BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Yujie Peng,Meng Zhang,Libo Zhu,Wenqiang Qian,Jingjing Yan,Huidi Jiang,Yu Xin,Ying Zhang,Dongli Sun,Weidong Fei,Mengdan Zhao
Background and Purpose Endometriosis is a chronic, hormone-dependent disorder characterized by ectopic implantation of endometrial tissue, often accompanied by pain and infertility. Although the progesterone receptor modulator RU486 is effective for pain relief, its impact on lesion regression is limited, possibly due to apoptosis resistance and overexpression of PARP1 in endometriotic cells. This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53-dependent apoptosis in endometriotic lesions. Experimental Approach Primary ectopic endometrial stromal cells (EESCs) were used to assess the effects of RU486 and olaparib on cytotoxicity, apoptosis, DNA damage, mitochondrial membrane potential, and cell migration. Mechanistic investigations included flow cytometry, western blotting, RT-qPCR, immunofluorescence, and comet assays. A murine endometriosis model was established to evaluate in vivo lesion suppression, pain behaviour, hormone levels, and treatment safety following combination therapy. Key Results RU486 and olaparib exhibited strong synergy at a 1:4 ratio, significantly enhancing apoptosis in EESCs by coactivating p53 through distinct mechanisms—transcriptional up-regulation by RU486 and posttranslational stabilization by olaparib. This synergy intensified Bax/Bcl-2-mediated mitochondrial dysfunction, caspase-3 activation, and PARP1 cleavage. In vivo, the combination therapy achieved a 77.5% lesion weight regression, significantly exceeding monotherapies, while maintaining robust analgesic effects. Histological and molecular analyses confirmed DNA damage and enhanced apoptosis in lesions. Conclusion and Implications The combination medication enhanced apoptotic sensitivity in endometriosis by restoring p53 activity through targeting hormonal signalling and DNA repair pathways. This strategy offered strong potential for clinical translation. Graphical
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Clinical and Experimental Obstetrics & Gynecology
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2026
·Vol. 53
·期 1
·
IF 0.6
Caiqun Huang,Ying Lyu,E Fen Cheng
Background:Although multiple factors contribute to recurrent spontaneous abortion (RSA), recent studies have highlighted a role for regulatory T cells (Tregs) in maintaining immune tolerance during pregnancy. Understanding the intricate relationship between RSA and Tregs offers promising avenues for diagnosis and therapeutic strategies in reproductive medicine.Methods:We successfully established a mouse model of RSA, and all animals were euthanized on gestational day 13. Uterine horns were examined upon dissection to determine the number of viable fetuses and resorption sites, after which the post-implantation loss rate (abortion rate) was calculated. Placental morphology was evaluated via hematoxylin and eosin staining, whereas gene expression was analysed by immunohistochemistry. Treg abundance was determined by flow cytometry. Gene expression and cytokine levels in EL4 cells and patient samples were evaluated by quantitative real-time polymerase chain reaction (qPCR) and Western blotting.Results:The abortion rate of RSA mice was 31.64%. In addition, Treg numbers were reduced in both RSA mice and patients, while the expression of Toll-like receptor 4 (TLR4) and p65 was upregulated, further suppressing forkhead box protein P3 (FOXP3) expression. Blocking p65 expression with small interfering RNA (siRNA) targeting p65 prevented the lipopolysaccharide (LPS)-induced downregulation of FOXP3 in EL4 cells. The TLR4 inhibitor IAXO102 was ineffective at increasing FOXP3 expression in EL4 cells following p65 overexpression p65.Conclusions:The results of this study suggest that activation of the TLR4/p65 signalling in RSA inhibits FOXP3 expression and contributes to abortion. Importantly, the findings indicate that Treg suppression in RSA is p65-dependent.
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GENERAL AND COMPARATIVE ENDOCRINOLOGY
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2025
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IF 1.7
Xuanhan Zhang,Chenpeng Zuo,Jiaqi Liu,Xiao Jing,Ziyi Zhao,Jing Yang,Zhijun Wang,Xin Qi
Gonadal development is closely linked to cortisol levels, a major stress response indicator, which is mediated by the glucocorticoid receptor (GR) in teleost fish. Stress activates the HPI axis (hypothalamic-pituitary-adrenocortical axis), triggering cortisol release, which subsequently affects the reproductive system. Therefore, GR is considered a mediator in elucidating the relationship between stress and gonadal development. In this study, we cloned and analyzed the gr1 and gr2 genes of the Japanese eel ( Anguilla japonica ). The phylogenetic tree of GR revealed that gr1 and gr2 exhibit a unique evolutionary distribution in teleost fish. Quantitative real-time PCR results indicated that gr1 and gr2 were primarily expressed in the ovary and brain. To investigate whether glucocorticoids mediate their inhibitory effects through GR, we performed in vivo DXMS injection experiments. The results indicated that DXMS stimulation significantly altered the expression of key genes in the HPG axis (hypothalamic-pituitary–gonadal axis) of the Japanese eel, particularly those related to ovarian development. Additionally, in vitro experiments with isolated brain, pituitary, and gonadal cells revealed that DXMS treatment significantly suppressed the expression of several reproduction-related genes, and the GR antagonist RU486 partially reversed this suppression. This study reveals the mechanisms through which glucocorticoids regulate ovarian development in the Japanese eel via GR and HPI-HPG axis interactions. These findings offer new insights into the role of stress in fish reproduction and provide a theoretical basis for optimizing artificial reproduction techniques in the Japanese eel.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Qi-qiang Zhang,Xue-mei Di,Xiang Cao,Yonghong Nie,Wen Shuai,Jun Li,Hai Zhang
Ethnopharmacological relevance Fuyuan Shenghua Granule (FYSHG) is a traditional Chinese medicine preparation widely used in our hospital for the treatment of incomplete postpartum uterine repair. However, its pharmacological action, main components, and synergistic mechanism are still unclear. Aim of the study The study aims to verify the pharmacological action, identify the main components and explore the synergistic mechanisms of FYSHG for the treatment of medical-induced incomplete abortion. Materials and methods The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was employed to identify the main components of FYSHG after extraction with water and methanol. A medical-induced incomplete abortion rat model was established, and the uterine status was evaluated by morphological and H&E staining analysis. The KEGG enrichment analysis and network pharmacology analysis were used to screen the potential synergistic mechanisms of FYSHG. Hemorheological analysis was employed to analyze the blood viscosity and coagulation of FYSHG-treated rats. The ELISA was used to measure the concentration of E2, progesterone, RCG, IL-1, IL-6, and TNF. The Western blot analysis was employed to measure the protein expression of p38 and NF-κB signaling pathways. Results A total 106 of components of FYSHG were identified and characterized rapidly by UHPLC-Q-TOF/MS technology. Intragastric administration of FYSHG could play a role in promoting uterine involution in rats with medical-induced incomplete abortion. The analysis of its components and targets by network pharmacology showed that the synergetic effect of FYSHG on anti-uterine involution mainly focused on anti-inflammatory, anticoagulant, and hormone regulation. ELISA and Western blot analysis showed that FYSHG mainly inhibited the protein expression of p38 and NF-κB signaling pathways. Conclusions Our study suggested that FYSHG suppressed the p38 and NF-κB signaling pathway to alleviate inflammation, regulate coagulant function, and correct hormone level, which might contribute to the treatment of medical-induced incomplete abortion.
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NEUROSCIENCE LETTERS
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2022
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IF 3.197
Sheng Hu,Pei Shen,Bin Chen,Shao-Wen Tian,Yong You
Neuroinflammation is usually associated with cognitive decline, which is involved in neurodegenerative diseases. Apelin , a neuropeptide, exerts various biological roles in central nervous system. Recent evidence showed that apelin-13, an active form of apelin, suppresses neuroinflammation and improves cognitive decline in diverse pathological processes. However, the underlying mechanism of apelin-13 in neuroinflammation remains largely unknown. The present study aimed to determine underlying mechanism of apelin-13 on neuroinflammation-related cognitive decline. The lipopolysaccharide (LPS) intracerebroventricular (i.c.v.) to is used to establish a rat model of neuroinflammation-related cognitive decline. The results showed that apelin-13 inhibits LPS-induced neuroinflammation and improves cognitive impairment. Apelin-13 upregulates the GR level and nuclear translocation in hippocampus of rats. Moreover, glucocorticoid receptor inhibitor RU486 prevents apelin-13-mediated neuroprotective actions on cognitive function. Taken together, apelin-13 could exert a protective effect in neuroinflammation-mediated cognitive impairment via the activation of GR expression and nuclear translocation.
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TOXICOLOGY LETTERS
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2022
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IF 4.271
Mingyang Chen,Mengru Bai,Yaodong Yi,Shuanghui Lu,Jun Luo,Ping Li,Hengbin Zhang,Huidi Jiang,Hui Zhou
Glucocorticoids such as dexamethasone (DEX) are widely prescribed to treat numerous conditions and diseases. However, glucocorticoid-induced liver lipid metabolism disorder, even nonalcoholic fatty liver disease , has caused extensive attention. Since fatty acid transporters such as CD36 and FATP play crucial roles in hepatic fatty acid uptake, this work examined their potential involvement in DEX-induced liver lipid accumulation. Chronic DEX administration (1–5 mg/kg/day over 28 days) induced hepatic lipid accumulation in mice. Fatty acid uptake in HepG2 cells and mouse primary hepatocytes was also stimulated after incubation with 0.5–2 μM DEX. Meanwhile, qPCR and western blotting demonstrated dose-dependent upregulation of CD36 expression by DEX in the mouse liver and in cultured hepatocytes. Glucocorticoid receptor (GR) inhibition with mifepristone (RU486) and siRNA-mediated GR knockdown attenuated lipid accumulation in hepatocytes by inhibiting DEX-induced CD36 upregulation, and direct binding of GR to the CD36 promoter was demonstrated by luciferase reporter and chromatin immunoprecipitation assays. These results indicate that DEX promotes free fatty acid uptake leading to hepatic steatosis by upregulating CD36 expression via activation of GR. Thus, strategies aimed at inhibiting GR/CD36 expression or activity might help prevent or reduce the onset and progression of hepatic lipid metabolism disorders induced by glucocorticoid drugs.
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BRITISH JOURNAL OF PHARMACOLOGY
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2022
·Vol. 179
·期 17
·4440-4456
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IF 9.473
Mengru Bai,Mingyang Chen,Qingquan Zeng,Shuanghui Lu,Ping Li,Zhiyuan Ma,Nengming Lin,Caihong Zheng,Hui Zhou,Su Zeng,Dongli Sun,Huidi Jiang
Background and Purpose Plasma triglyceride (TG) levels increase as gestation proceeds, and abnormal elevation of TG increases the risk of pregnancy complications. The current study explored the mechanisms involved in hypertriglyceridaemia during pregnancy. Experimental Approach Lipid profile and expression levels of key genes involved in liver TG metabolism in non-pregnant and pregnant mice were studied. The effects of pregnancy-related hormones on key genes and the underlying mechanisms were uncovered in vitro and in vivo. Key Results Plasma and hepatic TG levels were elevated, while hepatic fatty acid translocase (FAT/CD36) was up-regulated in pregnant mice. Corticosterone and cortisol (endogenous glucocorticoids that are elevated during pregnancy), but not oestradiol or progesterone, significantly up-regulated CD36 in hepatocytes, and this was abolished after knockdown of the glucocorticoid receptor (GR) using a siRNA or in the presence of GR antagonists, RU486 and AL082D06. The luciferase reporter gene and chromatin immunoprecipitation assay further revealed that corticosterone/cortisol promoted the direct binding of GR to the CD36 promoter and up-regulated its transcription. Chronic corticosterone exposure induced liver lipid accumulation and increased plasma TG levels in mice, which were attenuated by RU486 via inhibition of the GR-CD36 pathway. Conclusions and Implications Increased corticosterone/cortisol induces liver lipid accumulation and hypertriglyceridaemia during pregnancy by accelerating fatty acid uptake into hepatocytes via activation of GR and its target gene, CD36. Our results may be useful for the prevention of severe hypertriglyceridaemia and associated pregnancy complications. Graphical
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ACTA PHARMACOLOGICA SINICA
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2021
·Vol. 43
·期 1
·146-156
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IF 6.15
Yao Xin-peng,Jiao Ting-ying,Jiang Yi-ming,Fan Shi-cheng,Zhao Ying-yuan,Yang Xiao,Gao Yue,Li Fei,Zhou Yan-ying,Chen Pan-pan,Huang Min,Bi Hui-chang
Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced hepatomegaly in C57BL/6 mice and Pxr -knockout mice. The results demonstrated that high-dose Mif (100 mg · kg −1 · d −1 , i.p .) treatment for 5 days significantly induced hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg −1 · d −1 , i.p .) cannot induce hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg −1 · d −1 , i.p .) failed to induce hepatomegaly in Pxr -knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
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ANALYST
·
2020
·Vol. 146
·期 5
·1725-1733
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IF 3.978
Chang Shu,Teng-Fei Li,Duo Li,Zhong-Qiu Li,Xing-Hua Xia
Protein drugs showing strong pharmaceutical activity, high specificity, and low toxicity and side effects have drawn extensive attention in the field of life sciences and medicine. Precise evaluation of the function of these drugs requires accurate and sensitive detection methods. Here, we report a novel chromatography-tandem mass spectrometry (LC-MS/MS) method for sensitive and selective detection of protein drugs. Magnetic nanoparticles (Apt29@MNPs) were functionalized by thrombin aptamers, and quantum dots (Apt15@ss@QDs) were dual-functionalized with quantitative thrombin aptamers and small molecules with high ionization efficiency as the mass barcode. After Apt29@MNPs specifically purify and enrich thrombin from biological samples, they can form a nano “sandwich structure” when Apt15@ss@QDs are added, resulting in the release of the mass barcode for LC-MS/MS analysis via the cutting of the disulfide bond. Since there is a higher quantitative molecular ratio of mass barcode to thrombin in the nano-“sandwich structure”, quantitative detection of thrombin with high sensitivity and selectivity can be achieved via the LC-MS/MS detection of the mass barcode with high ionization efficiency rather than thrombin, which effectively avoids the disadvantages of direct protein detection by mass spectrometry. The established method for thrombin detection shows a good linear relationship in a concentration range of 0.00115–1.15 nM with a limit of detection (LOD) of 0.0007 nM. The present work provides a new approach for the effective and sensitive quantitative analysis of protein drugs and would be of great significance in promoting the development of protein drugs and clinical applications.
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PLACENTA
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2024
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IF 3
Caiqun Huang
Introduction T oxoplasma gondii is an opportunistic intracellular parasite that is a major pathogenic factor in miscarriage, especially when it occurs early in pregnancy. We have previously demonstrated that the regulation of forkhead box transcription factor (Foxp3) is associated with abortion in early pregnancy caused by excretory-secretory antigen (ESA) of strain China 1. We aimed to reveal the underlying mechanism of miscarriage caused by ESA. Methods A TLR4 −/− pregnant mouse model was successfully constructed. Pregnant mice at gestational day 5 (G5) were injected with ESA. All animals were sacrificed on G13, pregnancy outcomes were observed, and abortion rates were calculated. Placental status observed by Hematoxylin-eosin staining; gene expression was measured by IHC; flow cytometry analysis was used to determine the number and function of regulatory T cells. In EL4 cells, real-time PCR and Western blot were used to evaluate gene expression and cytokines assay. Results In vivo studies revealed that ESA injection caused 83% abortion in pregnant mice but only 35% abortion in TLR4−/− pregnant mice. In addition, ESA attenuated the number and function of regulatory T cells, further suppressed Foxp3, FOXO1 levels, and upregulated CD127 expression. TLR4 −/− mice partially reversed this inhibitory effect on regulatory T cells. Furthermore, in vitro studies revealed that ESA inhibited TLR4/NF-κB signaling pathway expression and that TLR4 agonists significantly restored the ESA-induced decrease in Foxp3. Discussion These findings suggest that ESA suppresses Foxp3 expression by blocking TLR4/NF-κB signaling, resulting in miscarriage. More importantly, the results indicated that miscarriage caused by ESA is TLR4 dependent.
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Cell Reports
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2024
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IF 7.5
Lihong Sheng,Jianpeng Gao,Qingyuan Wei,Ye Gong,Zhi-Xiang Xu
Lipid droplets (LDs) are dynamic organelles essential for lipid storage and organismal survival. Studies have highlighted the importance of glial function in brain LD formation during aging; however, the genes and mechanisms involved remain elusive. Here, we found that Ugt35b , a member of the uridine diphosphate (UDP)-glycosyltransferases that catalyze the transfer of glycosyl groups to acceptors, is highly expressed in glia and crucial for Drosophila lifespan. By integrating multiomics data, we demonstrated that glial Ugt35b plays key roles in regulating glycerolipid and glycerophospholipid metabolism in the brain. Notably, we found that Ugt35b and Lsd-2 are co-expressed in glia and confirmed their protein interaction in vivo . Knockdown of Ugt35b significantly reduced LD formation by downregulating Lsd-2 expression, while overexpression of Lsd-2 partially rescued the shortened lifespan in glial Ugt35b RNAi flies. Our findings reveal the crucial role of glial Ugt35b in regulating LD formation to maintain brain lipid homeostasis and support Drosophila lifespan.
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Acta Biomaterialia
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2024
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IF 9.4
Meng Zhang,Yiqing Ye,Zhengyun Chen,Xiaodong Wu,Yue Chen,Pengfei Zhao,Mengdan Zhao,Caihong Zheng
Endometriosis seriously affects 6–10% of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. Statement of Significance Macrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.
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