are abundant in pectic polysaccharides, their potential applications in the food industry are quite scarce. Therefore, to promote their potential applications as functional or fortified food ingredients, both deep-eutectic-solvent-assisted extraction (DESE) and high-pressure-assisted deep eutectic solvent extraction (HPDEE) were used to efficiently and selectively extract pectic polysaccharides from Tartary buckwheat green leaves (TBP). The results revealed that both the DESE and HPDEE techniques not only improved the extraction efficiency of TBP but also regulated its structural properties and beneficial effects. The primary chemical structures of TBP extracted using different methods were stable overall, mainly consisting of homogalacturonan and rhamnogalacturonan-I (RG-I) pectic regions. However, both the DESE and HPDEE methods could selectively extract RG-I-enriched TBP, and the proportion of the RG-I pectic region in TBP obviously improved. Additionally, both the DESE and HPDEE methods could improve the antioxidant and anti-glycosylation effects of TBP by increasing its proportion of free uronic acids and content of bound polyphenolics and reducing its molecular weight. Moreover, both the DESE and HPDEE methods could partially intensify the immunostimulatory effect of TBP by increasing its proportion of the RG-I pectic region. These findings suggest that DES-based extraction techniques, especially the HPDEE method, can be promising techniques for the efficient and selective extraction of RG-I-enriched TBP.

Tumor Microenvironment ROS/pH Cascade-Responsive Supramolecular Nanoplatform with ROS Regeneration Property for Enhanced Hepatocellular Carcinoma Therapy.

The low targeted drug delivery efficiency, including poor tumor accumulation and penetration and uncontrolled drug release, leads to the failure of cancer therapy. Herein, a multifunctional supramolecular nanoplatform loading triptolide (TPL/PBAETK@GA NPs) was fabricated via the host-guest interaction between glycyrrhetinic-acid-modified poly(ethylene glycol)-adamantanecarboxylic acid moiety and reactive oxygen species (ROS)/pH cascade-responsive copolymer poly(ß-amino esters)-thioketal (TK)-ß-cyclodextrin. TPL/PBAETK@GA NPs could accumulate in hepatocellular carcinoma (HCC) tissue effectively, mediated by nanoscale advantage and GA' recognition to specific receptors. The elevated concentration of ROS in tumor microenvironment (TME) quickly breaks the TK linkages, causing the detachment of shell (cyclodextrin) CD layer. Then, the accompanying negative-to-positive charge-reversal of NPs was realized via the PBAE moiety protonation under the slightly acidic TME, significantly enhancing the NPs' cellular internalization. Remarkably, the pH-responsive endo/lysosome escape of PBAE core triggered intracellular TPL burst release, promoting the cancer cell apoptosis, autophagy, and intracellular ROS generation, leading to the self-amplification of ROS in TME. Afterward, the ROS positive-feedback loop was generated to further promote size-shrinkage and charge-reversal of NPs. Both in vitro and in vivo tests verified that TPL/PBAETK@GA NPs produced a satisfactory anti-HCC therapy outcome. Collectively, this study offers a potential appealing paradigm to enhance TPL-based HCC therapy outcomes via multifunctionalized supramolecular nanodrugs.

Efficient extraction of pectic polysaccharides from thinned unripe kiwifruits by deep eutectic solvent-based methods: Chemical structures and bioactivities.

To promote the potentially industrial applications of thinned unripe kiwifruits, two deep eutectic solvent-based methods, including deep eutectic solvent-assisted extraction (DAE) and microwave-assisted deep eutectic solvent extraction (MDE), were optimized for the extraction of polysaccharides from thinned unripe kiwifruits (YKP). Results showed that the yields of YKP-D prepared by DAE and YKP-DM prepared by MDE were extremely higher than YKP-H prepared by hot water extraction. Furthermore, YKP-H, YKP-D, and YKP-DM were mainly composed of pectic polysaccharides, including homogalacturonan (HG) and rhamnogalacturonan I (RG I) domains. Besides, both YKP-D and YKP-DM exhibited stronger antioxidant, anti-glycosylation, and immunomodulatory effects than those of YKP-H, and their higher contents of uronic acids and bound polyphenols as well as lower molecular weights could partially contribute to their bioactivities. Overall, these results revealed that the developed MDE method could be utilized as a promising method for highly efficient extraction of YKP with superior beneficial effects.

Polyphenol-enriched Penthorum chinense Pursh ameliorates alcohol-related liver injury through Ras/Raf/MEK/ERK pathway: Integrating network pharmacology and experiment validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Penthorum chinense Pursh (PCP) has acknowledged as an edible herbal medicinal plant for the prevention and treatment of alcoholic liver injury (ALI). However, only few of researches focus on the chemical material basis and potential mechanisms of PCP against ALI. AIM OF THE STUDY: Herein, we explored the therapeutic effects of PCP extract against ALI based on the integration of network pharmacology, molecular docking, and experiment validation. METHODS: Based on the standard quality control of PCP herbs by UPLC fingerprint and quantitative determination, 80% ethanol extract fraction of PCP containing more polyphenols, compared to aqueous extract fraction of PCP, were chosen for further experiments. After oral administration of PCP ethanol extract, serum pharmacochemistry based on UPLC-Q-Exactive-MS analysis was implemented to evaluate the potential effective compounds. These absorbed prototypes in PCP were used to construct network pharmacology and predict the potential mechanisms of PCP extract against ALI. Then, the predicted targets and biological mechanisms of PCP extract were validated using animal experiments and molecular docking analysis. RESULTS: Although totally 19 polyphenol compounds were identified in PCP ethanol extract by UPLC-MS analysis, only 18 absorbed prototypes were found in the serum collected from mice at 1 h post-administration with PCP extract. These candidate active compounds were further screened into 13 compounds to construct network pharmacology and 433 targets were identified as PCP targets. GO and KEGG pathway enrichment analyses indicated that the effects of PCP extract would involve in Ras signaling pathway. The animal experiments on chronic ALI model mice shown that the oral administration of PCP can alleviate ALI by attenuating hepatic oxidative stress, inflammation and down-regulating the target proteins in Ras/Raf/MEK/ERK pathway. Molecular docking analysis revealed the good binding ability between the three polyphenols (i.e. quercetin, apigenin, thonningianin B) in PCP with the top contribution in network pharmacology, and these target proteins (Ras, Raf, MEK1/2, and ERK1/2). CONCLUSION: Our results clarified that PCP ethanol extract could effectively alleviate ALI by down-regulating Ras/Raf/MEK/ERK signaling pathway promisingly. Quercetin, apigenin, and thonningianin B may be the active compounds of PCP, attributing to the intervention benefits of PCP against ALI.

Structural properties and biological activities of soluble dietary fibers rich in pectic-polysaccharides from different buckwheat green leaves.

Buckwheat green leaves are commonly consumed as functional tea materials due to their various beneficial effects. Although buckwheat green leaves have abundant soluble dietary fibers (SDFs), the information about their structural properties and functional properties remains unknown, largely hindering their applications as functional/health products. Hence, to enhance the usage and application of SDFs from buckwheat green leaves as value-added health products, the structures and biological activities of SDFs derived from different buckwheat green leaves were investigated and compared. Results revealed that SDFs derived from Tartary buckwheat green leaves (TBSDF) and common buckwheat green leaves (CBSDF) were rich in complex pectic-polysaccharides, mainly composing of homogalacturonan (HG) and rhamnogalacturonan I (RG I) pectic domains. Besides, TBSDF had higher proportion of RG I pectic domains than that of CBSDF. Furthermore, the existence of a high content of complex pectic-polysaccharides in TBSDF and CBSDF could contribute to their various biological activities, such as antioxidant, antiglycation, fat/bile acid binding, anticancer, and prebiotic effects. These results can provide some new insights into further development of buckwheat green leaves and related SDFs as value-added health products.

Ultrasound-Assisted Deep Eutectic Solvent Extraction of Phenolic Compounds from Thinned Young Kiwifruits and Their Beneficial Effects.

Fruit thinning is a common practice employed to enhance the quality and yield of kiwifruits during the growing period, and about 30-50% of unripe kiwifruits will be thinned and discarded. In fact, these unripe kiwifruits are rich in nutrients and bioactive compounds. Nevertheless, the applications of thinned young kiwifruits and related bioactive compounds in the food and functional food industry are still limited. Therefore, to promote the potential applications of thinned young kiwifruits as value-added health products, the extraction, characterization, and evaluation of beneficial effects of phenolic compounds from thinned young fruits of red-fleshed Actinidia chinensis cv 'HY' were examined in the present study. A green and efficient ultrasound-assisted deep eutectic solvent extraction (UADE) method for extracting phenolic compounds from thinned young kiwifruits was established. A maximum yield (105.37 ± 1.2 mg GAE/g DW) of total phenolics extracted from thinned young kiwifruits by UADE was obtained, which was significantly higher than those of conventional organic solvent extraction (CSE, about 14.51 ± 0.26 mg GAE/g DW) and ultrasound-assisted ethanol extraction (UAEE, about 43.85 ± 1.17 mg GAE/g DW). In addition, 29 compounds, e.g., gallic acid, chlorogenic acid, neochlorogenic acid, catechin, epicatechin, procyanidin B1, procyanidin B2, quercetin-3-rhamnoside, and quercetin-3-O-glucoside, were identified in the kiwifruit extract by UPLC-MS/MS. Furthermore, the contents of major phenolic compounds in different kiwifruit extracts prepared by conventional organic solvent extraction (EE), ultrasound-assisted ethanol extraction (UEE), and ultrasound-assisted deep eutectic solvent extraction (UDE) were compared by HPLC analysis. Results revealed that the content of major phenolics in UDE (about 15.067 mg/g DW) was significantly higher than that in EE (about 2.218 mg/g DW) and UEE (about 6.122 mg/g DW), suggesting that the UADE method was more efficient for extracting polyphenolics from thinned young kiwifruits. In addition, compared with EE and UEE, UDE exhibited much higher antioxidant and anti-inflammatory effects as well as inhibitory effects against α-glucosidase and pancreatic lipase, which were closely associated with its higher content of phenolic compounds. Collectively, the findings suggest that the UADE method can be applied as an efficient technique for the preparation of bioactive polyphenolics from thinned young kiwifruits, and the thinned young fruits of red-fleshed A. chinensis cv 'HY' have good potential to be developed and utilized as functional foods and nutraceuticals.

A Comprehensive Review of Pea (Pisum sativum L.): Chemical Composition, Processing, Health Benefits, and Food Applications.

Pisum sativum L., commonly referred to as dry, green, or field pea, is one of the most common legumes that is popular and economically important. Due to its richness in a variety of nutritional and bioactive ingredients, the consumption of pea has been suggested to be associated with a wide range of health benefits, and there has been increasing focus on its potential as a functional food. However, there have been limited literature reviews concerning the bioactive compounds, health-promoting effects, and potential applications of pea up to now. This review, therefore, summarizes the literature from the last ten years regarding the chemical composition, physicochemical properties, processing, health benefits, and potential applications of pea. Whole peas are rich in macronutrients, including proteins, starches, dietary fiber, and non-starch polysaccharides. In addition, polyphenols, especially flavonoids and phenolic acids, are important bioactive ingredients that are mainly distributed in the pea coats. Anti-nutritional factors, such as phytic acid, lectin, and trypsin inhibitors, may hinder nutrient absorption. Whole pea seeds can be processed by different techniques such as drying, milling, soaking, and cooking to improve their functional properties. In addition, physicochemical and functional properties of pea starches and pea proteins can be improved by chemical, physical, enzymatic, and combined modification methods. Owing to the multiple bioactive ingredients in peas, the pea and its products exhibit various health benefits, such as antioxidant, anti-inflammatory, antimicrobial, anti-renal fibrosis, and regulation of metabolic syndrome effects. Peas have been processed into various products such as pea beverages, germinated pea products, pea flour-incorporated products, pea-based meat alternatives, and encapsulation and packing materials. Furthermore, recommendations are also provided on how to better utilize peas to promote their development as a sustainable and functional grain. Pea and its components can be further developed into more valuable and nutritious products.

Individual or mixing extrusion of Tartary buckwheat and adzuki bean: Effect on quality properties and starch digestibility of instant powder.

Introduction: Tartary buckwheat and adzuki bean, which are classified as coarse grain, has attracted increasing attention as potential functional ingredient or food source because of their high levels of bioactive components and various health benefits. Methods: This work investigated the effect of two different extrusion modes including individual extrusion and mixing extrusion on the phytochemical compositions, physicochemical properties and in vitro starch digestibility of instant powder which consists mainly of Tartary buckwheat and adzuki bean flour. Results: Compared to mixing extrusion, instant powder obtained with individual extrusion retained higher levels of protein, resistant starch, polyphenols, flavonoids and lower gelatinization degree and estimated glycemic index. The α-glucosidase inhibitory activity (35.45%) of the instant powder obtained with individual extrusion was stronger than that obtained with mixing extrusion (26.58%). Lower levels of digestibility (39.65%) and slower digestion rate coefficient (0.25 min-1) were observed in the instant powder obtained with individual extrusion than in mixing extrusion (50.40%, 0.40 min-1) by logarithm-of-slope analysis. Moreover, two extrusion modes had no significant impact on the sensory quality of instant powder. Correlation analysis showed that the flavonoids were significantly correlated with physicochemical properties and starch digestibility of the instant powder. Discussion: These findings suggest that the instant powder obtained with individual extrusion could be used as an ideal functional food resource with anti-diabetic potential.

Meta-analysis reveals Helicobacter pylori mutual exclusivity and reproducible gastric microbiome alterations during gastric carcinoma progression.

Accumulating evidence shows that the gastric bacterial community may contribute to the development of gastric cancer (GC). However, the reported alterations of gastric microbiota were not always consistent among the literature. To assess reproducible signals in gastric microbiota during the progression of GC across studies, we performed a meta-analysis of nine publicly available 16S datasets with standard tools of the state-of-the-art. Despite study-specific batch effect, significant changes in the composition of the gastric microbiome were found during the progression of gastric carcinogenesis, especially when the Helicobacter pylori (HP) reads were removed from analyses to mitigate its compositional effect as they accounted for extremely large proportions of sequencing depths in many gastric samples. Differential microbes, including Fusobacterium, Leptotrichia, and several lactic acid bacteria such as Bifidobacterium, Lactobacillus, and Streptococcus anginosus, which were frequently and significantly enriched in GC patients compared with gastritis across studies, had good discriminatory capacity to distinguish GC samples from gastritis. Oral microbes were significantly enriched in GC compared to precancerous stages. Intriguingly, we observed mutual exclusivity of different HP species across studies. In addition, the comparison between gastric fluid and mucosal microbiome suggested their convergent dysbiosis during gastric disease progression. Taken together, our systematic analysis identified novel and consistent microbial patterns in gastric carcinogenesis.

Ar-turmerone suppresses Aspergillus flavus growth and aflatoxin accumulation: Finding a new antifungal agent based on stored maize.

Aspergillus flavus (A. flavus) is a common saprophytic pathogenic fungus that produces toxic and carcinogenic aflatoxins prone to contaminate food. Here, we optimized the synthesis method of Ar-turmerone, the main active ingredient in turmeric essential oil, improved its yield and reduced the operation requirements. Moreover, 50.0 µg/mL Ar-turmerone 100.0 % inhibited the colonies growth, spore germination, mycelium biomass and aflatoxin accumulation in 7 days. 2,018 differentially expressed genes (DEGs) such as catA, ppoC, erg7, erg6 and aflO related to the A. flavus growth and aflatoxin product were significantly downregulated including 45 DEGs were 100.0 % suppressed. Besides, Ar-turmerone greatly reduced A. flavus in maize, the optimal storage conditions for maize to avoid A. flavus contamination were determined as 0.940 aw, 400.0 µg/mL Ar-turmerone, and 16.0 °C. Satisfactory odor, luster, taste, and mildew in maize observed after three weeks of storage under the optimal conditions. Thus, Ar-turmerone can be used as a potential food antifungal agent against A. flavus growth and aflatoxin accumulation during food storage.

Physicochemical characteristics and biological activities of soluble dietary fibers isolated from the leaves of different quinoa cultivars.

Quinoa leaf is consumed as a promising value-added vegetable in the diet. Although quinoa leaf is rich in soluble dietary fibers, the knowledge regarding their chemical structures and biological activities is still limited, which astricts their application in the functional food industry. Thus, to improve the precise use and application of soluble dietary fibers (SDFs) isolated from quinoa leaves in the food industry, the physicochemical structures and bioactivities of SDFs isolated from different quinoa leaves were systematically investigated. Results indicated that quinoa leaves were rich in SDFs, ranging from 3.30 % to 4.55 % (w/w). Quinoa SDFs were mainly composed of acidic polysaccharides, such as homogalacturonan and rhamnogalacturonan I, which had the molecular weights in the range of 4.228 × 104 -7.059 × 104 Da. Besides, quinoa SDFs exerted potential in vitro antioxidant activities, lipid and bile acid-adsorption capacities, immunoregulatory activities, and prebiotic effects, which might be partially associated with their molecular mass, content of uronic acid, and content of bound polyphenol. Collectively, these findings are beneficial to better understanding the chemical structures and bioactivities of SDFs extracted from different quinoa leaves, which can also provide a scientific basis for developing quinoa SDFs into functional foods in the food industry.

Bioactive compounds, health benefits, and industrial applications of Tartary buckwheat (Fagopyrum tataricum).

Tartary buckwheat belongs to the family Polygonaceae, which is a traditionally edible and medicinal plant. Due to its various bioactive compounds, the consumption of Tartary buckwheat is correlated to a wide range of health benefits, and increasing attention has been paid to its potential as a functional food. This review summarizes the main bioactive compounds and important bioactivities and health benefits of Tartary buckwheat, emphasizing its protective effects on metabolic diseases and relevant molecular mechanisms. Tartary buckwheat contains a wide range of bioactive compounds, such as flavonoids, phenolic acids, triterpenoids, phenylpropanoid glycosides, bioactive polysaccharides, and bioactive proteins and peptides, as well as D-chiro-inositol and its derivatives. Consumption of Tartary buckwheat and Tartary buckwheat-enriched products is linked to multiple health benefits, e.g., antioxidant, anti-inflammatory, antihyperlipidemic, anticancer, antidiabetic, antiobesity, antihypertensive, and hepatoprotective activities. Especially, clinical studies indicate that Tartary buckwheat exhibits remarkable antidiabetic activities. Various tartary buckwheat -based foods presenting major health benefits as fat and blood glucose-lowering agents have been commercialized. Additionally, to address the safety concerns, i.e., allergic reactions, heavy metal and mycotoxin contaminations, the quality control standards for Tartary buckwheat and its products should be drafted and completed in the future.

Effects of various degrees of esterification on antioxidant and immunostimulatory activities of okra pectic-polysaccharides.

Pectic-polysaccharides are considered as one of the most abundant bioactive components in okra, which possess various promising health-promoting effects. However, the knowledge regarding the structure-bioactivity relationship of okra pectic-polysaccharides (OPP) is still limited. In this study, effects of various degrees of esterification (DEs) on in vitro antioxidant and immunostimulatory activities of OPP were analyzed. Results displayed that OPP with high (42.13%), middle (25.88%), and low (4.77%) DE values were successfully prepared by mild alkaline de-esterification, and their primary chemical structures (compositional monosaccharide and glycosidic linkage) and molecular characteristics (molecular weight distribution, particle size, and rheological property) were overall stable. Additionally, results showed that the notable decrease of DE value did not significantly affect antioxidant activities [2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) and nitric oxide (NO) radical scavenging abilities as well as ferric reducing antioxidant power (FRAP)] of OPP, suggesting that the DE was not closely related to its antioxidant activity. In fact, the slight decrease of antioxidant activity of OPP after the alkaline de-esterification might be attributed to the slight decrease of uronic acid content. Nevertheless, the immunostimulatory effect of OPP was closely related to its DE, and a suitable degree of acetylation was beneficial to its in vitro immunostimulatory effect. Besides, the complete de-acetylation resulted in a remarkable reduction of immune response. The findings are beneficial to better understanding the effect of DE value on antioxidant and immunomodulatory activities of OPP, which also provide theoretical foundations for developing OPP as functional foods or health products.

Pressurized hot water extraction, structural properties, biological effects, and in vitro microbial fermentation characteristics of sweet tea polysaccharide.

Although sweet tea is rich in bioactive polysaccharides, the knowledge regarding their structures, bioactivities, and gut microbial metabolism is still limited. Therefore, in order to promote the application of sweet tea polysaccharide (STP) in the food industry, the pressurized hot water extraction (PHWE) of STP was optimized, and its structural properties and biological effects as well as microbial fermentation characteristics were investigated. The maximum extraction yield (4.64 % ± 0.03 %) of STP extracted by PHWE was obtained under the optimal conditions. Both homogalacturonan and arabinogalactan might exist as major polysaccharide fragments in STP. Additionally, STP exerted obviously in vitro antioxidant, anti-diabetic, and immunostimulatory effects, which might be related to its chemical properties, such as uronic acids, conjugated polyphenolics, and esterification degree. Furthermore, STP could be consumed by intestinal microbiota, and its fermentability was about 54 % at the end stage of fecal fermentation. Indeed, STP could modulate the microbial composition via improving the growth of several beneficial microbes, causing the release of beneficial short-chain fatty acids. Collectively, the findings indicate that the PHWE is an efficient method for extracting bioactive polysaccharides from sweet tea, and results can also provide a scientific basis for developing STP into functional foods or functional ingredients.

Research progress on natural ß-glucan in intestinal diseases.

ß-Glucan, an essential natural polysaccharide widely distributed in cereals and microorganisms, exhibits extensive biological activities, including immunoregulation, anti-inflammatory, antioxidant, antitumor properties, and flora regulation. Recently, increasing evidence has shown that ß-glucan has activities that may be useful for treating intestinal diseases, such as inflammatory bowel disease (IBD), and colorectal cancer. The advantages of ß-glucan, which include its multiple roles, safety, abundant sources, good encapsulation capacity, economic development costs, and clinical evidence, indicate that ß-glucan is a promising polysaccharide that could be developed as a health product or medicine for the treatment of intestinal disease. Unfortunately, few reports have summarized the progress of studies investigating natural ß-glucan in intestinal diseases. This review comprehensively summarizes the structure-activity relationship of ß-glucan, its pharmacological mechanism in IBD and colorectal cancer, its absorption and transportation mechanisms, and its application in food, medicine, and drug delivery, which will be beneficial to further understand the role of ß-glucan in intestinal diseases.

Microwave-Assisted Deep Eutectic Solvent Extraction, Structural Characteristics, and Biological Functions of Polysaccharides from Sweet Tea (Lithocarpus litseifolius) Leaves.

The leaf of sweet tea (Lithocarpus litseifolius) is widely used as an edible and medicinal plant in China, which is rich in bioactive polysaccharides. In order to explore and promote the application of sweet tea polysaccharides in the functional food industry, the microwave-assisted deep eutectic solvent extraction (MDAE) of polysaccharides from sweet tea leaves was optimized, and the structural properties and biological functions of sweet tea polysaccharides prepared by MDAE (P-DM) were investigated and compared with that of hot water extraction (P-W). The maximum yield (4.16% ± 0.09%, w/w) of P-DM was obtained under the optimal extraction conditions (extraction time of 11.0 min, extraction power of 576.0 W, water content in deep eutectic solvent of 21.0%, and liquid-solid ratio of 29.0 mL/g). Additionally, P-DM and P-W possessed similar constituent monosaccharides and glycosidic bonds, and the homogalacturonan (HG) and arabinogalactan (AG) might exist in both P-DM and P-W. Notably, the lower molecular weight, higher content of total uronic acids, and higher content of conjugated polyphenols were observed in P-DW compared to P-W, which might contribute to its much stronger in vitro antioxidant, anti-diabetic, antiglycation, and prebiotic effects. Besides, both P-DW and P-W exhibited remarkable in vitro immunostimulatory effects. The findings from the present study indicate that the MDAE has good potential to be used for efficient extraction of bioactive polysaccharides from sweet tea leaves and P-DM can be developed as functional food ingredients in the food industry.

Cancer type classification using plasma cell-free RNAs derived from human and microbes.

The utility of cell-free nucleic acids in monitoring cancer has been recognized by both scientists and clinicians. In addition to human transcripts, a fraction of cell-free nucleic acids in human plasma were proven to be derived from microbes and reported to have relevance to cancer. To obtain a better understanding of plasma cell-free RNAs (cfRNAs) in cancer patients, we profiled cfRNAs in ~300 plasma samples of 5 cancer types (colorectal cancer, stomach cancer, liver cancer, lung cancer, and esophageal cancer) and healthy donors (HDs) with RNA-seq. Microbe-derived cfRNAs were consistently detected by different computational methods when potential contaminations were carefully filtered. Clinically relevant signals were identified from human and microbial reads, and enriched Kyoto Encyclopedia of Genes and Genomes pathways of downregulated human genes and higher prevalence torque teno viruses both suggest that a fraction of cancer patients were immunosuppressed. Our data support the diagnostic value of human and microbe-derived plasma cfRNAs for cancer detection, as an area under the ROC curve of approximately 0.9 for distinguishing cancer patients from HDs was achieved. Moreover, human and microbial cfRNAs both have cancer type specificity, and combining two types of features could distinguish tumors of five different primary locations with an average recall of 60.4%. Compared to using human features alone, adding microbial features improved the average recall by approximately 8%. In summary, this work provides evidence for the clinical relevance of human and microbe-derived plasma cfRNAs and their potential utilities in cancer detection as well as the determination of tumor sites.

Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment.

The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks. Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host-guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery. In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.

Anti-inflammatory effect of Rhein on ulcerative colitis via inhibiting PI3K/Akt/mTOR signaling pathway and regulating gut microbiota.

This study aimed to analyze the therapeutic effect of Rhein on ulcerative colitis (UC) in mice and its possible mechanism. LPS-induced UC cell model and DSS-induced UC mouse model were used to analyze the antiinflammatory effect of Rhein on UC in vitro and in vivo, respectively. Network pharmacology analysis was conducted to identify potential signaling pathways involved in Rhein treating UC, and the results were further confirmed through western blotting assay. 16sRNA sequencing was performed to study the regulatory effect of Rhein on gut microbiota in UC mice. As indicated by the results, Rhein could significantly inhibit the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6 and IL-1ß) in vivo and in vitro, and alleviate DSS-induced UC-associated symptoms in mice (e.g., colon shortening, weight loss, diarrhea and hematochezia). The PI3K/Akt/mTOR signaling pathway was predicted as the potential interacting protein of Rhein in the treatment of UC through network pharmacology analysis. It was found through western blotting assay that the Rhein treatment could significantly inhibit the PI3K/Akt/mTOR signaling pathway by decreasing the phosphorylated protein levels of PI3K, Akt, mTOR and p70S6K1. By 16sRNA gene sequencing analysis, Rhein administration could partially reverse the gut dysbacteriosis of mice induced by DSS and decrease pathogenic bacteria (e.g., Enterobacteriaceae and Turicibacter). It was positively correlated with the production of pro-inflammatory cytokines above, whereas the increase in probiotics (e.g., Unspecified-S24-7 and Rikenellaceae) was negatively correlated with the production of pro-inflammatory cytokines. In conclusion, Rhine had anti-UC efficacy, which was demonstrated by mitigating the UC symptoms and reducing intestinal inflammation by inhibiting the PI3K/Akt/mTOR signaling pathway and modulating gut microbiota.

pH/ROS dual-sensitive and chondroitin sulfate wrapped poly (ß-amino ester)-SA-PAPE copolymer nanoparticles for macrophage-targeted oral therapy for ulcerative colitis.

An oral nanoparticle (NPs) encapsulated in chitosan/alginate hydrogel (CA-Gel) with dual-sensitive in pH and reactive oxygen species (ROS) was developed to load curcumin (CUR) based on the intracellular-specific characteristics of macrophages. Chondroitin sulfate (CS) wrapped PBAE-SA-PAPE with intracellular pH/ROS dual-sensitive characteristics and CUR via a simple nanoprecipitation method to form NPs (CS-CUR-NPs), and mixed CA-Gel to acquire the final preparation (CS-CUR-NPs-Gel). CS-CUR-NPs displayed an ideal average particle size (179.19±5.61nm) and high encapsulating efficiency (94.74±1.15%). CS showed a good targeting ability on macrophages and the CA-Gel contribution in protecting NPs from being destroyed in the upper gastrointestinal tract. As expected, CS-CUR-NPs-Gel could significantly alleviate inflammation in DSS-induced UC mice via TLR4-MAPK/NF-κB pathway. This study is the first to attempt to design a novel pH/ROS dual-stimulated release strategy in helping intracellular CUR delivery and anticipated for efficient anti-UC therapy.