GPRC5A promotes gallbladder cancer metastasis by upregulating TNS4 via the JAK2-STAT3 pathway.

Aberrant expression of G protein-coupled receptor class C group 5 member A (GPRC5A) has been reported in multiple cancers and is closely related to patient prognosis. However, the mechanistic role of GPRC5A in gallbladder cancer (GBC) remains unclear. Here, we determined tumor expression levels of GPRC5A and the molecular mechanisms by which GPRC5A regulates gallbladder cancer metastasis. We found that GPRC5A was significantly upregulated in GBC, correlating with poorer patient survival. Knocking down GPRC5A inhibited GBC cell metastasis both in vitro and in vivo. GRPRC5A knockdown resulted in downregulation of TNS4 expression through the JAK2-STAT3 axis. Clinically, GPRC5A expression positively correlated with TNS4. Finally, STAT3 bound to TNS4's promoter region, inducing its expression. Overall, GPRC5A showed high expression in GBC tissues, associated with poor patient prognosis. Our findings first demonstrate that the GPRC5A-JAK2-STAT3-TNS4 pathway promotes GBC cell metastasis, suggesting potential therapy targets.

Alpha-synuclein Affects Certain Iron Transporters of BV2 Microglia Cell through its ferric reductase activity.

OBJECTIVE: Alpha-synuclein (α-syn) is a major component of lewy bodies, which is biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacts (SNpc) to form insoluble aggregates and cause neurotoxicity, which is often accompanied by iron deposition. METHOD: We compared the iron reductase activity between monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn), investigated the effect of α-syn on iron metabolism of BV2 microglia cells as well. RESULTS: α-syn had ferric reductase activity, and O-α-syn had stronger enzyme activity than M-α-syn. M-α-syn upregulated iron uptake protein, divalent metal transporter1 (DMT1) expression and iron influx, but did not regulate iron release protein, ferroportin1 (FPN1) expression and iron efflux. O-α-syn elevated the expression of both DMT1 and FPN1, thus increased the iron influx and efflux in BV2 microglial cells, but the expressions of iron regulatory protein1 (IRP1) and hypoxia inducible factor2α (HIF-2α) had no significant change. Moreover, both M-α-syn and O-α-syn could increase the mRNA expressions of TNF-α and IL-1ß in BV2 microglia cells. CONCLUSION: Both types of α-syn can activate microglia, which leads to increased expressions of pro-inflammatory factors. α-syn can affect DMT1 and FPN1 expressions in BV2 microglia cells, which might be through its ferric reductase activity.

Effects of eugenol on physicochemical properties of sturgeon skin collagen-chitosan composite membrane.

In this study, a series of collagen-chitosan-eugenol (CO-CS-Eu) flow-casting composite films were prepared using collagen from sturgeon skin, chitosan, and eugenol. The physicochemical properties, mechanical properties, microstructure, as well as antioxidant and antimicrobial activities of the composite membranes were investigated by various characterization techniques. The findings revealed that the inclusion of eugenol augmented the thickness of the film, darkened its color, reduced the transparency, and enhanced the ultraviolet light-blocking capabilities, with the physicochemical properties of the CO-CS-0.25%Eu film being notably favorable. Eugenol generates increasingly intricate matrices that disperse within the system, thereby modifying the optical properties of the material. Furthermore, the tensile strength of the film decreased from 70.97 to 20.32 MPa, indicating that eugenol enhances the fluidity and ductility of the film. Added eugenol also exhibited structural impact by loosening the film cross-section and decreasing its density. The Fourier transform infrared spectroscopy results revealed the occurrence of several intermolecular interactions among collagen, chitosan, and eugenol. Moreover, the incorporation of eugenol bolstered the antioxidant and antimicrobial capabilities of the composite film. This is primarily attributed to the abundant phenolic/hydroxyl groups present in eugenol, which can react with free radicals by forming phenoxy groups and neutralizing hydroxyl groups. Consequently, inclusion of eugenol substantially enhances the freshness retention performance of the composite film. PRACTICAL APPLICATION: ● The CO-CS-Eu film utilizes collagen from sturgeon skin, improving the use of sturgeon resources.● Different concentrations of eugenol altered its synergistic effect with chitosan.● The CO-CS-Eu film is composed of natural products with safe and edible properties.

Effect of commercial fibrolytic enzymes application to normal- and slightly lower energy diets on lactational performance, digestibility and plasma nutrients in high-producing dairy cows.

The inclusion of fibrolytic enzymes in the diet is believed to have positive effects on animal production. Hence, the objective of this study was to investigate the impact of supplementing diets with a commercial fibrolytic enzyme preparation (Vistamax; mixture of xylanase and cellulase) derived from Trichoderma reesei on lactational performance, digestibility, and plasma nutrient levels in high-producing dairy cows. Two dietary energy levels were considered: a normal energy diet (metabolizable energy = 2.68 Mcal/kg) and a slightly lower energy diet (metabolizable energy = 2.55 Mcal/kg). A total of 120 lactating Holstein cows (parity = 2; Days in Milk = 113 ± 23) were randomly assigned to four treatment groups using a 2 * 2 factorial arrangement. The dietary treatments consisted of: (1) normal energy diet without enzyme supplementation (NL); (2) normal energy diet with enzyme supplementation (NLE); (3) slightly lower energy diet without enzyme supplementation (SL); and (4) slightly lower energy diet with enzyme supplementation (SLE). The amount of enzyme added to the diets was determined based on previous in vitro studies and supplier recommendations. The enzyme and premix were mixed prior to the preparation of the total mixed ration, and the trial lasted for a duration of 42 days. The results indicated that the application of the fibrolytic enzyme did not have a significant effect on dry matter intake (DMI), but it did enhance the digestibility of dry matter (DM), neutral detergent fiber (NDF), potentially digestible NDF (pdNDF), organic matter (OM), milk production, milk urea nitrogen (MUN), and blood urea nitrogen (BUN). On the other hand, the slightly lower energy diet resulted in a decrease in DMI, milk production, milk protein yield, plasma free amino acids (FAA), and an increase in plasma B-hydroxybutyrate (BHBA). In conclusion, the inclusion of the fibrolytic enzyme in the diets of dairy cows led to improvements in the digestibility of DM, NDF, pdNDF, OM, milk production, and feed efficiency. Furthermore, the application of the enzyme to the slightly lower energy diet resulted in milk production levels comparable to those observed in cows fed the untreated normal energy diet.

Acylcarnitines promote gallbladder cancer metastasis through lncBCL2L11-THOC5-JNK axis.

BACKGROUND: The progression of gallbladder cancer (GBC) is accompanied by abnormal fatty acid ß-oxidation (FAO) metabolism. Different types of lipids perform various biological functions. This study aimed to determine the role of acyl carnitines in the molecular mechanisms of GBC progression. METHODS: Distribution of lipids in GBC was described by LC-MS-based lipidomics. Cellular localization, expression level and full-length of lncBCL2L11 were detected using fluorescence in situ hybridization (FISH) assays, subcellular fractionation assay and 5' and 3' rapid amplification of the cDNA ends (RACE), respectively. In vitro and in vivo experiments were used to verify the biological function of lncBCL2L11 in GBC cells. Methylated RNA Immunoprecipitation (MeRIP) was performed to detect the methylation levels of lncBCL2L11. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were used to identify lncBCL2L11 interacting proteins. Co-Immunoprecipitation (Co-IP) and Western blot assay were performed to validate the regulatory mechanism of lncBCL2L11 and THO complex. RESULTS: Acylcarnitines were significantly up-regulated in GBC tissues. High serum triglycerides correlated to decreased survival in GBC patients and promoted tumor migration. LncBCL2L11 was identified in the joint analysis of highly metastatic cells and RNA sequencing data. LncBCl2L11 prevented the binding of THOC6 and THOC5 and causes the degradation of THOC5, thus promoting the accumulation of acylcarnitines in GBC cells, leading to the malignant progression of cancer cells. In addition, highly expressed acylcarnitines stabilized the expression of lncBCL2L11 through N6-methyladenosine methylation (m6A), forming a positive feedback regulation in tumor dissemination. CONCLUSIONS: LncBCL2L11 is involved in gallbladder cancer metastasis through FAO metabolism. High lipid intake is associated with poor prognosis of GBC. Therefore, targeting lncBCL2L11 and its pathway-related proteins or reducing lipid intake may be significant for the treatment of GBC patients.

Multiplex Assay of Cytokines with Tunable Detection Ranges for the Precise Diagnosis of Breast Cancer.

Precise profiling of the cytokine panel consisting of different levels of cytokines can provide personalized information about several diseases at certain stages. In this study, we have designed and fabricated an "all-in-one" diagnostic tool kit to bioassay multiple inflammatory cytokines ranging from picograms per milliliter to µg/mL in a small cytokine panel. Taking advantage of the kit fabricated by the DNA-encoded assembly of nanocatalysts in dynamic regulation and signal amplification, we have demonstrated the multiplex, visual, and quantitative detection of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) with limits of detection of 1.6 ng/mL (61.54 pM), 20 pg/mL (1.57 pM), and 4 pg/mL (0.19 pM), respectively. This diagnostic tool kit can work well with commercial kits for detecting serum cytokines from breast cancer patients treated with immunotherapies. Furthermore, a small cytokine panel composed of CRP, PCT, and IL-6 is revealed to be significantly heterogeneous in each patient and highly dynamic for different treatment courses, showing promise as a panel of quantitative biomarker candidates for individual treatments. So, our work may provide a versatile diagnostic tool kit for the visual detection of clinical biomarkers with an adjustable broad detection range.

UBA3 promotes the occurrence and metastasis of intrahepatic cholangiocarcinoma through MAPK signaling pathway.

Intrahepatic cholangiocarcinoma (ICC) accounts for approximately 15% of primary liver cancers, and the incidence rate has been increasing in recent years. Surgical resection is the best treatment for ICC, but the 5-year survival rate is less than 30%. ICC signature genes are crucial for the early diagnosis of ICC, so it is especially important to identify signature genes. The aim of this study is to screen the signature genes of ICC and find the potential target for the treatment of ICC. We find that UBA3 is highly expressed in ICC, and knockdown of UBA3 inhibits ICC proliferation, invasion and migration. Mechanistic experiments show that UBA3 promotes ICC proliferation, invasion and migration by affecting ANXA2 through the MAPK signaling pathway. UBA3 is a target of bufalin, and bufalin targeting UBA3 inhibits ICC development and progression through the MAPK signaling pathway. In conclusion, our study shows that bufalin inhibits ICC by targeting UBA3, which has emerged as a new biomarker and potential therapeutic target for ICC.

An electrochemical biosensor to assay Trop-2 of breast cancer cells fabricated by methylene blue-assisted assembly of DNA nanoparticles.

Human trophoblast surface cell antigen 2 (Trop-2) on the tumor cell membrane can not only serve as the target for chemotherapy drugs, but also as a biomarker for typing and prognosis of breast cancer; however, assay of Trop-2 is seriously hampered due to the limitations of available tool. Herein, we have designed and fabricated an electrochemical biosensor for the assay of Trop-2 based on methylene blue (MB)-assisted assembly of DNA nanocomposite particles (DNPs). Specially, the recognition between Trop-2 and its aptamer may activate the primer exchange reaction (PER) on an electrode surface to produce long single-strand DNA (ssDNA) which can be self-assembled into DNPs by electrostatic interaction between negative charged DNA and positive charged and electro-active MB molecules which can also be used to give electrochemical signal. By using this electrochemical biosensor, ultrasensitive detection of tumor cells with high Trop-2 expressions can be conducted, with the limit of detection (LOD) of 1 cell/mL. Moreover, this biosensor can be further used for accurately profiling Trop-2 expression of tumor cells in mouse tissues, suggesting its great potential in the precise definition of breast cancer.

Contrasting Iron Metabolism in Undifferentiated Versus Differentiated MO3.13 Oligodendrocytes via IL-1ß-Induced Iron Regulatory Protein 1.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of iron in the substantia nigra. While iron accumulation and inflammation are implicated in PD pathogenesis, their impact on oligodendrocytes, the brain's myelin-forming cells, remains elusive. This study investigated the influence of interleukin-1ß (IL-1ß), an elevated proinflammatory cytokine in PD, on iron-related proteins in MO3.13 oligodendrocytes. We found that IL-1ß treatment in undifferentiated MO3.13 oligodendrocytes increased iron regulatory protein 1 and transferrin receptor 1 (TfR1) expression while decreasing ferroportin 1 (FPN1) expression. Consequently, iron uptake was enhanced, and iron release was reduced, leading to intracellular iron accumulation. Conversely, IL-1ß treatment in differentiated MO3.13 oligodendrocytes exhibited the opposite effect, with decreased TfR1 expression, increased FPN1 expression, and reduced iron uptake. These findings suggest that IL-1ß-induced dysregulation of iron metabolism in oligodendrocytes may contribute to the pathological processes observed in PD. IL-1ß can increase the iron content in undifferentiated oligodendrocytes, thus facilitating the differentiation of undifferentiated MO3.13 oligodendrocytes. In differentiated oligodendrocytes, IL-1ß may facilitate iron release, providing a potential source of iron for neighboring dopaminergic neurons, thereby initiating a cascade of deleterious events. This study provides valuable insights into the intricate interplay between inflammation, abnormal iron accumulation, and oligodendrocyte dysfunction in PD. Targeting the IL-1ß-mediated alterations in iron metabolism may hold therapeutic potential for mitigating neurodegeneration and preserving dopaminergic function in PD.

A Reasoned Action Approach to Social Connection and Mental Health: Racial Group Differences and Similarities in Attitudes, Norms, and Intentions.

This study employed a Reasoned Action Approach to investigate two communication behaviors that were being built into a statewide behavioral health campaign: initiating a conversation about one's own mental health struggles, and starting a conversation to discuss someone else's mental health difficulties. We examined whether the extent of attitudes, perceived norms, and perceived behavioral control regarding intent to perform these behaviors varied by racial identity. Using original survey data from Texans (N = 2,033), we conducted regression analyses for the two communication behaviors and found that intention to seek help was primarily explained by instrumental attitude, injunctive norm, descriptive norm, and perceived capacity; and intention to start a conversation to help someone else was primarily explained by instrumental attitude, injunctive norm, and perceived capacity. Additionally, we identified important common and distinct determinants of the two behaviors across different racial groups. Implications for health communication campaign message development and audience segmentation are discussed.

Heme oxygenase-1: The roles of both good and evil in neurodegenerative diseases.

Heme oxygenase-1 (HO-1) is the only way for cells to decompose heme. It can cleave heme to produce carbon monoxide (CO), ferrous iron (Fe2+ ), and biliverdin (BV). BV is reduced to bilirubin (BR) by biliverdin reductase(BVR). In previous studies, HO-1 was considered to have protective effects because of its anti-inflammatory, anti-apoptosis, and antiproliferation functions. However, emerging experimental studies have found that the metabolites derived from HO-1 can cause increase iin intracellular oxidative stress, mitochondrial damage, iron death, and autophagy. Because of its particularity, it is very meaningful to understand its exact mechanism. In this review, we summarized the protective and toxic effects of HO-1, its potential mechanism, its role in neurodegenerative diseases and related drug research. This knowledge may be beneficial to the development of new therapies for neurodegenerative diseases and is crucial to the development of new therapeutic strategies and biomarkers.

Alpha-synuclein Affects Certain Iron Transporters of BV2 Microglia Cell through its ferric reductase activity.

Alpha-synuclein (α-syn) is a major component of lewy bodies, which is biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacts (SNpc) to form insoluble aggregates and cause neurotoxicity, which is often accompanied by iron deposition. In this study, we compared the iron reductase activity between monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn), investigated the effect of α-syn on iron metabolism of BV2 microglia cells as well. We found that α-syn had ferric reductase activity, and O-α-syn had stronger enzyme activity than M-α-syn. M-α-syn upregulated iron uptake protein, divalent metal transporter1 (DMT1) expression and iron influx, but did not regulate iron release protein, ferroportin1 (FPN1) expression and iron efflux. O-α-syn elevated the expression of both DMT1 and FPN1, thus increased the iron influx and efflux in BV2 microglial cells, but the expressions of iron regulatory protein1 and hypoxia inducible factor2α have no significant change. Moreover, both M-α-syn and O-α-syn could increase the mRNA expressions of TNF-α and IL-1ß in BV2 microglia cells. Taken together, our data suggest that both types of α-syn can activate microglia, which leads to increased expressions of pro-inflammatory factors. α-syn can affect DMT1 and FPN1 expressions in BV2 microglia cells, which might be through its ferric reductase activity.

Roles of macrophages on ulcerative colitis and colitis-associated colorectal cancer.

Colitis-associated colorectal cancer is the most serious complication of ulcerative colitis. Long-term chronic inflammation increases the incidence of CAC in UC patients. Compared with sporadic colorectal cancer, CAC means multiple lesions, worse pathological type and worse prognosis. Macrophage is a kind of innate immune cell, which play an important role both in inflammatory response and tumor immunity. Macrophages are polarized into two phenotypes under different conditions: M1 and M2. In UC, enhanced macrophage infiltration produces a large number of inflammatory cytokines, which promote tumorigenesis of UC. M1 polarization has an anti-tumor effect after CAC formation, whereas M2 polarization promotes tumor growth. M2 polarization plays a tumor-promoting role. Some drugs have been shown to that prevent and treat CAC effectively by targeting macrophages.

Effect of fermentation methods on properties of dough and whole wheat bread.

BACKGROUND: Whole wheat bread is high in nutritional value but poor in technological quality; therefore, research on how to improve its technological quality has attracted extensive attention. The effects of fermentation methods, including straight dough(STD), sourdough (SOD), sponge dough (SPD), and refrigerated SPD (RSD) methods, on the dough and bread quality of whole wheat bread were investigated, focusing on pasting properties, rheological properties, thermal properties, microstructure, basic quality, and starch digestibility. RESULTS: The rapid viscosity analysis and rheological results demonstrated that SOD had the highest pasting temperature and the lowest viscosity, indicating an inhibition of starch pasting and partial protein hydrolysis, whereas the opposite trend presented by SPD and RSD indicated a greater starch hydration and a stronger gluten network. Thermal gravimetric analysis and differential scanning calorimetry results indicated reduced starch thermal degradation and increased starch pasting enthalpy in SOD and RSD. Scanning electron microscopy images revealed that the starch granules of SOD and RSD were tightly wrapped by a gluten network. SOD and RSD breads had the largest specific volume, the softest texture, and the lowest glycemic index. CONCLUSION: The effects of different fermentation methods on dough and bread structure can provide instructive information for future studies on their applications in whole wheat bread production. © 2023 Society of Chemical Industry.

α­hederin overcomes hypoxia­mediated drug resistance in colorectal cancer by inhibiting the AKT/Bcl2 pathway.

Currently, chemoresistance is a major challenge that directly affects the prognosis of patients with colorectal cancer (CRC). In addition, hypoxia is associated with poor prognosis and therapeutic resistance in patients with cancer. Accumulating evidence has shown that α­hederin has significant antitumour effects and that α­hederin can inhibit hypoxia­mediated drug resistance in CRC; however, the underlying mechanism remains unclear. In the present study, viability and proliferation assays were used to evaluate the effect of α­hederin on the drug resistance of CRC cells under hypoxia. Sequencing analysis and apoptosis assays were used to determine the effect of α­hederin on apoptosis under hypoxia. Western blot analysis and reverse transcription­quantitative PCR were used to measure apoptosis­related protein and mRNA expression levels. Furthermore, different mouse models were established to study the effect of α­hederin on hypoxia­mediated CRC drug resistance in vivo. In the present study, the high expression of Bcl2 in hypoxic CRC cells was revealed to be a key factor in their drug resistance, whereas α­hederin inhibited the expression of Bcl2 by reducing AKT phosphorylation in vitro and in vivo, and promoted the apoptosis of CRC cells under hypoxia. By contrast, overexpression of AKT reversed the effect of α­hederin on CRC cell apoptosis under hypoxia. Taken together, these results suggested that α­hederin may overcome hypoxia­mediated drug resistance in CRC by inhibiting the AKT/Bcl2 pathway. In the future, α­hederin may be used as a novel adjuvant for reversing drug resistance in CRC.

Bufalin reverses cancer-associated fibroblast-mediated colorectal cancer metastasis by inhibiting the STAT3 signaling pathway.

At present, recurrence and metastasis are still important factors that lead to a poor prognosis among colorectal cancer (CRC) patients. Cancer-associated fibroblasts (CAFs) can promote tumorigenesis and development. Bufalin is the main active monomer of the clinical drug cinobufacini, which exhibits antitumor activity in various cancers. But few research have investigated the effect of bufalin in inhibiting metastasis from the perspective of the tumor microenvironment. We first isolated CAFs from freshly resected colorectal cancer patient specimens and observed the effect of CAFs on CRC cell invasion through a series of experiments. We explored the effect of bufalin on the physiological activity of CRC mediated by CAFs through experiments. In our study, we found that CAFs could promote CRC cell activity through the STAT3 pathway. Bufalin reversed CAF-mediated CRC invasion and metastasis by inhibiting the STAT3 pathway. Overexpression of STAT3 attenuated the inhibitory function of bufalin on invasion and metastasis. Taken together, bufalin can reverse CAF-mediated colorectal cancer metastasis based on inhibiting the STAT3 signaling pathway.

The Effectiveness of CDC's Rx Awareness Campaigns on Reducing Opioid Stigma: Implications for Health Communication.

Often health communication campaigns addressing misusing prescription opioids and opioid use disorder (OUD) do not pay enough attention to the associated stigma. This study investigated the effectiveness of a well-designed opioid awareness campaign on reducing stigma and provided evidence for future health communication design. CDC's Rx Awareness videos were used as the experiment material. 137 college students participated in this online experiment, and audience characteristics and video features were considered and tested. The results showed that Rx Awareness videos significantly reduced participants' stigmatizing attitudes and perceived public stigma and increased their empathy toward people with OUD. Empathy is a promising strategy to reduce opioid stigma. People with an opioid prescription history expressed more empathy. Recovery information, prescription history, and narrators' race influenced the audience's perceived public stigma. Implications for health communications and limitations of the study are discussed.

An electrochemical biosensor for SARS-CoV-2 detection via its papain-like cysteine protease and the protease inhibitor screening.

The persistent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still infecting hundreds of thousands of people every day. Enriching the kits for SARS-CoV-2 detection and developing the drugs for patient treatments are still urgently needed for combating the spreading virus, especially after the emergence of various mutants. Herein, an electrochemical biosensor has been fabricated in this work for the detection of SARS-CoV-2 via its papain-like cysteine protease (PLpro) and the screening of protease inhibitor against SARS-CoV-2 by using our designed chimeric peptide-DNA (pDNA) nanoprobes. Utilizing this biosensor, the sensitive and specific detection of SARS-CoV-2 PLpro can be conducted in complex real environments including blood and saliva. Five positive and five negative patient throat swab samples have also been tested to verify the practical application capability of the biosensor. Moreover, we have obtained a detection limit of 27.18 fM and a linear detection range from 1 pg mL-1 to 10 µg mL-1 (I = 1.63 + 4.44 lgC). Meanwhile, rapid inhibitor screening against SARS-CoV-2 PLpro can be also obtained. Therefore, this electrochemical biosensor has the great potential for COVID-19 combating and drug development.

Iron Overload Causes Ferroptosis But Not Apoptosis in MO3.13 Oligodendrocytes.

Oligodendrocytes are the most iron-rich cells in the brain. Studies have shown that oligodendrocytes are very sensitive to oxidative stress, and iron overload is more likely to cause damage to oligodendrocytes. The purpose of this experiment was to investigate the damaging effect and mechanism of ferric ammonium citrate (FAC) on MO3.13 oligodendrocytes. In FAC treatment group, the intracellular iron concentration and intracellular reactive oxygen species were increased. There were no obvious changes in nucleus and chromatin, but increased mitochondrial membrane density, decreased mitochondrial cristae and mitochondrial length were observed. Glutathione peroxidase 4 (GPX4) expression was decreased, but the ratio of Bcl-2/Bax protein levels and cleaved caspase-3 expression did not change. Moreover, the iron chelator deferoxamine (DFO) and the ferroptosis inhibitor ferrostatin-1(Fer-1) could inhibit the upregulation of GPX4, which indicating that DFO and Fer-1 could inhibit ferroptosis in MO3.13 oligodendrocytes induced by iron overload. Furthermore, the phosphorylation level of p53 was not changed, while the ratio of protein expressions of p-Erk1/2/Erk1/2 were markedly increased. Taken together, our data suggest that iron overload induces ferroptosis but not apoptosis in oligodendrocytes. The mechanism may be related to mitogen-activated protein kinase pathway activation rather than p53 pathway activation.

Long-term exposure to genistein inhibits the proliferation of gallbladder cancer by downregulating the MCM complex.

Soy isoflavones are natural tyrosine kinase inhibitors closely associated with decreased morbidity and mortality of various tumors. The activation of tyrosine kinases such as ERBB2 is the mechanism by which cholecystitis transforms into gallbladder cancer (GBC), therefore, it is important to investigate the relationship between long-term exposure to soy isoflavones and the occurrence and progression of GBC. This case-control study (n = 85 pairs) found that the high level of plasma soy isoflavone-genistein (GEN) was associated with a lower risk of gallbladder cancer (≥326.00 ng/mL compared to ≤19.30 ng/mL, crude odds ratio 0.15, 95% CI 0.04-0.59; P for trend = 0.016), and that the level of GEN exposure negatively correlated with Ki67 expression in GBC tissue (n = 85). Consistent with these results, the proliferation of GBC cells was inhibited in the long-term exposure models of GEN in vitro and in vivo. The long-term exposure to GEN reduced the tyrosine kinase activity of ERBB2 and impaired the function of the PTK6-AKT-GSK3ß axis, leading to downregulation of the MCM complex in GBC cells. In summary, long-term exposure to GEN associated with soy products intake might play a certain role in preventing GBC and even inhibiting the proliferation of GBC cells.