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Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor. [ABSTRACT FROM AUTHOR]

Decades have witnessed rapid progress of polymeric materials for vascular embolic or chemoembolic applications. Commercially available polymeric embolics range from gelatin foam to synthetic polymers such as poly(vinyl alcohol). Current systems under investigation include tunable, bioresorbable microspheres composed of chitosan or poly(ethylene glycol) derivatives, in situ gelling liquid embolics with improved safety profiles, and radiopaque embolics that are trackable in vivo. In this paper, we proposed a concept of ‘responsive embolization’. Sevelamer, clinically proved as an inorganic phosphate binder, was ground into nanoparticles. Sevelamer nanoparticle is highly mobile and capable of swelling and aggregating in the presence of endogenous inorganic phosphate, thereby effectively occluding blood flow in the vessel as it was administered as an embolic agent for interventional therapy. Moreover, citrated sevelamer nanoparticles delayed the aggregation, preferable to penetrate deeply into the capillary system. On the rabbit VX2 liver cancer model, both sevelamer particles aggregates occlude the tumor feeding artery, but backflow was found for the pristine one, thereby citrate passivation of sevelamer nanoparticles endows it have potential from ‘bench to bedside’ as a new type of vascular embolic. [ABSTRACT FROM AUTHOR]

Background: Surgical resection is the standard treatment for localized and potentially resectable gastrointestinal stromal tumors (GISTs), If the postoperative pathology diagnosis indicates that patients are at high risk of recurrence, they should be treated with imatinib. Even though the introduction of imatinib substantially improved the outcome of GIST patients, it is unclear whether different imatinib treatment regimens affect patients' survival. Methods: This retrospective study included 120 patients who underwent tumor resection for high-risk GISTs between January 2009 and October 2018. The patients were divided into three groups: one group of patients received postoperative imatinib adjuvant therapy regularly (regular treatment group); the second group was not treated with imatinib until they were found to have disease progression (observation group); the third group was treated with postoperative imatinib adjuvant therapy irregularly (irregularly treatment group). The progression-free survival (PFS) and overall survival (OS) were compared between the three groups, and the prognostic risk factors were analysed by the Cox regression model. Results: The median PFS was 45 months (range: 25–59). The 3- and 5-year PFS values were 71.3% and 49.9%, respectively. The PFS in the regular group was longer than in the observation group and irregular group (P<0.001). The median OS was 59 months (range:47–78). The 3- and 5-year OS values were 91.6% and 84.2%, respectively. There were no differences in OS among the three groups (P=0.150). The extent of radical resection (P<0.001) and intraoperative tumor rupture (P=0.005) were independent prognostic factors influencing OS. Conclusions: Irregular administration of imatinib was associated with a worse PFS, but it did not affect the OS of patients with high-risk GISTs. Avoiding intraoperative tumor rupture and R0 resection were associated with better survival. [ABSTRACT FROM AUTHOR]

A growing number of reports have demonstrated that the widely-used herbicide Atrazine (ATR) can cause injury to dopamine (DA) neurons, but the exact mechanism remains unclear. In this study, we examined the effects of lactational ATR exposure in Sprague-Dawley rats on dopaminergic neuron health later in life. Compared with control rats, rats exposed to ATR during a critical period of neural development showed decreased striatal DA content and increased rates of DA turnover. The expression of Monoamine oxidase (MAO), which is associated with DA degradation, was up-regulated, and the expression of Vesicular Monoamine Transporter 2 (VMAT2), which is associated with DA transport, was down-regulated. The expression of transcription factor Nuclear Receptor Related Factor 1 (Nurr1), which is associated with DA neuron development, was down-regulated. Increased age (6–12 months old) increased the statistical significance of the differences of the above indicators in the ATR-treated rats compared to the control rats ( P < 0.05). Taken together, our results indicate that ATR exposure during the critical neural development period causes a down-regulation of Nurr1, which in turn affects Nurr1 target genes, including MAO, VMAT2 and DAT, which are involved in DA degradation and transport. Reduced expression of these genes impairs the capacity for vesicular storage or reuptake of DA, causing decreased levels of striatal DA, which can ultimately lead to DA neuron injury. DA neuron injuries become more severe over time, which suggests that aging can synergistically promote the ATR-associated DA neuron injuries. [ABSTRACT FROM AUTHOR]

[Display omitted] Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor β (TGF-β) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-β expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases. [ABSTRACT FROM AUTHOR]