Cucurbitacin B induces ferroptosis in oral leukoplakia via the SLC7A11/mitochondrial oxidative stress pathway.

BACKGROUND: Oral leukoplakia (OLK), characterized by abnormal epithelial hyperplasia, is the most common precancerous oral mucosa lesion and is closely related to oxidative stress. Cucurbitacin B (CuB), a tetracyclic triterpenoid molecule derived from plants, has shown promising anti-proliferative and antioxidant effects in preclinical studies. However, whether CuB can play an antiproliferative role in OLK by regulating oxidative stress remains elusive. PURPOSE: To investigate the role of CuB in inhibiting the malignant progression of oral leukoplakia and to further explore its underlying mechanisms of action. METHODS: In vitro, the effect of CuB on the proliferation, migration, apoptosis, and cell cycle of OLK cells DOK was detected. The core genes and key pathways of OLK and CuB were analyzed in the transcriptome database, by using immunofluorescence, qRT-PCR, and Western blot to evaluate the expression levels of the ferroptosis markers ROS, GSH, MDA, Fe2+, and marker genes SLC7A11, GPX4, and FTH1. Immunohistochemistry of human tissue was performed to investigate the expression of the SLC7A11. In vivo, the model of OLK was established in C57BL/6 mice and the biosafety of CuB treatment for OLK was further evaluated. RESULTS: CuB substantially suppressed the proliferation of DOK cells. Bioinformatics analysis showed that the core targets of OLK crossing with CuB include SLC7A11 and that the essential pathways involve ROS and ferroptosis. In vitro experiments indicated that CuB might promote ferroptosis by down-regulating the expression of SLC7A11. We observed a gradual increase in SLC7A11 expression levels during the progression from normal oral mucosa to oral leukoplakia with varying degrees of epithelial dysplasia. In vivo experiments demonstrated that CuB inhibited the malignant progression of OLK by promoting ferroptosis in OLK mice and exhibited a certain level of biosafety. CONCLUSION: This study demonstrated for the first time that CuB could effectively inhibit the malignant progression of OLK by inducing ferroptosis via activating the SLC7A11/ mitochondrial oxidative stress pathway. These findings indicate that CuB could serve as the lead compound for the future development of anti-oral leukoplakia drugs.

Yin Yang 1 impacts upon preeclampsia by regulating Treg/TH17 cells and PI3K/AKT pathway.

Preeclampsia (PE) is a common obstetric syndrome with an unclear etiology and pathogenesis. The study here aimed to investigate the role of Yin Yang 1 (YY1) in PE, and to reveal any YY1-regulated mechanisms in PE. Peripheral blood, placenta, and endometrial tissues of PE patients, healthy volunteers, and patients who had undergone an elective Cesarean section and had a scarred uterus (control group) were collected for analyses. Rat PE models were established by lipopolysaccharide induction. Subsets of these rats were then made to over-express YY1. At 18 d after the PE was established, urine, blood, and placental tissues from all rats were collected. Levels of regulatory-T (Treg) and helper T-type 17 (TH17) cells in both human and rat blood were measured by flow cytometry. ELISA kits were used to evaluate blood levels of inflammatory factors (i.e. IL-6, IL-10, and IL-17) as well. RT-qPCR and Western blot assays were performed to quantify levels of forkhead box P3 (Foxp3), retinoic acid-related orphan receptor C (RORc), and YY1 in the human and rat placenta and endometrial tissues. Expressions of PI3K/AKT pathway-related proteins were also evaluated by Western blots. The results indicated that the PE patients, relative to levels in control group and the healthy control subjects, had decreased circulating levels of Treg cells/increased TH17 cells; tissues from these patients also had relatively-decreased FoxP3 mRNA and protein expressions and elevated RORc mRNA and protein expressions. YY1 was expressed only at low levels in the PE patient placenta and endometrial tissues. In rats, PE rats treated with over-expressed YY1 had (relative to in PE rats without over-induced YY1) increased circulating levels of Treg cells/decreased TH17 cells; tissues from these rats had elevated FoxP3 mRNA and protein expressions and reduced mRNA and protein RORc expressions, as well as indications of alleviated inflammation. In the rat placenta samples, YY1 was also determined to activate the PI3K/AKT pathway. In summary, YY1 regulates the balance among Treg/TH17 cells and so affect the PE process in part through activation of the PI3K/AKT pathway.

Structural Characterization, In Vitro Digestion Property, and Biological Activity of Sweet Corn Cob Polysaccharide Iron (III) Complexes.

This study aimed to enhance the utilization value of sweet corn cob, an agricultural cereal byproduct. Sweet corn cob polysaccharide-ron (III) complexes were prepared at four different temperatures (40 °C, 50 °C, 60 °C, and 70 °C). It was demonstrated that the complexes prepared at different temperatures were successfully bound to iron (III), and there was no significant difference in chemical composition; and SCCP-Fe-C demonstrated the highest iron content. The structural characterization suggested that sweet corn cob polysaccharide (SCCP) formed stable ß-FeOOH iron nuclei with -OH and -OOH. All the four complexes' thermal stability was enhanced, especially in SCCP-Fe-C. In vitro iron (III) release experiments revealed that all four complexes were rapidly released and acted as iron (III) supplements. Moreover, in vitro antioxidant, α-glucosidase, and α-amylase inhibition studies revealed that the biological activities of all four complexes were enhanced compared with those of SCCP. SCCP-Fe-B and SCCP-Fe-C exhibited the highest in vitro antioxidant, α-glucosidase, and α-amylase inhibition abilities. This study will suggest using sweet corn cobs, a natural agricultural cereal byproduct, in functional foods. Furthermore, we proposed that the complexes prepared from agricultural byproducts can be used as a potential iron supplement.

Exploring the mechanism of Alisma orientale for the treatment of pregnancy induced hypertension and potential hepato-nephrotoxicity by using network pharmacology, network toxicology, molecular docking and molecular dynamics simulation.

Background: Pregnancy-induced Hypertension (PIH) is a disease that causes serious maternal and fetal morbidity and mortality. Alisma Orientale (AO) has a long history of use as traditional Chinese medicine therapy for PIH. This study explores its potential mechanism and biosafety based on network pharmacology, network toxicology, molecular docking and molecular dynamics simulation. Methods: Compounds of AO were screened in TCMSP, TCM-ID, TCM@Taiwan, BATMAN, TOXNET and CTD database; PharmMapper and SwissTargetPrediction, GeneCards, DisGeNET and OMIM databases were used to predict the targets of AO anti-PIH. The protein-protein interaction analysis and the KEGG/GO enrichment analysis were applied by STRING and Metascape databases, respectively. Then, we constructed the "herb-compound-target-pathway-disease" map in Cytoscape software to show the core regulatory network. Finally, molecular docking and molecular dynamics simulation were applied to analyze binding affinity and reliability. The same procedure was conducted for network toxicology to illustrate the mechanisms of AO hepatotoxicity and nephrotoxicity. Results: 29 compounds with 78 potential targets associated with the therapeutic effect of AO on PIH, 10 compounds with 117 and 111 targets associated with AO induced hepatotoxicity and nephrotoxicity were obtained, respectively. The PPI network analysis showed that core therapeutic targets were IGF, MAPK1, AKT1 and EGFR, while PPARG and TNF were toxicity-related targets. Besides, GO/KEGG enrichment analysis showed that AO might modulate the PI3K-AKT and MAPK pathways in treating PIH and mainly interfere with the lipid and atherosclerosis pathways to induce liver and kidney injury. The "herb-compound-target-pathway-disease" network showed that triterpenoids were the main therapeutic compounds, such as Alisol B 23-Acetate and Alisol C, while emodin was the main toxic compounds. The results of molecular docking and molecular dynamics simulation also showed good binding affinity between core compounds and targets. Conclusion: This research illustrated the mechanism underlying the therapeutic effects of AO against PIH and AO induced hepato-nephrotoxicity. However, further experimental verification is warranted for optimal use of AO during clinical practice.

[Influencing factors of insufficient and excessive folate intake in early pregnancy in Chengdu in 2017].

OBJECTIVE: To investigate the folate intake level of early pregnant women and its influencing factors in Chengdu. METHODS: The healthy singleton pregnant women with 8-14 weeks of pregnancy in an obstetrical clinic of maternal-and-child health care institution in Chengdu in 2017 were selected as the object of the study. The basic information of pregnant women was collected by questionnaire survey, and the dietary intake of all kinds of food in early pregnancy was collected by 3-day 24-hour dietary recall method, and the average daily intake of folate was calculated according to China Food Composition(2018). A self-designed questionnaire was used to collect the use of folic acid supplements in pregnant women in the past one month, and the average daily intake of folic acid supplements was calculated. According to the Chinese Dietary Reference Intakes(2013), the folate intake <600 µg DFE/d was defined as insufficient, and folic acid supplements intake ≥1000 µg/d was defined as excessive. The influencing factors of folate intake were analyzed by binary Logistic regression model. RESULTS: A total of 1579 valid samples were included. The average folate intake of early pregnant women in Chengdu was 865.8(778.6, 1461.0) µg DFE/d, the average dietary folate intake was 145.4(101.9, 200.7) µg/d, and the average folic acid supplements intake was 400.0(400.0, 800.0) µg/d. The rate of insufficient intake of folate in early pregnancy was 12.1%, and the rate of excessive intake of folic acid supplements was 13.0%. Compared with the primiparous group, the risk of insufficient folate intake was higher in the multiparous group(OR=1.708, 95%CI 1.175-2.482). Compared with the low income group, risk of insufficient folate intake in the medium and high income group was lower(OR=0.660, 95%CI 0.477-0.913); taking folic acid supplements before pregnancy has a lower risk of overdose of folic acid than the non-taking group(OR=0.594, 95%CI 0.423-0.835). CONCLUSION: The phenomenon of insufficient intake of total folate and excessive intake of folic acid supplements coexists among women in early pregnancy in Chengdu, and the rational use of folic acid supplements is worthy of attention.

Does Baking Soda Function as a Magic Bullet for Patients With Cancer? A Mini Review.

Sodium bicarbonate, commonly known as baking soda, is widely used in the clinic as an antacid for treating gastric hyperacidity, among other conditions. Chao et al have reported a clinical trial about targeting intratumor lactic acidosis-transarterial chemoembolization. Based on conventional transarterial chemoembolization, the authors added a 5% sodium bicarbonate solution to cytotoxic drugs, resulting in a high local control rate. The explanation for the antitumor effects of sodium bicarbonate is related to acidosis in the tumor microenvironment. In this review, we summarize the findings from studies administering sodium bicarbonate alone or in combination with other anticancer therapies as cancer treatments, and discuss methods for safe and effective use of sodium bicarbonate in the clinic.

The Role of Hyperthermia in the Multidisciplinary Treatment of Malignant Tumors.

Hyperthermia is often used in combination with chemotherapy and radiotherapy for cancer treatment. Recently, immunotherapy has become a popular research area, breaking exciting new ground with concurrent immunotherapy and hyperthermia. Much evidence has demonstrated the effectiveness of multidisciplinary synergistic therapy, and the underlying mechanism has been gradually explored. In this review, we focus on the mechanism of various cancer treatments in the current literature and recent advances in hyperthermia. Additionally, we review clinical studies of hyperthermia combined with other therapies in the previous 10 years and propose future prospects for hyperthermia in multidisciplinary synergistic therapy.

A porous collagen-carboxymethyl cellulose/hydroxyapatite composite for bone tissue engineering by bi-molecular template method.

Inspired by the mechanism of bone formation, a porous collagen-carboxymethyl cellulose/hydroxyapatite (Col-CMC/HA) composite was designed and fabricated using a biomimetic template of Col and CMC protein-polysaccharide bi-molecules. The morphology, composition and physical properties of Col-CMC/HA composites were characterized systematically. It was found that the nano-HA homogenously distributed on the surface of Col-CMC bi-templates while the composite presented 3D porous structure with pore size from 100 µm to 300 µm. The porosities of composites were located at the range of 71%-85%. Besides, the compressive strength of composites was highly depended on the ratio of Col to CMC in the organic template. The optimized composite in respect to physical properties showed a compressive strength as high as 7.06 MPa, quite close to that of natural bone. The high relative growth rate of wild-type mouse embryonic fibroblasts cells was found for the composite, indicating a good biocompatibility. The organic-inorganic composite also behaved good in collagenase resistance and could be biodegraded in 8 weeks, with about 50% of initial weight left at the ratio of Col to CMC of 1:9. The results demonstrated that the Col-CMC/HA composite by bi-molecular template method was a rational and safe method to prepare biomaterials with tunable properties.