Purpose While the prevailing view holds that the prostaglandin E2 (PGE 2 ) signaling plays a vital role in endometriosis, PGE 2 also is known to be anti‐fibrotic. We investigated the immunostaining of COX‐2, EP2, and EP4, along with fibrotic content in ovarian endometrioma (OE) and deep endometriosis (DE) lesions, and in OE lesions from adolescent and adult patients. In addition, we evaluated the effect of substrate stiffness on the expression of COX‐2, EP2, and EP4 in endometrial stromal cells. Methods Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the quantification of lesional fibrosis, was conducted for OE and DE lesion samples and also OE lesion samples from adolescent and adult patients. The effect of substrate rigidity on fibroblast‐to‐myofibroblast transdifferentiation (FMT) and the expression of COX‐2, EP2, and EP4, with or without TGF‐β1 stimulation, were investigated. Results The immunostaining of COX‐2, EP2, and EP4 was substantially reduced in endometriotic lesions as lesions became more fibrotic. Both TGF‐β1 stimulation and stiff substrates induced FMT and reduced the expression of COX‐2, EP2, and EP4. Conclusions Since fibrosis is a common feature of endometriosis, our results thus cast doubts on the use of therapeutics that suppresses the PGE 2 signaling pathway, either by inhibiting COX‐2 or EP2/EP4.
Photodynamic therapy has emerged as a promising tool for inducing immunogenic cell death (ICD), which shows the potential to convert tumor cells into in situ vaccines. However, large amounts of as‐generated tumor‐associated antigens (TAAs) are entrapped in the endo‐lysosomes of tumor‐infiltrating dendritic cells (DCs), resulting in unsatisfactory TAA cross‐presentation and poor or moderate ICD‐associated antitumor responses. Herein, an immune‐enhancing polymer‐reinforced liposome (IERL) with a stable nanostructure and a bioactive surface is developed and it demonstrates its capability to collect TAAs, facilitates TAA endo‐lysosomal escape in DCs, and enhances cross‐presentation of TAAs, which results in the amplification of ICD‐associated antitumor immune responses. By loading photosensitizers, IERLs are able to induce robust antitumor immune responses and immune memory after local irradiation, thereby inhibiting the growth of both primary and distant/metastatic tumors. Additionally, considering the wide applications of liposomal carriers, photosensitizers in IERLs can be easily replaced with photothermal agents and radiosensitizers (or their combinations), which provides a general platform for the rapid development of combined cancer immunotherapy.
BackgroundPhotodynamic therapy (PDT), a clinical anticancer therapeutic modality, has a long history in clinical cancer treatments since the 1970s. However, PDT has not been widely used largely because of metabolic problems and off-target phototoxicities of the current clinical photosensitizers.PurposeThe objective of the study is to develop a high-efficiency and high-specificity carrier to precisely deliver photosensitizers to tumor sites, aiming at addressing metabolic problems, as well as the systemic damages current clinical photosensitizers are known to cause.MethodsWe synthesized a polydopamine (PDA)-based carrier with the modification of folic acid (FA), which is to target the overexpressed folate receptors on tumor surfaces. We used this carrier to load a cationic phthalocyanine-type photosensitizer (Pc) and generated a PDA-FA-Pc nanomedicine. We determined the antitumor effects and the specificity to tumor cell lines in vitro. In addition, we established human cancer-xenografted mice models to evaluate the tumor-targeting property and anticancer efficacies in vivo.ResultsOur PDA-FA-Pc nanomedicine demonstrated a high stability in normal physiological conditions, however, could specifically release photosensitizers in acidic conditions, eg, tumor microenvironment and lysosomes in cancer cells. Additionally, PDA-FA-Pc nanomedicine demonstrated a much higher cellular uptake and phototoxicity in cancer cell lines than in healthy cell lines. Moreover, the in vivo imaging data indicated excellent tumor-targeting properties of PDA-FA-Pc nanomedicine in human cancer-xenografted mice. Lastly, PDA-FA-Pc nanomedicine was found to significantly suppress tumor growth within two human cancer-xenografted mice models.ConclusionOur current study not only demonstrates PDA-FA-Pc nanomedicine as a highly potent and specific anticancer agent, but also suggests a strategy to address the metabolic and specificity problems of clinical photosensitizers.
Xuefu Zhuyu Decoction (XFZYD), the classical recipe for promoting blood circulation by removing blood stasis, has been used in China for a long history clinically. XFZYD has been found to improve cardiac function through reducing inflammation. However, the effect of XFZYD on myocardial apoptosis remains unclear. Herein, we investigated the mechanism of XFZYD preconditioning on myocardial injury in sepsis rats. The rats were treated with XFZYD one week, followed with intraperitoneal injection of lipopolysaccharide (LPS: 10 mg/kg) to induce sepsis. Pretreatment with XFZYD could reverse the effects of LPS-induced decreased mean arterial pressure (MAP) and increased heart rate (HR). XFZYD decreased the levels of malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in serum or in heart. TUNEL staining revealed that the apoptotic index of XFZYD was significantly lower compared with the LPS group (P<0.05). Western blot results showed that the high doses of pretreatment XFZYD group can reduce the Bax expression of myocardial tissue in rats (P<0.05, P<0.01). The expression of Bcl-2 in XFZYD group was significantly higher than that in the LPS group (P<0.01), while the expression of caspase-3 in treatment group was significantly lower than that in the LPS group only after 12 h modeling (P<0.01). In addition, caspase-3 activity in rat cardiomyocytes of XFZYD-treated animals was significantly decreased. These findings suggest that pretreatment with XFZYD exerts a protective effect in the myocardium of septic rats by inhibiting myocardial cell apoptosis and antioxidation.
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