Bisphenol A (BPA), a commonly used plastic additive, is believed to cause obesity. As an environmental endocrine disruptor, BPA is closely associated with the onset and progression of BC. However, the molecular mechanisms underlying the promotion of breast cancer by BPA remain unclear. As obesity is a significant risk factor for breast cancer, this study aimed at exploring whether BPA facilitates the progression of breast cancer by inducing obesity. Using the National Health and Nutrition Examination Survey data, a positive correlation was observed between BPA exposure and the risk of sex-specific cancers among US adults with body mass index ≥30, suggesting that obesity may be influenced by urinary BPA. 3T3-L1 cells differentiated into mature adipocytes following treatment with 10-8 M BPA, and subsequent treatment with 4T1-conditioned medium acquired properties associated with cancer-associated adipocytes (CAAs). Network pharmacology suggested that CXCL12 may serve as a key target gene in breast cancer progression. Follow-up PCR analysis revealed high CXCL12 expression in BPA-induced CAAs. Overexpression of CXCL12 promoted epithelial-mesenchymal transition (EMT) and 4T1 cell migration by activating the AKT pathway. In vivo, BPA-induced CAAs accelerated tumor growth compared to a controls xenografted with only 4T1 cells. In tissues from the BPA-CAAs group, the expression of CXCL12, markers associated with CAAs, phosphorylated AKT, N-cadherin, and vimentin was markedly elevated, whereas the expression of E-cadherin was reduced. In conclusion, BPA may induce adipose cells to differentiate into CAA-like cells and subsequently advance breast cancer EMT through the CXCL12/AKT pathway.

BACKGROUND:The occurrence and development of cancer are deeply intertwined with chronic inflammatory processes. Epigallocatechin gallate (EGCG), the most pharmacologically potent catechin derived from tea, has garnered attention for its anti-inflammatory and anti-carcinogenic properties. However, the molecular mechanisms through which EGCG modulates tobacco smoke (TS)-induced inflammatory responses in lung carcinogenesis remain incompletely elucidated. PURPOSE:To unravel the molecular mechanisms by which EGCG mitigates TS-induced inflammatory processes in lung carcinogenesis. METHODS:Network pharmacology analysis was conducted to explore the potential target genes of EGCG involved in the inhibition of TS-induced lung cancer inflammation. In vitro and in vivo experiments were conducted to demonstrate EGCG's chemopreventive potential against lung carcinogenesis. RESULTS:Utilizing data from the US adults, it was uncovered that tea consumption could suppress the inflammatory response in patients with various cancer types. CCL5 (chemokine (CC motif) ligand 5) could function as a core regulator of TS-induced lung cancer cell proliferation, and EGCG exerted beneficial effects. The following experiments revealed that TS upregulated CCL5 expression in H1299 and H226 cells. CCL5 recombinant protein elevated both ROS production and Nrf2 expression to promote lung cancer cell proliferation. EGCG could suppress CCL5-stimulated lung cancer cell proliferation by downregulating Nrf2 expression. In the mouse model, EGCG reduced tumor weight and volume, diminished the levels of CCL5, Ki67, Cyclin D1, PCNA, and Nrf2, and elevated the expression of Keap1 relative to the control group. CONCLUSION:EGCG targets CCL5 to inhibit the proliferation of TS-induced lung cancer cells and may serve as a new treatment strategy.

The effects of high doses of folic acid (FA) during pregnancy on anxiety- and depression-like behaviors in adolescent offspring mice were determined and the potential underlying mechanisms were elucidated. Pregnant C57BL/6 mice were randomly assigned to Control (2 mg/kg in feed), high FA (20 mg/kg in feed), and ultrahigh FA (40 mg/kg in feed) groups. The physiological development of the offspring, their preweaning neurobehavioral milestones, and adolescent behaviors indicative of anxiety and depression were assessed. High doses of FA during pregnancy delayed key developmental milestones such as pinna detachment, fur appearance, and incisor eruption. Furthermore, it triggered anxiety-like behavior in the passive avoidance test and led to depression-like behavior, as reflected by reduced movement distance in the center zone and decreased shuttling frequency in the light-dark box test and open field test. Additionally, brain tissues of the offspring exhibited increased expression of the microglia marker ionized calcium-binding adaptor molecule 1 and the Nod-like receptor protein 3 inflammasome. These findings suggest that high doses of FA during pregnancy may impair physiological development and increase the susceptibility of the offspring to anxiety- and depression-like behaviors, potentially mediated through the induction of low-grade inflammation in the brain.

Doxorubicin (DOX), a widely used anthracycline chemotherapeutic, is clinically limited by cumulative and dose-dependent cardiotoxicity. Oxidative stress and inflammation are central pathogenic mechanisms of DOX-induced cardiomyopathy (DIC), characterized by extensive innate immune cells infiltration into the injured myocardium. The immune landscape of DIC mouse models is systematically characterized, identifying macrophages as the predominant immune subset. Based on this, a hybrid nanozyme (PB@CeO2 NPs) is developed, comprising Prussian blue nanoparticles (PB NPs) and cerium oxide nanoparticles (CeO2 NPs). The PB NPs core provides magnetic resonance imaging (MRI) contrast, while CeO2 NPs surface modification enhances immune cell uptake, promotes retention in inflamed cardiac tissue, and augments reactive oxygen species (ROS) scavenging and anti-inflammatory efficacy. In vitro experiments demonstrate that PB@CeO2 NPs alleviate mitochondrial damage, inhibit apoptosis, and induce macrophage M2 polarization. In vivo studies show that PB@CeO2 NPs facilitate myocardial accumulation, reduce cardiac inflammation and fibrosis, and improve cardiac function. By integrating the antioxidative and anti-inflammatory effects of PB@CeO2 NPs with inflammation-mediated immune cell retention in injured myocardium, this study presents a promising nanotherapeutic platform for targeted and precise intervention in anthracycline-induced cardiotoxicity.

BACKGROUND:Despite extensive research on muscle loss in people living with HIV (PLWH), the prevalence and contributing factors specifically among middle-aged men remain unclear. This study aimed to determine the prevalence of low muscle mass within this demographic and to identify associated factors. METHODS:A total of 378 men living with HIV were enrolled in the study. They were classified into low muscle mass group if they displayed a skeletal muscle index (SMI) <7.00 kg/m2 or fell within the lowest quintile of SMI based on the criteria established by the Asian Working Group for Sarcopenia 2019. RESULTS:Out of the 378 men living with HIV enrolled, 351 had normal muscle mass, while 27 (7.1%) had low muscle mass. Antiretroviral drugs Zidovudine (AZT) (OR = 0.246, P = 0.022) and higher serum albumin levels (OR = 0.899, P = 0.026) were found to be protective factors against low muscle mass according to quintile grouping. Strong positive associations between SMI and body mass index (BMI), nutritional risk index (NRI), oedema index and fat-free mass index (FFMI) (R > 0.5, P < 0.001) were observed. In addition, both BMI (sensitivity = 0.741, specificity = 0.906) and NRI (sensitivity = 0.963, specificity = 0.601) had high sensitivity and specificity in diagnosing low muscle mass, with critical values of 19.85 and 114.177 for BMI and NRI, respectively. The oedema index was the most effective measure of body composition in detecting abnormal fluid retention with high sensitivity (92.6%) and moderate specificity (71.8%) in identifying individuals with low muscle mass. Notably, PLWH with low muscle mass participants had a significantly higher prevalence (92.6%) of a high oedema index compared with those with normal muscle mass (28.2%). This observation indicates that individuals with HIV who experience reduced muscle mass is commonly accompanied with abnormal fluid retention within the body. CONCLUSIONS:Antiretroviral medication types, specifically Zidovudine, BMI and NRI can be independent risk factors for low muscle mass in men with HIV. These factors, along with BMI, could be used conveniently to predict low muscle mass. Furthermore, the association between the oedema index and muscle mass suggests that observing signs of oedema may indicate a risk of low muscle mass in PLWH.

Background. Bisphenol A (BPA) disrupts glucose homeostasis via inflammatory pathways in liver cells, affecting insulin sensitivity. This study examines sulforaphane (SFN), known for its anti‐inflammatory and antioxidative properties, for counteracting BPA’s effects. Methods. We evaluated SFN’s impact on BPA‐exposed C57/BL6J mice and HepG2 cells, focusing on metabolic parameters, insulin signaling, and inflammatory markers. Mice were treated with SFN (10 mg/kg) for six weeks, with assessments including body weight, serum glucose, insulin levels, and glucose tolerance. Molecular analyses in both models included gene expressions related to glucose metabolism, insulin and MAPK signaling pathways, and markers of inflammation and oxidative stress. Results. SFN reduced blood glucose and improved glucose tolerance of BPA‐treated mice. In BPA‐treated HepG2 cells, SFN significantly boosted glucose consumption in vitro. Moreover, SFN treatment enhanced the protein expression of phosphorylated‐insulin receptor and phosphorylated‐AKT and reversed glycolytic and gluconeogenic gene expression in HepG2 cells and mice liver. SFN also decreased phosphorylation levels of p38 and JNK and reduced inflammation and oxidative stress markers in vitro and in vivo. Conclusion. Our findings underscore SFN’s capacity to ameliorate BPA‐induced glucose intolerance and insulin resistance by enhancing hepatic insulin signaling and metabolic functions. This action is likely mediated through SFN’s inhibitory effects on inflammatory and oxidative pathways. Consequently, SFN holds promise as an intervention for mitigating BPA‐related metabolic disorders.

To investigate how antiretroviral therapy (ART) regimens and body mass index (BMI) interact to affect triglyceride (TG) levels in people living with HIV (PLWH). This research involved 451 men living with HIV for cross-sectional analysis, and 132 underwent follow-up assessments in 2021 and 2023. Multivariate logistic regression identified key factors, while covariance regression models assessed interactions between ART regimens and BMI on TG levels. The result of this cross-sectional study indicated that advanced AIDS (acquired immune deficiency syndrome) stage (OR = 2.756, P = 0.003), higher BMI (OR = 1.131, P = 0.003), and waist-hip ratio (WHR, OR = 44.684, P = 0.019) are closely associated with high triglyceride levels. Additionally, regimens containing zidovudine (AZT) (OR = 3.927, P < 0.001) or protease inhibitors/integrase strand transfer inhibitors (PI/INSTI) (OR = 5.167, P < 0.001) were significantly linked to hypertriglyceridemia. Cross-sectional and longitudinal analyses from 2021 to 2023 emphasized that changes in BMI interact with antiretroviral treatment regimens to affect TG levels in PLWH (Pinteraction < 0.05). Especially in the AZT-based drug regimen, the correlation between BMI and TG is more prominent. The interaction between ART regimens and BMI influences TG levels in PLWH, indicating that weight management is crucial for reducing the risk of hypertriglyceridemia in this population.

Lung cancer stem cells (CSCs) drive continuous cancer growth and metastatic dissemination; thus, there is an urgent requirement to acquire effective therapeutic strategies for targeting lung CSCs. Diallyl trisulfide (DATS), a garlic organosulfide, possesses suppressive potential in lung cancer; however, its underlying mechanism is still unclear. In this study, we identified DATS as a pyroptosis inducer in lung cancer cells. DATS-treated A549 and H460 cells exhibited pyroptotic cell death, with characteristic large bubbles appearing on their plasma membrane and LDH release. DATS induced cell death, arrested the cell cycle at the G2/M phase, and inhibited colony formation in lung cancer cells. Meanwhile, we found that DATS significantly suppressed the malignant features by impairing lung CSC-like properties, including sphere formation ability, CD133 positive cell number, and lung CSCs marker expression. Mechanistically, DATS induced cell pyroptosis via increasing the expression of NLRP3, ASC, Pro Caspase 1, Cleaved Caspase 1, GSDMD, GSDMD-N, and IL-1β. The verification experiments showed that the effects of DATS on pyroptosis and lung CSC-like properties were weakened after Caspase 1 inhibitor VX-765 treatment, indicating that DATS activated NLRP3 inflammasome-mediated pyroptosis by targeting Caspase 1 in lung cancer cells. Moreover, DATS increased ROS overproduction and mitochondrial dysfunction, which contributed to DATS-induced pyroptosis of lung cancer cells. NAC treatment reversed the effects of DATS on pyroptosis and CSC-like properties. In vivo experiment further confirmed that DATS restrained tumor growth. Together, our results suggest that DATS promotes pyroptosis and impairs lung CSC-like properties by activating ROS/Caspase 1 signaling pathway, thereby retarding lung cancer progression.

The prevalence and mortality of hepatocellular carcinoma (HCC) are still increasing. This study aimed to identify potential therapeutic targets related to patient prognosis. Data were downloaded from TCGA, GSE25097, GSE36376, and GSE76427 datasets. Differential analysis and enrichment analysis were performed in HCC. Cell deaths were evaluated, and least absolute shrinkage and selection operator regression (LASSO) regression was analyzed to screen candidate genes. Additionally, immune cell infiltration in HCC was assessed. We identified 4088 common DEGs with the same direction of differential expression in all four datasets, they were mainly enriched in immunoinflammation and cell cycle pathways. Apoptosis was significantly suppressed in HCC in GSEA and GSVA. After LASSO regression analysis, we screened CD69, CDC25B, MGMT, TOP2A, and TXNIP as candidate genes. Among them, CD69 significantly influenced the overall survival of HCC patients in both TCGA and GSE76427. CD69 may be a protective factor for outcome of HCC patients. In addition, CD69 was positive correlation with T cells and CD3E. CD69, CDC25B, MGMT, TOP2A, and TXNIP were potential diagnostic and prognostic target for HCC, especially CD69.

PURPOSE:This study aimed to investigate the diagnostic performance of the histogram array and convolutional neural network (CNN) based on diffusion-weighted imaging (DWI) with multiple b-values under magnetic resonance imaging (MRI) to distinguish pancreatic ductal adenocarcinomas (PDACs) from solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine neoplasms (PNENs). METHODS:This retrospective study consisted of patients diagnosed with PDACs (n = 132), PNENs (n = 45) and SPNs (n = 54). All patients underwent 3.0-T MRI including DWI with 10 b values. The regions of interest (ROIs) of pancreatic tumor were manually drawn using ITK-SNAP software, which included entire tumor at DWI (b = 1500 s/m2). The histogram array was obtained through the ROIs from multiple b-value data. PyTorch (version 1.11) was used to construct a CNN classifier to categorize the histogram array into PDACs, PNENs or SPNs. RESULTS:The area under the curves (AUCs) of the histogram array and the CNN model for differentiating PDACs from PNENs and SPNs were 0.896, 0.846, and 0.839 in the training, validation and testing cohorts, respectively. The accuracy, sensitivity and specificity were 90.22%, 96.23%, and 82.05% in the training cohort, 84.78%, 96.15%, and 70.0% in the validation cohort, and 81.72%, 90.57%, and 70.0% in the testing cohort. The performance of CNN with AUC of 0.865 for this differentiation was significantly higher than that of f with AUC = 0.755 (P = 0.0057) and α with AUC = 0.776 (P = 0.0278) in all patients. CONCLUSION:The histogram array and CNN based on DWI data with multiple b-values using MRI provided an accurate diagnostic performance to differentiate PDACs from PNENs and SPNs.

Gastric cancer is one of the deadliest malignant tumors, and half of the patients develop recurrences or metastasis within 5 years after eradication therapy. Cancer stem cells (CSCs) are considered to be important in this progress. The sonic hedgehog (SHH) pathway plays an important role in the maintenance of gastric CSCs characteristics. The p63 proteins are vital transcription factors belonging to the p53 family, while their functions in regulating CSCs remain unclear. The preventive effects of dietary diallyl trisulfide (DATS) against human gastric cancer have been verified. However, whether DATS can target gastric CSCs are poorly understood. Here, we investigated the role of ?Np63/SHH pathway in gastric CSCs and the inhibitory effect of DATS on gastric CSCs via ?Np63/SHH pathway. We found that ?Np63 was upregulated in serum-free medium cultured gastric tumorspheres compared with the parental cells. Overexpression of ANp63 elevated the self renewal capacity and CSC markers' levels in gastric sphere-forming cells. Furthermore, we found that ?Np63 directly bound to the promoter region of Gli1, the key transcriptional factor of SHH pathway, to enhance its expression and to activate SHH pathway. In addition, it was revealed that DATS effectively inhibited gastric CSC properties both in vitro and in vivo settings. Activation of SHH pathway attenuated the suppressive effects of DATS on the stemness of gastric cancer. Moreover, DATS suppression of gastric CSC properties was also diminished by ?Np63 upregulation through SHH pathway activation. These findings illustrated the role of ?Np63/SHH pathway in DATS inhibition of gastric cancer stemness. Taken together, the present study suggested for the first time that DATS inhibited gastric CSCs properties by ?Np63/SHH pathway.

Resveratrol (RES) has various pharmacological bioactivities and its anticancer effects in lung cancer have been proven. However, the underlying mechanisms of action of RES in lung cancer remain unclear. This study focused on Nrf2‐mediated antioxidant systems in RES‐treated lung cancer cells. A549 and H1299 cells were treated with various concentrations of RES at different times. RES decreased cell viability, inhibited cell proliferation, and increased the number of senescent and apoptotic cells in a concentration‐ and time‐dependent manner. Moreover, RES‐induced lung cancer cell arrest at the G1 phase was accompanied by changes in apoptotic proteins (Bax, Bcl‐2, and cleaved caspase 3). Furthermore, RES induced a senescent phenotype along with changes in senescence‐related markers (senescence‐associated β‐galactosidase activity, p21, and p‐γH2AX). More importantly, with prolonged exposure time and increased exposure concentration, intracellular reactive oxygen species (ROS) continuously accumulated, resulting in a decrease in Nrf2 and its downstream antioxidant response elements, including CAT, HO‐1, NQO1, and SOD1. Meanwhile, RES‐induced ROS accumulation and cell apoptosis were reversed by N‐acetyl‐ l ‐cysteine treatment. Taken together, these results suggest that RES disturb lung cancer cellular homeostasis by destroying the intracellular antioxidant pool to increase ROS production. Our findings provide a new perspective on RES intervention in lung cancer.

Background: The omnipresence of human phthalate (PAE) exposure is linked to various adverse health issues, including breast cancer. However, the effects of low-dose PAE exposure on breast cancer stem cells (BCSCs) and the underlying mechanism remain unexplored.Methods: BCSCs from breast cancer cell lines (MDA-MB-231 and MCF-7) were enriched using a tumorsphere formation assay. Gene and protein expression was detected by measurement of quantitative real-time reverse transcription PCR, western blot, and immunofluorescence assays. Transient transfection assays were used to evaluate the involvement of Gli1, a signaling pathway molecule and ANp63 alpha, an oncogene in influencing the PAE-induced characteristics of BCSCs.Results: PAE (butylbenzyl phthalate, BBP; di-butyl phthalate, DBP; di-2-ethylhexyl phthalate, DEHP) exposure of 10-9 M significantly promoted the tumorsphere formation ability in BCSCs. Breast cancer spheroids with a 10-9 M PAE exposure had higher levels of BCSC marker mRNA and protein expression, activated sonic hedgehog (SHH) pathway, and increased mRNA and protein levels of an oncogene, ANp63 alpha. Furthermore, suppression of the SHH pathway attenuated the effects of PAEs on BCSCs. And the overexpression of ANp63 alpha enhanced PAEinduced characteristics of BCSCs, while low expression of ANp63 alpha inhibited the promotion effects of PAEs on BCSCs and the SHH pathway.Conclusion: Low-dose PAE exposure promoted the stem cell properties of BCSCs in a ANp63 alpha- and SHHdependent manner. The influence of low-dose exposure of PAEs and its relevance for the lowest observed effect concentrations requires further investigation, and the precise underlying mechanism needs to be further explored.

The aim of the present study was to investigate the role of endoplasmic reticulum (ER) stress in bisphenol A (BPA) – induced hepatic lipid accumulation as well as the protective effects of Sulforaphane (SFN) in this process. Human hepatocyte cell line (LO2) and C57/BL6J mice were used to examine BPA-triggered hepatic lipid accumulation and the underlying mechanism. Hepatic lipid accumulation, triglycerides (TGs) levels, the expression levels of lipogenesis-related genes and proteins in the ER stress pathway were measured. It was revealed that BPA treatment increased the number of lipid droplets, the levels of TG and mRNAs expression of lipogenesis-related genes, and activated the ER stress pathway. These changes were inhibited by an ER stress inhibitor 4-phenylbutyric acid. SFN treatment abrogated BPA-altered hepatic lipid metabolism and ameliorated BPA-induced ER stress-related markers. Together, these findings suggested that BPA activated ER stress to promote hepatic lipid accumulation, and that SFN reversed those BPA effects by alleviating ER stress.

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/β-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/β-catenin signaling by LiCl (GSK3β agonist). IL-6-promoted LCSC properties and Wnt/β-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound.

Liver disease has become a major cause of premature mortality worldwide. It is well known that dysregulated inflammation response plays a crucial role in most liver diseases. As a Chinese medicinal herb, Magnesium isoglycyrrhizinate (MgIG) has been proven to have good hepatoprotective activity and has been used in clinic to treat liver disease. However, the mechanisms by which MgIG regulates LPS-induced liver injury and inflammation in vivo remain elusive. In our study, MgIG pretreatment mitigated LPS-induced liver damage by suppressing apoptosis and inflammation via regulating macrophage/neutrophil infiltration. MgIG ameliorated the effects of LPS on pro-oxidant enzymes (NOX1/2/4) and anti-oxidant enzymes (SOD1/2). Interestingly, we found that the level of the hepatoprotective cytokine interleukin (IL)-22 was significantly upregulated in MgIG-treated liver tissues, which might be a potential mechanism of MgIG against liver injury. Moreover, we found that MgIG treatment not only inhibited TLR4/MyD88/NF-κB signaling pathway, but also activated autophagy. Furthermore, IL-22 treatment activated autophagy and inhibited TLR4/NF-κB signaling pathway in vitro, suggesting that IL-22-activated autophagy and -inhibited inflammation also participated in the protective effects of MgIG. Altogether, our results uncovered the potential mechanisms of the hepatoprotective effects of MgIG, which provided critical evidence to support the use of MgIG to prevent and treat liver diseases.