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.

Purpose We investigated the change, if any, in prostaglandin E2 (PGE 2 ) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE 2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX‐2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis‐associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE 2 signaling dose‐dependently. In contrast, treatment with metformin resulted in increased PGE 2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE 2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE 2 signaling.

Super elongation complex (SEC) is a positive regulator of RNA polymerase II, which is required for HIV-1 proviral transcription. AFF1/4 is the scaffold protein that recruits other components of SEC and forms dimer depending on its THD domain (TPRL with Handle Region Dimerization Domain). Here we report the crystal structure of the human AFF4-THD at the resolution of 2.4 Å. The α4, α5, and α6 of one AFF4-THD mediate the formation of a dimer and pack tightly against the equivalent part of the second molecule in the dimer of AFF-THD. Mutagenesis analysis revealed that single mutations of either Phe1014 or Tyr1096 of AFF4 to alanine impair the formation of the AFF4 dimer. In addition, transactivation assay also indicated that Phe1014 and Tyr1096 of AFF4 are critical to the transactivation activity of AFF4. Interestingly, the corresponding residues Phe1063 and Tyr1145 in AFF1 have an effect on the transactivation of HIV-1 provirus. However, such mutations of AFF1/4 have no effect on the interaction of AFF1/4 with other subunits of the SEC. Together, our data demonstrated that the dimerization of AFF1/4 is essential to transactivation of HIV-1 provirus.

Purpose To investigate how the extent of fibrosis in adenomyosis lesions contributes to heavy menstrual bleeding (HMB). Methods We recruited 57 women with histologically confirmed adenomyosis, 29 of whom reported moderate/heavy bleeding (MHB) (menstrual blood loss (MBL) ≥20 but <100 mL) and the remaining 28, excessive MBL (EXB; ≥100 mL). Lesional stiffness was measured by transvaginal elastosonography. Full‐thickness uterine tissue columns containing the lesion and its neighboring endometrial‐myometrial interface (EMI) and endometrial tissues were evaluated for tissue fibrosis and immunohistochemical analysis of HIF‐1α, COX‐2, EP2, and EP4. Results The lesional stiffness in the EXB group was significantly higher than that of MHB, and consistently, the extent of lesional fibrosis and the extent of tissue fibrosis in both EMI and eutopic endometrium were also significantly higher. In adenomyotic lesions and their neighboring EMI and eutopic endometrial tissues, the immunostaining of HIF‐1α, COX‐2, EP2, and EP4 was significantly reduced. The extent of fibrosis and the immunostaining levels of HIF‐1α, COX‐2, EP2, and EP4 were negatively correlated in all tissues. Conclusions Lesional fibrosis begets stiffening matrix, propagating fibrosis to neighboring EMI and eutopic endometrium, resulting in reduced PGE 2 and HIF‐1α signaling, and thus likely reduced hypoxia necessary for endometrial repair, leading to HMB.

Background Chemotherapy and gene therapy are used in clinical practice for the treatment of castration-resistant prostate cancer. However, the poor efficiency of drug delivery and serious systemic side effects remain an obstacle to wider application of these drugs. Herein, we report newly designed PEO-PCL micelles that were self-assembled and modified by spermine ligand, DCL ligand and TAT peptide to carry docetaxel and anti-nucleostemin siRNA. Results The particle size of the micelles was 42 nm, the zeta potential increased from − 12.8 to 15 mV after grafting with spermine, and the optimal N/P ratio was 25:1. Cellular MTT experiments suggested that introduction of the DCL ligand resulted in high toxicity toward PSMA-positive cells and that the TAT peptide enhanced the effect. The expression of nucleostemin was significantly suppressed in vitro and in vivo, and the tumour-inhibition experiment showed that the dual-drug delivery system suppressed CRPC tumour proliferation. Conclusions This targeted drug delivery system inhibited the G1/S and G2/M mitotic cycle via synergistic interaction of chemotherapeutics and gene drugs.