miRNA omics reveal neferine induces apoptosis through Ca2+mediated endoplasmic reticulum stress pathway in human endometrial cancer.

BACKGROUND: Endometrial cancer (EC) as one of the most prevalent malignancies in the female reproductive system, usually has a poor diagnosis and unfavorable health effects. Neferine (Nef), derived from the edible and medicinal lotus seed, has been known for its functional activity; however, its anti-cancer mechanism for EC remains elusive. PURPOSE: We explored the potential anti-cancer effects and underlying molecular mechanisms of Nef on EC. METHODS: The cytotoxicity was tested using MTT, and the cell cycle, apoptosis, Ca2+ levels, and the mitochondrial membrane potential (MMP) were observed through flow cytometry. After Nef treatment, differences in miRNA expression were identified using miRNA-seq data. Furthermore, western blot and immunohistochemistry (IHC) were employed to identify the proteins associated with apoptosis in both mice and cells. RESULTS: Nef treatment led to Ishikawa cell apoptosis and blocked cell proliferation in the G2/M phase. In total, 101 significantly different miRNA (p 〈 0.05 and |logFC| 〉 1) were obtained and subjected to GO and KEGG enrichment analysis, which revealed the Ca2+ and PI3K/AKT signaling pathways pertaining to apoptosis. Nef treatment significantly changed intracellular Ca2+ levels and MMP, activating the endoplasmic reticulum stress (ERS) pathway and the expression of key proteins in the mitochondrial pathway. In addition, Nef also inhibited the expression of key proteins in the PI3K/AKT pathway, causing cell apoptosis. Moreover, in mouse tumor tissues, the expression of CHOP, Bcl-2, Caspase 3, Cyto-c, and p-AKT was also consistent with the results in vitro. CONCLUSION: Nef could block the cell cycle and induce the activation of the mitochondrial apoptotic pathway involving the Ca2+-mediated ERS pathway and the PI3K/AKT pathway, thereby inducing apoptosis in EC cells, confirming the potential role of Nef in the prevention and treatment of EC.

Carbon Dot-Mediated Photodynamic Treatment Improves the Quality Attributes of Post-Harvest Goji Berries (Lycium barbarum L.) via Regulating the Antioxidant System.

Carbon dots (CDs) have been proposed as photosensitizers in photodynamic treatment (PDT), owing to their excellent biological attributes and budding fruit preservation applications. In the present study, CDs (4.66 nm) were synthesized for photodynamic treatment to improve the quality attributes in post-harvest goji berries. The prepared CDs extended the storage time of the post-harvest goji berries by 9 d. The CD-mediated PDT postponed the hardness and decay index loss, reduced the formation of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anion (O2•-) significantly, and delayed the loss of vital nutrients like the total protein, phenols, and flavonoids. The CD-mediated PDT improved the catalase (CAT), ascorbate peroxidase (APX), peroxidase (POD), phenylalanine ammonia-lyase (PAL), glutathione reductase (GR), and superoxide dismutase (SOD) activities, but did not improve polyphenol oxidase (PPO) activity. In addition, The CD-mediated PDT induced the accumulation of ascorbic acid (ASA) and glutathione (GSH). Overall, a CD-mediated PDT could extend the storage time and augment the quality attributes in post-harvest fresh goji berries by regulating the antioxidant system.

Structural characterization and stability of glycated bovine serum albumin-kaempferol nanocomplexes.

Kaempferol (Kae), a flavonoid is endowed with various functions. However, due to its poor water solubility and stability, its application in the food and pharmaceutical fields remains elusive. Emerging reports have emphasized the importance of bovine serum albumin (BSA), and glycosylated BSA (GBSA) prepared in the nature deep eutectic solvent system as drug delivery system carriers. In our study, ultraviolet and fluorescence spectra revealed the higher interactions of BSA and GBSA with Kae. Through analysis of Z-average diameter, zeta-potential, polydispersity index (PDI), encapsulation efficiency (EE), loading capacity (LC) of BSA-Kae nanocomplexes (NPs) and GBSA-Kae NPs, GBSA-Kae NPs showed a higher absolute value of zeta-potential and lower PDI, while its EE and LC were also higher. Structural characterization and stability analysis revealed that GBSA-Kae NPs had more stable properties. This study laid the theoretical foundation for improving the solubility and stability of Kae during its delivery and transport.

Lycium barbarum (Goji) as functional food: a review of its nutrition, phytochemical structure, biological features, and food industry prospects.

Lycium genus (Goji berry) is recognized as a good source of homology of medicine and food, with various nutrients and phytochemicals. Lately, numerous studies have focused on the chemical constituents and biological functions of the L. barbarum L., covering phytochemical and pharmacological aspects. We aim to provide exclusive data on the nutrients of L. barbarum L. fruits and phytochemicals, including their structural characterization, the evolution of extraction, and purification processes of different phytochemicals of L. barbarum L. fruit while placing greater emphasis on their wide-ranging health effects. This review also profitably offers innovative approaches for the food industry and industrial applications of L. barbarum L. and addresses some current situations and problems in the development of L. barbarum L. in deep processing products, which can provide clues for the sustainable development of L. barbarum L. industry.

Evolutionary research trend of Polygonatum species: a comprehensive account of their transformation from traditional medicines to functional foods.

With the advances in Polygonatum research, there is a huge interest in harnessing the valuable functional ingredients of this genus with the potential for functional foods. This review emphasizes the different aspects of Ploygonatum based research starting from its bioactive compounds, their structural characterization, various extraction methods, as well as biological activities. In view of its integral use as an essential medicinal plant, our review emphasizes on its promising food applications both as an ingredient and as a whole food, and its improved health benefits with potential for agricultural and environmental relevance are also discussed. As we collated the recent research information, we present the main challenges and limitations of the current research trend in this area which can upgrade the further expansion of Polygonatum-related research that will strengthen its economic and accessible nutritional value in the food and health industries. By highlighting the need for the unattended species, this review not only fills existing research gaps, but also encourages the researchers to find new avenues for the natural production of bio-based functional materials and the development of highly functional and health-promoting foods for disease prevention and treatment.

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.

Isorhamnetin Induces Apoptosis and Suppresses Metastasis of Human Endometrial Carcinoma Ishikawa Cells via Endoplasmic Reticulum Stress Promotion and Matrix Metalloproteinase-2/9 Inhibition In Vitro and In Vivo.

Endometrial cancer (EC) is a very common female cancer which has attracted more and more attention. According to the individual patient's condition, the current treatment of EC patients is mainly based on surgery, which is supplemented by chemotherapy, radiotherapy, and endocrine intervention. However, these existing treatment strategies also have some inevitable limitations. Therefore, it is particularly important to find an active ingredient with low toxicity and a high safety profile against EC. Isorhamnetin is a flavonoid known to be present in a variety of plants, such as sea buckthorn, dry willow, and wolfberry. In recent years, the anti-tumor effects of isorhamnetin have been reported. In our study, isorhamnetin was shown to induce apoptosis in Ishikawa cells by inducing the endogenous mitochondrial apoptotic pathway and exogenous death receptor pathway, promoting the endoplasmic reticulum stress-related pathway, and activating the corresponding markers of UPR response. In addition, isorhamnetin affected the expression of MMP2 and MMP9-related proteins in vitro and in vivo and eventually repressed metastasis. Therefore, isorhamnetin can be used as a promising medicinal material for the treatment of EC.

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.

Ginsenoside CK induces apoptosis of human cervical cancer HeLa cells by regulating autophagy and endoplasmic reticulum stress.

Ginsenoside CK (GCK), as a metabolite of ginsenoside Rb1, has been studied for its anti-cancer activity. However, its in-depth anti-cancer mechanism on cervical cancer (CC) HeLa cells has not been fully elucidated. This study found that GCK inhibited the proliferation of CC HeLa cells and caused alteration in cell morphology with an IC50 of 45.95 µM. At the same time, GCK treatment blocked the cell cycle in the G0/G1 phase, elevated the reactive oxygen species (ROS) level, decreased mitochondrial membrane potential (Δψm), contributed to Ca2+ leakage, inhibited HeLa cell metastasis, and stimulated the key markers related to apoptosis, mitochondrial and endoplasmic reticulum pathways. GCK altered the regulation of the Caspase family, Bak/Bcl-xl and down-regulated the endoplasmic reticulum pathways (PERK and IRE1α). Starting from flow cytometry and the protein level, we found that autophagy inhibitors inhibited autophagy while promoting apoptosis, and apoptosis inhibitors reduced the rate of apoptosis while promoting autophagy, which proved that GCK can be used as a suitable novel natural product for CC treatment.

Effects of roasting level on physicochemical, sensory, and volatile profiles of soybeans using electronic nose and HS-SPME-GC-MS.

We applied oven-roasting on soybean in order to investigate their physicochemical, sensory, and volatile profiles using electronic nose and HS-SPME-GC-MS. Results revealed a temperature dependent kinetic on the physicochemical index except fat content. Roasting at 200 °C for 20 min decreased the protein dispersibility index about 38%; while, lipoxygenase and peroxidase were entirely inactivated. The primary heat sensitive amino acids were methionine, arginine, and cysteine. Electronic nose showed certain capacity to discriminate varying roasted soybeans. Out of 41 volatile compounds identified in soybean headspace, 2,5-dimethylpyrazine showed the highest abundance of 411.18 µg/Kg. Regression model suggested the association of hexanal and aliphatic alcohols with beany flavor, while pyrazines, heterocycles, and furanoids showed a positive correlation with roasted flavor. The selected flavor markers can be used to predict the development of flavor in roasted soybeans. Our study emphasized the effect of roasting level on nutritive value and flavor profiles of soybeans.

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.

Multi-omics reveals the anticancer mechanism of asparagus saponin-asparanin A on endometrial cancer Ishikawa cells.

Endometrial cancer (EC) is a malignancy that severely threatens women's health and there is an urgent need to find novel natural compounds as effective treatment drugs. At the same time, multi-omics analysis of cells has been widely used in basic research to find new pathogenesis and mechanisms. Due to the lack of data on the functional importance of mRNAs and miRNAs in plant-derived asparanin A (AA) induced cancer cells, the underlying mechanisms of AA on endometrial cancer (EC) Ishikawa cells were investigated using mRNA-seq and miRNA-seq, qRT-PCR, western blot, and immunohistochemistry. The combined analysis of 37 differentially expressed miRNAs (DEMs) and 489 differentially expressed genes (DEGs) with negative regulatory relationships revealed that AA not only induced apoptosis, but also triggered autophagy through endoplasmic reticulum (ER) stress and DNA damage-related pathways. 23 DEMs and 39 DEGs participated in protein processing in the endoplasmic reticulum (PPER) and p53 signaling pathways, as shown by miRNA-target gene network analyses. Among them, we concluded that miR-6236-p5, miR-1246-p5, miR-11987_L-1, PC-5p-21544, and miR-5100-p3_1ss17TC function as hub miRNAs, and their regulation may be essential for the anti-cancer activity of AA. This study may provide a comprehensive understanding of the potential anticancer regulation of AA on EC, suggesting AA as a potential candidate for dietary supplementation in cancer medication and prevention.

A recent update on the multifaceted health benefits associated with ginger and its bioactive components.

Due to recent lifestyle shifts and health discernments among consumers, synthetic drugs are facing the challenge of controlling disease development and progression. Various medicinal plants and their constituents are recognized for their imminent role in disease management via modulation of biological activities. At present, research scholars have diverted their attention on natural bioactive entities with health-boosting perception to combat the lifestyle-related disarrays. In particular, Zingiber officinale is a medicinal herb that has been commonly used in food and pharmaceutical products. Its detailed chemical composition and high value-added active components have been extensively studied. In this review, we have summarized the pharmacological potential of this well-endowed chemo preventive agent. It was revealed that its functionalities are attributed to several inherent chemical constituents, including 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 6-hydroshogaol, and oleoresin, which were established through many studies (in vitro, in vivo, and cell lines). In this review, we also focused on the therapeutic effects of ginger and its constituents for their effective antioxidant properties. Their consumption may reduce or delay the progression of related diseases, such as cancer, diabetes, and obesity, via modulation of genetic and metabolic activities. The updated data could elucidate the relationship of the extraction processes with the constituents and biological manifestations. We have collated the current knowledge (including the latest clinical data) about the bioactive compounds and bioactivities of ginger. Their detailed mechanisms, which can lay foundation for their food and medical applications are also discussed.

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.

Asparanin A from Asparagus officinalis L. Induces G0/G1 Cell Cycle Arrest and Apoptosis in Human Endometrial Carcinoma Ishikawa Cells via Mitochondrial and PI3K/AKT Signaling Pathways.

Asparanin A (AA), a steroidal saponin from Asparagus officinalis L., has anticancer activity: however, its detailed molecular mechanisms in endometrial cancer (EC) have not been studied so far. We evaluated the anticancer activity and underlying mechanism of AA on EC cell line Ishikawa in vitro and in vivo. AA inhibited the Ishikawa cell proliferation and caused cell morphology alteration and cell cycle arrest in G0/G1 phase. Moreover, it could induce apoptosis through mitochondrial pathway, including the deregulation of Bak/Bcl-xl ratio which led to the generation of ROS, up-regulation of cytochrome c followed by decrease of Δψm, and activation of caspases, besides inhibition of the PI3K/AKT/mTOR pathway. In vivo data showed that administration of AA significantly inhibited the tumor tissue cell proliferation, reduced the tumor growth, and induced the apoptosis occurrence. AA can be a possible functional food ingredient to cure endometrial cancer followed by clinical trials.

Hydrogen Sulfide Alleviates Postharvest Senescence of Grape by Modulating the Antioxidant Defenses.

Hydrogen sulfide (H2S) has been identified as an important gaseous signal in plants. Here, we investigated the mechanism of H2S in alleviating postharvest senescence and rotting of Kyoho grape. Exogenous application of H2S released from 1.0 mM NaHS remarkably decreased the rotting and threshing rate of grape berries. H2S application also prevented the weight loss in grape clusters and inhibited the decreases in firmness, soluble solids, and titratable acidity in grape pulp during postharvest storage. The data of chlorophyll and carotenoid content suggested the role of H2S in preventing chlorophyll breakdown and carotenoid accumulation in both grape rachis and pulp. In comparison to water control, exogenous H2S application maintained significantly higher levels of ascorbic acid and flavonoid and total phenolics and reducing sugar and soluble protein in grape pulp. Meanwhile, H2S significantly reduced the accumulation of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anion (O2 (∙-)) in grape pulp. Further investigations showed that H2S enhanced the activities of antioxidant enzymes ascorbate peroxidase (APX) and catalase (CAT) and decreased those of lipoxygenase (LOX) in both grape peels and pulp. In all, we provided strong evidence that H2S effectively alleviated postharvest senescence and rotting of Kyoho grape by modulating antioxidant enzymes and attenuating lipid peroxidation.