Cyclopeptide Alkaloids from Discaria chacaye (Rhamnaceae) as Result of Symbiosis with Frankia (Actinomycetales).

Cyclopeptide alkaloids with different biological activities are present in plants of the family Rhamnaceae. Plants of this family grow in a symbiotic relationship with aerobic Gram-positive actinomycetes belonging to the genus Frankia. This goal of this research was a study of the comparative profile of alkaloids present in Discaria chacaye and to establish a connection between the presence or absence of Frankia sp. and the alkaloids. In addition, insecticidal activities of the alkaloidal extract were examined. A total of 24 alkaloids were identified, of which 12 have a benzylisoquinoline skeleton, 9 were cyclopeptides, 2 isoquinolines, and 1 aporphine. The presence of cyclopeptide alkaloids is associated with Frankia nodules in the plant root. The alkaloid extracts showed insecticidal activity with mortality dose-dependence and LD50 values between 44 to 71 µg/mL.

In vitro micropropagation and alkaloids analysis by GC-MS of Chilean Amaryllidaceae plants: Rhodophiala pratensis.

INTRODUCTION: Plants from Amaryllidaceae family are of interest since they produce a particular type of alkaloid useful for the treatment of neurodegenerative diseases of the central nervous system, such as Galanthamine. Given the low content of these secondary metabolites in the plant, it is necessary to study mechanisms to increase the productivity of them. OBJECTIVE: To obtain fast qualitative and quantitative analysis of the alkaloids and extend the understanding of biosynthesis and metabolism in these kinds of plants. Furthermore, establish a reliable, simple and fast analytical method for the in vitro callus culture of vegetative organs for Rhodophiala pratensis species. METHODS: The alkaloids composition of the callus culture of R. pratensis were analysed by gas chromatography coupled with mass spectrometry (GC-MS). RESULTS: A methodology for the qualitative and quantitative analysis of the alkaloids present in fresh callus culture of this wild plant species was established. The analysis showed alternation in the alkaloids type ratio and number of compounds between wild bulbs, in vitro bulbs and callus. It was possible to identify 24 alkaloids from a pool of 60 signals whose fragmentation pattern corresponds to the alkaloids of Amaryllidaceae plants. Together with the aforementioned, the amount and type of alkaloid present in the plant material obtained by in vitro culture of R. pratensis was determined in the same way. The results show the high biosynthetic potential of in vitro grown bulbs and callus tissue that are able to produce significant amounts of pharmacologically relevant alkaloids from R. pratensis in various proportions that depend on the culture conditions such as supplementation with growth substances. The in vitro grown bulbs produce an alkaloidal extract that contain a 52.6% w/w of alkaloids. CONCLUSION: This study allowed the alkaloid content in callus culture of R. pratensis to be found by means of GC-MS. These results allowed a relationship between the type of growth regulator and the type of alkaloids found to be established. Finally, we can say that the results achieved to state that the production of alkaloids using different combinations of growth regulators could be directed during in vitro micropropagation from provided plant material.

Assessment of Insecticidal Activity of Benzylisoquinoline Alkaloids from Chilean Rhamnaceae Plants against Fruit-Fly Drosophila melanogaster and the Lepidopteran Crop Pest Cydia pomonella.

The Chilean plants Discaria chacaye, Talguenea quinquenervia (Rhamnaceae), Peumus boldus (Monimiaceae), and Cryptocarya alba (Lauraceae) were evaluated against Codling moth: Cydia pomonella L. (Lepidoptera: Tortricidae) and fruit fly Drosophila melanogaster (Diptera: Drosophilidae), which is one of the most widespread and destructive primary pests of Prunus (plums, cherries, peaches, nectarines, apricots, almonds), pear, walnuts, and chestnuts, among other. Four benzylisoquinoline alkaloids (coclaurine, laurolitsine, boldine, and pukateine) were isolated from the above mentioned plant species and evaluated regarding their insecticidal activity against the codling moth and fruit fly. The results showed that these alkaloids possess acute and chronic insecticidal effects. The most relevant effect was observed at 10 µg/mL against D. melanogaster and at 50 µg/mL against C. pomonella, being the alteration of the feeding, deformations, failure in the displacement of the larvae in the feeding medium of D. melanogaster, and mortality visible effects. In addition, the docking results show that these type of alkaloids present a good interaction with octopamine and ecdysone receptor showing a possible action mechanism.

Identification of structurally diverse alkaloids in Talguenea quinquinervia (gill. Et hook) by liquid chromatography/electrospray ionisation tandem mass spectroscopy and insecticidal activity.

INTRODUCTION: Talguenea quinquinervia has been used in folk medicine and to dye wool, and the main constituents are alkaloids and triterpenes. Identification of these type of compounds in this specie is a necessary step to understand the biological properties. OBJECTIVE: To evaluate the relationship between the chemical composition of root from T. quinquinervia and its insecticidal properties using liquid chromatography electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS). METHODS: Alkaloids were extracted using Soxhlet extraction with methanol. Total extract was partitioned at pH 2 and 12 to enrich alkaloid constituents and to remove interferences. The separation of alkaloids in the Talguenea extract was performed on a C18 column using gradient elution and their tandem mass spectra were obtained by quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) to perform accurate mass measurements of fragment ions for the alkaloid constituents. RESULTS: Several types of alkaloids were separated and identified by LC-ESI-MS/MS. The structural assignment of individual alkaloids was performed based on convergence of MS/MS spectral data, pH partitioning behaviour, LC retention behaviour, and accurate mass measurements. The pH partition of the extract provided structural information about unknown alkaloids extracted from T. quinquinervia. A total of 20 compounds were identified and tentatively characterised, and of these 15 alkaloids were reported for the first time in the investigated T. quinquinervia. CONCLUSION: The chemical profiling of alkaloids in T. quinquinervia with different origins was performed for the first time and provided diagnostic ions for diverse alkaloids in T. quinquinervia. Insecticidal activity observed can be explain by the presence of alkaloid and pentacyclic triterpenes on the fractions assayed.

Could elderberry fruits processed by modern and conventional drying and extraction technology be considered a valuable source of health-promoting compounds?

The influence of drying and extraction processes on the phytochemical composition and biopotential of elderberry is challenging for the food industry. For this reason in this research two drying techniques (lyophilization and natural convection) and three extraction techniques (ultrasound (UAE), microwave (MAE), and conventional (maceration (MAC)) was applied using two"green" solvents (water and 50 % ethanol). Results of the research showed that lyophilization was a better way of drying than natural convection, while MAE extraction was the most efficient technique for the isolation of secondary metabolites. The most abundant phenolic compounds established by LC-MS/MS analysis, were chlorogenic acid and rutin, identified in extracts of lyophilized elderberries. Elderberry extracts achieved great antioxidant (CUPRAC: 2.30-5.13 mg TE/mL) and enzyme inhibitor potential (α-amylase: 0.51-8.34 mg ACAE/mL). The results suggest that elderberry is a rich natural source of bioactive compounds and could be used for the future development of dietary supplements and functional foods.

Integrated miRNA and mRNA omics reveal dioscin suppresses migration and invasion via MEK/ERK and JNK signaling pathways in human endometrial carcinoma in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonatum sibiricum Redouté (PS, also called Huangjing in traditional Chinese medicine), is a perennial herb as homology of medicine and food. According to the traditional Chinese medicine theory "Special Records of Famous Doctors", its functions include invigorating qi and nourishing yin, tonifying spleen and kidney. Traditionally, qi and blood therapy has been believed as most applicable to the treatment of uterine disease. The current research has focused on the effect and mechanism of dioscin, the main active component of PS, on Endometrial carcinoma (EC). AIM OF THE STUDY: To study the efficacy of dioscin on proliferation and migration of Endometrial carcinoma cell line, we conducted experiments by using xenograft model and Ishikawa cells, and explored the potential molecular mechanism. MATERIALS AND METHODS: mRNA and miRNA omics techniques were employed to investigate the regulatory mechanism of dioscin on EC Ishikawa cells. Based on in vivo and in vitro experiments, cell clone formation, cell scratching, Transwell, H&E staining, immunohistochemistry, q-PCR, and Western blot techniques were used to determine the molecular effects and mechanisms of dioscin on cell migration. RESULTS: Integrated miRNA and mRNA omics data showed that 513 significantly different genes marked enrichment in MAPK signaling pathway. The in vivo data showed that dioscin (24 mg/kg) significantly inhibited tumor growth. The in vitro proliferation and invasiveness of dioscin on Ishikawa cells showed that dioscin could significantly decrease the colony numbers, and suppress the Ishikawa cell wound healing, migration and invasion. Molecular data revealed that dioscin decreased the MMP2 and MMP9 expression in vitro and in vivo. The p-MEK, p-ERK, and p-JNK expression levels were also confirmed to be significantly reduced. Key regulators in the MAPK signaling pathway were further validated in xenograft tumors. CONCLUSION: Our data indicated that dioscin inhibited Ishikawa cell migration and invasion mediated through MEK/ERK and JNK signaling. More importantly, screened hub miRNAs and genes can be regarded as potential molecular targets for future EC treatment.

Structural characteristics and in vitro fermentation patterns of polysaccharides from Boletus mushrooms.

The aim of this study was to investigate the structural characteristics and in vitro fermentation patterns of polysaccharides from Boletus mushrooms. Polysaccharides were solubilized from fruit bodies of selected mushrooms Boletus auripes, B. bicolor, and B. griseus using subcritical water extraction. Boletus polysaccharides were characterized for their general physicochemical pattern, constituent monosaccharides and molecular weight. A simulated in vitro fermentation model was used to study the utilization of Boletus polysaccharides by the gut microbiota and their consequent modulation of microbial communities. Results showed that the main constituent monosaccharides of Boletus polysaccharides were glucose, galactose and mannose, followed by fucose, xylose and rhamnose, with glucose being the most abundant. The polysaccharides from B. bicolor and B. griseus exhibited a relatively high proportion of galactose and mannose, respectively. Boletus polysaccharides exhibited a wide range of molecular weights (5 kDa to 2000 kDa), which covered multiple polysaccharide populations, but the proportions of these populations varied among the samples. Boletus polysaccharides were gradually utilized by the human fecal microbiota, promoting the production of SCFAs. Boletus polysaccharides contributed to a healthier gut microbiota composition by increasing the relative abundance of beneficial bacterial genera such as Bacteroides and Faecalibacterium and reducing the relative abundance of harmful bacterial genera such as Sutterella and Escherichia-Shigella. B. bicolor polysaccharides showed better fermentability and prebiotic effects than the other Boletus polysaccharide groups. Therefore, the consumption of select Boletus mushrooms, particularly B. bicolor, could be a potential approach to obtain polysaccharides for microbiota modulation and to support gut health.

Lipotoxicity, glucotoxicity and some strategies to protect vascular smooth muscle cell against proliferative phenotype in metabolic syndrome.

Metabolic syndrome (MetS) is a risk factor for the development of cardiovascular disease (CVD) and atherosclerosis through a mechanism that involves vascular smooth muscle cell (VSMC) proliferation, lipotoxicity and glucotoxicity. Several molecules found to be increased in MetS, including free fatty acids, fatty acid binding protein 4, leptin, resistin, oxidized lipoprotein particles, and advanced glycation end products, influence VSMC proliferation. Most of these molecules act through their receptors on VSMCs by activating several signaling pathways associated with ROS generation in various cellular compartments. ROS from NADPH-oxidase and mitochondria have been found to promote VSMC proliferation and cell cycle progression. In addition, most of the natural or synthetic substances described in this review, including pharmaceuticals with hypoglycemic and hypolipidemic properties, attenuate VSMC proliferation by their simultaneous modulation of cell signaling and their scavenging property due to the presence of a phenolic ring in their structure. This review discusses recent data in the literature on the role that several MetS-related molecules and ROS play in the change from contractile to proliferative phenotype of VSMCs. Hence the importance of proposing an appropriate strategy to prevent uncontrolled VSMC proliferation using antioxidants, hypoglycemic and hypolipidemic agents.

Transcriptome and proteomics conjoint analysis reveal metastasis inhibitory effect of 6-shogaol as ferroptosis activator through the PI3K/AKT pathway in human endometrial carcinoma in vitro and in vivo.

Endometrial cancer remains as one of the widespread female malignancies despite the existing treatment measures mainly surgery, radiotherapy, and chemotherapy. In recent times, studies have focused on medicinal plants such as ginger due to its multifaceted characteristics compared to conventional medicine. 6-Shogaol is regarded as the main active compound of ginger participating in pharmacological activities and combating various health disorders, especially cancer. In our study, we compared the effects of 6-gingerol, 6-paradol, and 6-shogaol on Ishikawa cells, and found 6-shogaol as a more effective ingredient against Ishikawa cell proliferation. Moreover, its promoted ferroptosis, as a result, triggered mitochondrial morphologic alternation, as well as changed iron concentration, GSH and MDA levels. Furthermore, 6-Shogaol inhibited cell metastasis by influencing cell invasion and migration. Finally, 6-shogaol could trigger PI3K/AKT signaling pathways in vitro and in vivo confirmed by western blotting assay and immunohistochemical evaluation. These findings suggest that 6-shogaol can be used as promising functional food component in health diet and in drug target methods for endometrial cancer therapy.

Riboflavin Bioenriched Soymilk Alleviates Oxidative Stress Mediated Liver Injury, Intestinal Inflammation, and Gut Microbiota Modification in B2 Depletion-Repletion Mice.

Epidemiological evidence emphasizes that ariboflavinosis can lead to oxidative stress, which in turn may mediate the initiation and progression of liver injury and intestinal inflammation. Although vitamin B2 has gained worldwide attention for its antioxidant defense, the relationship between B2 status, oxidative stress, inflammatory response, and intestinal homeostasis remains indistinct. Herein, we developed a B2 depletion-repletion BALB/c mice model to investigate the ameliorative effects of B2 bioenriched fermented soymilk (B2FS) on ariboflavinosis, accompanied by oxidative stress, inflammation, and gut microbiota modulation in response to B2 deficiency. In vivo results revealed that the phenotypic ariboflavinosis symptoms, growth rate, EGRAC status, and hepatic function reverted to normal after B2FS supplementation. B2FS significantly elevated CAT, SOD, T-AOC, and compromised MDA levels in the serum, simultaneously up-regulated Nrf2, CAT, and SOD2, and down-regulated Keap1 gene in the colon. The histopathological characteristics revealed significant alleviation in the liver and intestinal inflammation, confirmed by the downregulation of inflammatory (IL-1ß and IL-6) and nuclear transcription (NF-κB) factors after B2FS supplementation. B2FS also increased the abundance and diversity of gut microbiota, increased the relative abundance of Prevotella and Absiella, as well as decreased Proteobacteria, Fusobacteria, Synergistetes, and Cyanobacteria in strong conjunction with antioxidant, anti-inflammatory properties, and gut homeostasis along with the remarkable increase in cecal SCFAs content. We hereby reveal that B2FS can effectively alleviate deleterious ariboflavinosis associated with oxidative stress mediated liver injury, chronic intestinal inflammation, and gut dysbiosis in the B2 depletion-repletion mice model via activation of the Nrf2 signaling pathway.

Pien-Tze-Huang alleviates CCl4-induced liver fibrosis through the inhibition of HSC autophagy and the TGF-ß1/Smad2 pathway.

Ethnopharmacological relevance: Pien-Tze-Huang (PZH)-a traditional Chinese medicine (TCM) compound-has been employed to treat various liver inflammation and tumors for over 10 decades. Interestingly, most of the pharmacological effects had been validated and explored toward liver ailment along with pro-inflammatory conditions and cancer at the cellular and molecular level to date. Aim of the study: The present study aimed to investigate the therapeutic effect of PZH on autophagy and TGF-ß1 signaling pathways in rats with liver fibrosis and hepatic stellate cell line (HSC). Materials and methods: Male SD rats with carbon tetrachloride (CCl4)-induced liver fibrosis were used as the animal model. Next, PZH treatment was given for 8 weeks. Afterward, the therapeutic effects of PZH were analyzed through a hepatic tissue structure by hematoxylin-eosin (H&E), Van Gieson (VG) staining, and transmission electron microscopy (TEM), activity of ALT and AST by enzyme-associated immunosorbent assay as well. Subsequently, mRNA and protein expression were examined by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC). Then, the cell vitality of PZH-treated HSC and the expression of key molecules prevailing to autophagy were studied in vitro. Meanwhile, SM16 (a novel small molecular inhibitor which inhibits TGFß-induced Smad2 phosphorylation) was employed to confirm PZH's effects on the proliferation and autophagy of HSC. Results: PZH pharmacologically exerted anti-hepatic fibrosis effects as demonstrated by protecting hepatocytes and improving hepatic function. The results revealed the reduced production of extracellular collagen by adjusting the balance of matrix metalloproteinase (MMP) 2, MMP9, and tissue inhibitor of matrix metalloproteinase 1 (TIMP1) in PZH-treated CCl4-induced liver fibrosis. Interestingly, PZH inhibited the activation of HSC by down-regulating TGF-ß1 and phosphorylating Smad2. Furthermore, PZH down-regulated yeast Atg6 (Beclin-1) and microtubule-associated protein light chain 3 (LC3) toward suppressing HSC autophagy, and PZH exhibited similar effects to that of SM16. Conclusion: To conclude, PZH alleviated CCl4-induced liver fibrosis to reduce the production of extracellular collagen and inhibiting the activation of HSC. In addition, their pharmacological mechanisms related to autophagy and TGF-ß1/Smad2 signaling pathways were revealed for the first time.

Spiraeoside extracted from red onion skin ameliorates apoptosis and exerts potent antitumor, antioxidant and enzyme inhibitory effects.

Red onion skin waste (ROSW) was analyzed for extraction of naturally occurring 4'-O-glucoside of quercetin, spiraeoside (SPI) with promising biological activities. Reversed-phase high-performance liquid chromatography was used to determine the SPI content in three different solvent extracts of ROSW: water (12.2 mg/g), methanol (27.6 mg/g), and ethanol (32.5 mg/g). The ethanol extract and SPI showed significant radical-scavenging and anti-inflammatory activities. In addition, the anti-cancer effects of SPI on a HeLa cells was investigated. The results indicated that SPI treatment significantly inhibited cell growth, and the dose of 50 µg/mL exhibited the highest anti-cancer activity. SPI inhibited the expression of B-cell lymphoma 2 and BH3-interacting domain-death agonist and promoted apoptosis by activating caspase-9/-3 expression. Notably, SPI inhibited the expression of mu-2-related death-inducing gene, a molecule involved in death receptor-mediated apoptotic signaling. Cyclin-dependent kinase 2-cyclin-E expression was also inhibited after SPI treatment, particularly at the G2/M checkpoint. Our findings provide novel insights into the apoptotic potential with promising anticancer and enzyme inhibitory effects of ROSW SPI.

Recent advances on bioactive polysaccharides from mulberry.

Mulberry (Moraceae family), commonly considered as a folk remedy, has a long history of usage in many regions of the world. Polysaccharides regarded as one of the major components in mulberry plants, and they possess antioxidant, antidiabetic, hepatoprotective, prebiotic, immunomodulatory and antitumor properties, among others. In recent decades, mulberry polysaccharides have been widely studied for their multiple health benefits and potential economic value. However, there are few reviews providing updated information on polysaccharides from mulberry. In this review, recent advances in the study of isolation, purification, structural characterization, biological activity and the structure-activity relationship of mulberry polysaccharides are summarized and discussed. Furthermore, a thorough analysis of the current trends and perspectives on mulberry polysaccharides is also proposed. Hopefully, these findings can provide a useful reference value for the development and application of natural polysaccharides in the field of functional food and medicine in the future.

Dioscin inhibits human endometrial carcinoma proliferation via G0/G1 cell cycle arrest and mitochondrial-dependent signaling pathway.

The present study emphasized on the anti-cancerous effects of dioscin and its underlying molecular mechanism in human endometrial cancer Ishikawa cells. Dioscin significantly suppressed the proliferation of Ishikawa cells at IC50 of 2.37 µM. Besides, dioscin could inhibit the proliferation of Ishikawa cells by blocking the G0/G1 cell cycle through up-regulation of p16, p21, and p27 and down-regulation of cycle-cellular protein (Cyclin A/D/E) and cyclin-dependent kinase (CDK2/4/6). Also, it promoted apoptosis through the mitochondrial pathway, including the regulation of Bcl family proteins, the increase of ROS levels, the activation of caspases (Caspase 9/3), and the decrease of mitochondrial membrane permeability. Whereas dioscin also effectively activated the marker genes and proteins (Fas, TNF-R1, and Caspase 8) related to the death receptor-mediated pathway which confirmed the involvement of both the pathways for dioscin-induced apoptosis. The current results demonstrated that dioscin possessed potential health benefits with respect to endometrial cancer prevention and treatment.

Asparanin A inhibits cell migration and invasion in human endometrial cancer via Ras/ERK/MAPK pathway.

Asparanin A (AA), a natural compound present in vegetables and medicinal herbs like Asparagus officinalis L., has been investigated extensively for its pharmacological attributes. So far, the effect of AA on endometrial cancer (EC) cell migration and invasion has not been explored. Herein, we elucidated the anti-metastasis mechanism of AA on Ishikawa cells based on miRNA-seq and mRNA-seq integrated analyses. AA treatment led to altered miRNAs expression in Ishikawa cells and inhibited the cell wound healing, cell migration and invasion. Gene Ontology and KEGG enrichment analyses showed that the target genes of different expression miRNAs were significantly enriched in Ras, Rap1 and MAPK signaling pathways. Further verification of these changes via qRT-PCR and Western blot assays in vitro and in vivo demonstrated that AA could suppress human EC cell migration and invasion through Ras/ERK/MAPK pathway. Furthermore, top two miRNAs (miR-6236-p5 and miR-12136_R+8) and top three target genes (KITLG, PDGFD, and NRAS) were identified as functional hub miRNAs and genes through miRNA-target gene network analysis. Our data presented a holistic approach to comprehend the anti-metastatic role of AA in EC after in vitro and in vivo analyses.

Evaluation of the Antimicrobial Activity of Some Components of the Essential Oils of Plants Used in the Traditional Medicine of the Tehuacán-Cuicatlán Valley, Puebla, México.

In Tehuacán-Cuicatlán valley (Mexico), studies have been carried out on the essential oils of medicinal plants with antimicrobial activity and it was found that they present compounds in common such as: α-pinene, ß-pinene, carvacrol, eugenol, limonene, myrcene, ocimene, cineole, methyl salicylate, farnesene, and thymol. The goal of this study was to assess the antimicrobial activity of essential oils' compounds. The qualitative evaluation was carried out by the Kirby Baüer agar diffusion technique in Gram-positive bacteria (11 strains), Gram-negative bacteria (18 strains), and yeasts (8 strains). For the determination of the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the agar dilution method was used. All the evaluated compounds presented antimicrobial activity. The compounds eugenol and carvacrol showed the largest inhibition zones. Regarding yeasts, the compounds ocimene, cineole, and farnesene did not show any activity. The compounds eugenol, carvacrol, and thymol presented the lowest MIC; bactericidal effect was observed at MIC level for S. aureus 75MR, E. coli 128 MR, and C albicans CUSI, for different compounds, eugenol, carvacrol, and thymol. Finally, this study shows that the essential oils of plants used by the population of Tehuacán-Cuicatlán valley share compounds and some of them have antibacterial and fungicidal activity.

Gut modulation based anti-diabetic effects of carboxymethylated wheat bran dietary fiber in high-fat diet/streptozotocin-induced diabetic mice and their potential mechanisms.

We explored the effect of carboxymethylated wheat bran dietary fibers (DFs) on mice with type 2 diabetes (T2D) (induced by HFD combined with STZ) and their possible hypoglycemic mechanism. After feeding the diabetic mice with modified DFs for four weeks, the DFs had lipid lowering and anti-hyperglycemic effect, via increasing the levels of insulin, GLP-1, PYY, and SCFAs in diabetic mice, and improving the histopathology of liver and pancreas. qRT-PCR results showed that the intake of DFs up-regulated the expression levels of G6Pase and Prkce, and down regulated the expression levels of Glut2 and InsR in the liver of diabetic mice. It is suggested that DFs may play a role by inhibiting 1,2-DAG-PKCε pathway, improving insulin receptor activity and insulin signal transduction. 16 S rDNA high-throughput sequencing results showed that the DFs significantly improved the relative abundance of Akkermansia muciniphila, increased the diversity of gut microbiota and reduced the ratio of Firmicutes to Bacteroidetes, thus promoting the hypoglycemic and hypolipidemic effect on diabetic mice. Our study can foster the further understanding of the gut modulatory biomarkers and related metabolites, and may extend the basis for DFs as a potential dietary intervention to prevent or treat the T2D.

Computer-assisted discovery of compounds with insecticidal activity against Musca domestica and Mythimna separata.

Pesticides are used to control and combat insects and pests in the agricultural sector, households, and public health programs. The frequent and disorderly use of these pesticides may lead to variety of undesired effects. Therefore, natural products have many advantages over to synthetic compounds to be used as insecticides. The goal of this study was to find natural products with insecticidal potential against Musca domestica and Mythimna separata. To achieve this goal, we developed predictive QSAR models using MuDRA, PLS, and RF approaches and performed virtual screening of 117 natural products. As a result of QSAR modeling, we formulated the recommendations regarding physico-chemical characteristics for promising compounds active against Musca domestica and Mythimna separata. Homology models were successfully built for both species and molecular docking of QSAR hits vs known insecticides allowed us to prioritize twenty-two compounds against Musca domestica and six against Mythimna separata. Our results suggest that pimarane diterpenes, abietanes diterpenes, dimeric diterpenes and scopadulane diterpenes obtained from aerial parts of species of the genus Calceolaria (Calceolariaceae: Scrophulariaceae) can be considered as potential insecticidal.

Palmitoyl-CoA effect on cytochrome c release, a key process of apoptosis, from liver mitochondria of rat with sucrose diet-induced obesity.

Cytochrome c (cyt-c) release from the mitochondria to the cytosol is a key process in the initiation of hepatocyte apoptosis involved in the progression of non-alcoholic fatty liver disease (NAFLD) to fibrosis, cirrhosis and hepatocellular carcinoma. Hepatocyte apoptosis may be related to lipotoxicity due to the accumulation of palmitic acid and palmitoyl-CoA (Pal-CoA). Therefore, the aim of this study is to examine whether Pal-CoA induces cyt-c release from liver mitochondria of sucrose-fed rat (SF). Pal-CoA-induced cyt-c release was sensitive to cyclosporine A indicating the involvement of the mitochondrial membrane permeability transition (mMPT). In addition, cyt-c release from SF mitochondria remains significantly lower than C mitochondria despite the increased rate of H2O2 generation in SF mitochondria. The decreased cyt-c release from SF may be also related to the increased proportion of the palmitic acid-enriched cardiolipin, due to the high availibilty of palmitic acid in SF liver. The enrichment of cardiolipin molecular species with palmitic acid makes cardiolipin more resistant to peroxidation, a mechanism involved in the dissociation of cyt-c from mitochondrial inner membrane. These results suggest that Pal-CoA may participate in the progression of NAFLD to more severe disease through mechanisms involving cyt-c release and mMPT, a key process of apoptosis.

Apigenin 7-O-glucoside promotes cell apoptosis through the PTEN/PI3K/AKT pathway and inhibits cell migration in cervical cancer HeLa cells.

Epidemiologic evidence promote the inclusion of flavones in diet due to their inhibitory effects on certain types of cancers, particularly in women. Among the naturally occurring plant flavonoids, Apigenin 7-O-glucoside (AGL) is endowed with anti-inflammatory, anti-oxidant, and anti-cancer activities. However, its mechanism of action on cervical cancer, the fourth largest cancer in women, has not yet been clarified. In the current study, we have determined the effect of AGL on human cervical cancer cells and studied its molecular mechanism against cervical cancer. The results showed that AGL inhibited the proliferation of HeLa cells (IC50 was 47.26 µM at 48 h) by inducing apoptosis. Furthermore, AGL treatment caused G0/G1 phase arrest, reduced mitochondrial membrane potential (MMP), and upgraded intracellular ROS production. AGL could promote the release of cytochrome c by regulating Bcl-2 family proteins, and then activated caspase 9/3 to promote cell apoptosis. Moreover, AGL treatment promoted the expression of p16 INK4A, while inhibited the expression of Cyclin A/D/E and CDK2/6. At the same time in HeLa cells treated with AGL, the PTEN/PI3K/AKT pathway was inhibited in a concentration-dependent manner, and cell migration was also impeded correspondingly through the matrix metalloproteinase 2 and 9. Our study may provide a new research direction for harnessing the novel natural compounds in cervical cancer treatment.