MANF

该研究表明，MANF通过NPM1下调和p53激活触发流产。因此，MANF下调或破坏MANF- npm1相互作用可能是URM治疗的靶点。 复发性流产(URM)定义为两次或两次以上自然流产，发生在怀孕第20周之前，不强调连续性。大多数URMs发生在妊娠的前三个月。 胚胎成功着床是早期妊娠建立的关键组成部分。植入后的发育和胎儿生长依赖于胎盘的形成。绒毛膜滋养细胞作为胎盘的组成部分，在妊娠早期过程中起着重要作用。虽然滋养层细胞被认为在功能上参与了URM的发病机制，但对于调节滋养层在母胎界面的迁移和侵袭的复杂机制知之甚少。 图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/38164189/ 近日，来自安徽医科大学的研究者们在Int J Biol Sci.杂志上发表了题为“MANF Promotes Unexplained Recurrent Miscarriages by Interacting with NPM1 and Downregulating Trophoblast Cell Migration and Invasion”的文章，该研究表明，MANF通过NPM1下调和p53激活触发流产。因此，MANF下调或破坏MANF- npm1相互作用可能是URM治疗的靶点。 早期滋养细胞发育不良和侵袭性缺陷会导致不明原因的复发性流产(urm)。中脑星形胶质细胞源性神经营养因子(MANF)可抑制某些癌细胞的迁移和侵袭，但其在妊娠相关疾病中的作用尚不清楚。 在这里，研究者发现，无论怀孕或流产，URM妇女外周血和流产组织中的MANF水平都高于正常对照组。研究者证实了URM患者滋养细胞中MANF与核磷蛋白1 (NPM1)的相互作用，增加了NPM1的泛素化降解，导致p53信号通路上调，抑制细胞增殖、迁移和侵袭能力。通过URM小鼠模型，研究者发现MANF下调导致胎儿吸收减少。然而，伴随的NPM1下调导致流产率增加。 URM发病过程中滋养细胞中MANF和NPM1相互作用示意图 图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/38164189/ 综上所述，这项研究揭示了MANF在URM人群中的潜在作用，这一发现丰富了关于这种神经营养因子在非神经元细胞中的功能的文献。MANF通过NPM1下调和p53激活触发流产。因此，MANF下调或破坏MANF- npm1相互作用可能是URM治疗的靶点。(生物谷 Bioon.com） 参考文献 Yuan Fang et al. MANF Promotes Unexplained Recurrent Miscarriages by Interacting with NPM1 and Downregulating Trophoblast Cell Migration and Invasion. Int J Biol Sci. 2024 Jan 1;20(1):296-311. doi: 10.7150/ijbs.85378.

A new preclinical study has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients. A new preclinical study from researchers at The University of Texas MD Anderson Cancer Center and the University of California San Francisco (UCSF) has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients. The study, published today in Science Translational Medicine, demonstrates how life-saving ICI treatment reduces levels of estrogen and important heart-protective proteins, sometimes leading to cardiovascular complications. The results suggest several treatment approaches, including hormone therapies, that could target this endocrine-cardiac-immune pathway without affecting treatment responses. "Immune checkpoint inhibitors can be life-saving for many patients, but increasing the dose or combining with other therapies also increases the risk for myocarditis, particularly in women," said co-corresponding author Liuqing Yang, Ph.D., associate professor of Molecular and Cellular Oncology. "With this study, we now understand the mechanisms behind this, and we've found several potential ways to reduce this risk without compromising the antitumor effects of treatment." Immune checkpoint inhibitors result in durable anti-tumor responses in many patients, but they are associated with an increased risk of cardiovascular toxicities caused by immune cells that infiltrate heart tissue. While this occurs in only about 1% of patients, these side effects can significantly increase the mortality rate in women. To better understand the mechanisms behind these gender differences, Yang worked with co-corresponding authors Chunru Lin, M.D., Ph.D., associate professor of Molecular and Cellular Oncology at MD Anderson, and Javid Moslehi, M.D., associate professor of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center. Checkpoint blockade reduces expression of heart-protective genes, particularly in females MD Anderson researchers collaborated with Moslehi and his team at UCSF to develop laboratory models of melanoma, breast and colorectal cancer to study ICI-associated myocarditis. Treatment with commonly used ICIs (anti-PD-1 and anti-CTLA-4 antibodies) inhibited tumor growth but also increased immune cell infiltration, particularly in female hearts, causing electrocardiographic abnormalities and systolic dysfunction associated with myocarditis. By studying these models, the team discovered that ICI treatment decreased expression of Manf and Hspa5 genes in heart tissue, especially in females. Similarly, models lacking the immune checkpoint genes Ctla4 and Pdcd1 also had a pronounced increase in heart-infiltrating immune cells and a lower expression of Manf and Hspa5. Further investigation revealed the same pattern in patients with ICI-associated myocarditis, where MANF and HSPA5 proteins were decreased and immune cells were elevated compared to healthy donors. These findings suggest that MANF and HSPA5 are involved in regulating interactions between the cardiovascular and immune systems. Infusions of recombinant MANF and HSPA5 proteins reversed these effects, improving cardiac function without affecting antitumor response after ICI, highlighting this as a possible therapeutic strategy. ICI treatment influences sex hormone levels, suggesting possible treatment approaches "The sex differences observed in both ICI-myocarditis mouse models are especially intriguing because in non-ICI myocarditis (viral or autoimmune) in the general population, male sex is considered a risk factor and defines a more severe course," Moslehi said. "If such an opposite sex difference in ICI-myocarditis is true, it suggests a possible interaction of immune checkpoints and sex hormones." Indeed, the researchers noted that serum concentrations of estrogen were significantly reduced in both males and females two weeks after ICI treatment, along with downregulation of Manf and Hspa5. Using an estrogen receptor β (ERβ) agonist to increase estrogen-dependent expression of Manf and Hspa5 resulted in tumor shrinkage and a decrease in heart-infiltrating immune cells following ICI treatment. Conversely, androgen deprivation therapy increased expression of these proteins and proved successful in laboratory models as an alternative strategy to lessen myocarditis. "Based on these results, we can envision several potential treatment strategies. For example, we may consider monitoring estrogen levels in patients after ICI treatment and potentially infusing them with recombinant MANF and HSPA5 proteins to bring their levels back up and improve outcomes," Lin said. "Likewise, targeting with an ERβ agonist to increase expression of Manf and Hspa5, or blocking androgens to do the same, might reduce the risk of adverse events, allowing us to tailor these strategies to individual patient needs so we can optimize the use of immunotherapy and minimize cardiac toxicities." While this is a preclinical study, the authors are planning clinical trials to evaluate these approaches using drugs already approved by the Federal Drug Administration (FDA). This work was supported by MD Anderson institutional funding, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP200423, RP180259), an American Association for Cancer Research (AACR)-The Mark Foundation for Cancer Research Science of the Patient Grant, the National Institutes of Health (R01CA218025, R01CA231011, R01HL141466, R01HL155990, R01HL156021), and the U.S. Department of Defense (BC180196).