BONE
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2021
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IF 4.398
FeiFei Liu,Hao Yang,DongZhe Li,XueJian Wu,QiCai Han
Background Punicalagin (PUN) is a common anti-inflammatory polyphenol. However, the function and mechanism of PUN in osteoarthritis remains unknown. Methods Chondrocytes were isolated from rats, and confirmed by toluidine blue staining and immunofluorescence. Chondrocytes were challenged by lipopolysaccharide (LPS), and rat osteoarthritis model was established by Hulth method. The secretion of inflammatory factors, cell viability and apoptosis were tested via enzyme linked immunosorbent assay (ELISA), MTT and flow cytometry. The levels of forkhead box O1 (Foxo1), proteoglycan 4 (Prg4), hypoxia-inducible factor-3α (HIF3α), autophagy-related genes or extracellular matrix (ECM)-related proteins were examined via quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot or immunohistochemistry . The cartilage tissue damage was assessed via hematoxylin-eosin (HE) staining, toluidine blue staining and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick and labeling (TUNEL) staining. Results LPS triggered inflammatory injury in chondrocytes. PUN promoted autophagy to mitigate LPS-induced inflammatory injury. Foxo1 silence attenuated the effect of PUN on LPS-mediated autophagy inhibition and inflammatory injury. Promotion of Prg4/HIF3α axis abolished the influence of Foxo1 knockdown on LPS-mediated chondrocytes injury. PUN mitigated the inflammatory injury in rat osteoarthritis model by promoting autophagy and inhibiting inflammation and ECM degradation via Foxo1/Prg4/HIF3α axis. Conclusion PUN attenuates LPS-induced chondrocyte injury and osteoarthritis progression by regulating Foxo1/Prg4/HIF3α axis.
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Scientific Reports
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2026
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IF 4.9
Chen Cong,Tao Wen,Chen Fei,Gong Jie
Cerebral ischemia–reperfusion (I/R) injury remains a major therapeutic challenge, primarily due to complex mechanisms involving oxidative stress and apoptosis. Growth arrest and DNA damage-inducible protein α (Gadd45α), a stress sensor linked to cellular stress responses, has been implicated in I/R injury, yet its precise role in ischemic stroke is incompletely understood. This study aimed to elucidate the function and underlying mechanisms of Gadd45α in cerebral I/R injury using both in vivo and in vitro models. In rats subjected to middle cerebral artery occlusion (MCAO) and in neurons exposed to oxygen–glucose deprivation/reperfusion (OGD/R), Gadd45α expression was significantly upregulated. Lentivirus-mediated knockdown of Gadd45α (sh-Gadd45α) reduced infarct volumes, improved neurological function and increased miniature excitatory postsynaptic current (mEPSC) amplitude. In primary cortical neurons exposed to OGD/R, Gadd45α knockdown decreased reactive oxygen species (ROS) production, DNA damage, and apoptosis, while Gadd45α overexpression exacerbated these effects. Mechanistically, Gadd45α directly interacts with forkhead box O1 (FOXO1) and positively regulates its transcriptional activity. Gadd45α knockdown attenuated the ischemia-induced upregulation of both total FOXO1 and its phosphorylated form (p-FOXO1), thereby suppressing FOXO1 signaling and mitigating cerebral I/R injury. Furthermore, FOXO1 overexpression reversed the neuroprotective effects of Gadd45α silencing, confirming that FOXO1 acts as a critical downstream mediator. These findings demonstrate that Gadd45α silencing alleviates cerebral I/R injury by suppressing FOXO1 signaling, suggesting the Gadd45α/FOXO1 axis as a promising therapeutic target for ischemic stroke.
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ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhang Chen-chun,Li Yuan,Jiang Chang-you,Le Qiu-min,Liu Xing,Ma Lan,Wang Fei-fei
The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H 2 O 2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H 2 O 2 -induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H 2 O 2 -treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H 2 O 2 -induced apoptosis of N2a cells.
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Frontiers in Pharmacology
·
2026
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IF 5.4
Yihuang Liu,Xiaofeng Li,Xia Zhang,Hua Cao,Nailin Zhang,Jianhui Sun,Pingping Chen
Introduction This research sought to investigate the therapeutic efficacy and underlying mechanisms of Shengjiang Powder (SJP) in the context of chronic gastritis. Methods A rat model of gastric mucosal injury was induced by 1-methyl-3-nitroso-1-nitrosoguanidine (MNNG) and a 10% NaCl solution, followed by treatment with either Vitacoenzyme or SJP. Histopathological changes in gastric tissues were evaluated using hematoxylin-eosin staining. Serum IL-6 levels were measured by enzyme-linked immunosorbent assay. Western blot (WB) analysis was performed to detect COX-2 expression. Immunohistochemistry was used to assess TFF1 and TFF2 expression. Serum metabolomics was conducted to identify differential metabolites and enriched pathways, while proteins related to the FOXO signaling pathway were further examined in vivo . WB analysis was used to detect SIRT1, FOXO1, and STAT3. CAT and SOD2 activities were measured using biochemical assays. Multiplex immunohistochemistry was used to examine SIRT1-FOXO1 co-localization and FOXO1 nuclear localization. For the in vitro experiments, normal human gastric epithelial cells were treated with MNNG to induce inflammatory injury, followed by SJP administration in the presence or absence of the SIRT1 inhibitor EX-527. Results SJP alleviated gastric mucosal injury, reduced serum IL-6 levels and COX-2 expression, and significantly increased TFF1 and TFF2 expression. Metabolomics analysis identified 13 differential metabolites. The targets of these metabolites were intersected with gastritis-related targets, yielding 522 overlapping targets that were significantly enriched in the FOXO signaling pathway. In vivo and in vitro experiments showed that SJP upregulated SIRT1 and FOXO1 expression, increased CAT and SOD2 activities, inhibited STAT3 expression, and promoted FOXO1 nuclear localization. EX-527 blocked the restorative effects of SJP on FOXO1 expression and antioxidant enzyme activities. Conclusion SJP ameliorates gastric mucosal injury and inflammation, potentially through modulation of the SIRT1/FOXO1 axis.
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npj Science of Food
·
2026
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IF 9.7
Wang Xiaoran,Song Yagang,Zhao Wenyu,Liu Yuting,Fu Yiping,Zhang Yu,Zhao Quanyou,Miao Mingsan,Zhao Wenxia,Wang Xianbo,Li Zhanzhan
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health burden with limited therapeutic options. Cinnamomum cassia , a medicinal-food homologous plant, contains principal bioactive cinnamaldehyde (CA), whose anti-MASLD mechanisms require clarification. This study employed both a high-fat diet (HFD)-induced MASLD model and a free fatty acid (FFA)-stimulated cell model. CA administration attenuated intracellular lipid accumulation in vitro and ameliorated both hepatic steatosis and systemic hyperlipidemia in vivo, while inhibiting hepatic lipid peroxidation. Mechanistically, integrated RNA-seq, network pharmacology, siRNA, immunofluorescence, and transmission electron microscopy analyses identified the SIRT1/FOXO1–autophagy axis as CA’s key regulatory pathway. Gut microbiome profiling revealed CA’s capacity to ameliorate HFD-induced dysbiosis, particularly enriching Lachnospiraceae_NK4A136 . Fecal microbiota transplantation (FMT) and Spearman correlations link serum lipids and hepatic injury factors to gut microbiota, indicating partially microbiota-mediated metabolic modulation by CA. Collectively, CA ameliorates MASLD through coordinated autophagy enhancement and microbial homeostasis restoration, holding promise as a functional food ingredient for metabolic liver disease prevention.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Weimin Lin,Xianyu Wen,Xuexin Li,Lei Chen,Wei Wei,Lifan Zhang,Jie Chen
CeRNA effect was an important regulation mode of miRNA mediated bio-activities, however, most of the researches of ceRNA were on ncRNAs synergetic with mRNAs, the exploration of ceRNA effect regulated mRNA interaction was still lack of. Besides, C/EBPα was one of the most crucial adipogenic regulators, which has been demonstrated to form a protein complex with FOXO1 to mediate AdipoQ expression. So that, we try to explore whether the ceRNA effect mediated the interaction of C/EBPα and FOXO1, and identified the key miRNAs of their ceRNA effect. In this paper, we found the ceRNA effect of C/EBPα and FOXO1 mediated their protein complex formation, furthermore regulated its transcriptional role for AdipoQ , thereby influencing pre-adipocytes adipogenesis . More importantly, we demonstrated that the miR-144 was the decisive factor that mediated the ceRNA effect of C/EBPα and FOXO1 to influence AdipoQ , thus regulated pre-adipocytes adipogenesis. This research will provide a new supplementary idea of the miRNA role in mediating coding RNA interaction that regulates pre-adipocyte adipogenesis.
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Advanced Science
·
2025
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IF 14.1
Shuaishuai Xing,Yanbing Lin,Yi Sun,Xiaoping Yue,Qigang Fan,Jisheng Nie,Zhihong Zhang,Yajing Liu,Juntang Yang,Qingzheng Kang,Yanxin Wang,Haijun Yan,Chan Tian,Ying Chang,Huidong Zhang
Lithium (Li) batteries have been used worldwide, but few are recycled, thus, the waste Li has been widely spread into the environment and finally accumulated in human body. Cuproptosis is a newly reported Cu-dependent and programmed cell death form. The unclear pathogenesis of unexplained miscarriage (UM) largely restricts its clinical treatment and global human reproduction. In this study, a UM case-control study shows that Li levels in serum or villous tissues, the levels of cuproptosis in villous tissue, and UM are positively associated. Li-exposed mouse models further confirm that Li exposure causes placental cuproptosis to induce miscarriage. Mechanistically, Li exposure up-regulates FOXO1 expression levels and thus promotes FOXO1-mediated STEAP4 transcription, up-regulating STEAP4 levels. STEAP4 up-regulates intracellular Cu + ion levels and causes cuproptosis, which further induces miscarriage. The cellular mechanisms are consistent with those in UM villous tissues and Li-exposed mouse placental tissues. Finally, treatment with TTM to suppress cuproptosis or the therapeutic down-regulation of FOXO1 or STEAP4 could efficiently suppress placental cuproptosis and alleviate mouse miscarriage in the Li-exposed mouse models. Collectively, this study not only discovers new healthy risks of Li exposure and novel pathogenesis of Li-induced unexplained miscarriage but also reveals new biological targets for treatment against miscarriage.
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JOURNAL OF ANIMAL SCIENCE
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2026
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IF 3.7
Zheng Jikang,Zhao Junyin,Li Minhao,Cheng Yuqin,Fang Xingqiang,Zhao Le,Zhao Yongju
Goat semen cryopreservation generates excessive reactive oxygen species (ROS), which impair post-thaw quality and physiological function. This study investigated the effects of resveratrol (RES) on cryopreserved goat sperm and the underlying signaling pathway. The results showed that supplementation with 150 μM RES significantly improved post-thaw sperm motility, plasma membrane integrity, and acrosome integrity (P < 0.05), enhanced SOD, CAT, and T-AOC activities, and reduced MDA content and sperm deformity rates (P < 0.05), while higher concentration (200 μM) showed no significant improvement compared to control, suggesting a detrimental effect of excessive RES. Furthermore, RES effectively alleviated cryo-induced ultrastructural damage to sperm. Mechanistically, RES activated AMPK signaling, increased AMPK phosphorylation, and upregulated the expression of SIRT1 and FoxO1 proteins. In contrast, the AMPK inhibitor Compound C partially blocked these beneficial effects. These findings indicate that RES improves the quality and antioxidant capacity of cryopreserved goat sperm by activating the AMPK/SIRT1/FoxO1 pathway, suggesting that RES can serve as a promising antioxidant additive for goat semen cryopreservation.
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CELLULAR SIGNALLING
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2022
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IF 4.85
Yao Ding,Qinan Wu
Background Type 2 diabetes mellitus (T2DM) is a global health problem that seriously threatens human health. Vitamin D (VD) has antidiabetic effects. However, the protective mechanism of 1,25-dihydroxyvitamin D3 (1,25D) on T2DM is still unclear. Methods A rat model of T2DM was constructed using a high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Glucose tolerance was assessed by an oral glucose tolerance test (OGTT). Insulin secretion in blood and cell supernatant was determined by ELISA. Cell viability was analysed by CCK-8 assay. The level of ROS was detected by the DCFH-DA fluorescent probe method. The iron level in pancreatic tissues and cells was detected by an iron assay kit. Immunofluorescence staining was used to detect the expression of the pancreatic β cell marker CD49a . Furthermore, the protein expression levels of ferroptosis pathway-related proteins and vitamin D receptor (VDR) were detected by western blot . Downstream VDR targets were screened by proteomic sequencing. Results The DM group had increased glucose levels and decreased insulin secretion, while 1,25D treatment decreased glucose levels and increased insulin secretion. 1,25D also suppressed DM-induced ferroptosis in pancreatic tissues in vivo. In addition, 1,25D significantly enhanced the viability of pancreatic β cells and reduced the levels of ROS and iron. 1,25D significantly upregulated the expression of VDR and the ferroptosis-related pathway protein GPX4 and downregulated the expression of ACSL4. Furthermore, knockdown of VDR reversed the effects of 1,25D on cell viability, ROS and iron levels, and ferroptosis-related protein expression in pancreatic β cells. Proteomic sequencing revealed that FOXO1 was the downstream target gene of VDR. Knockdown of FOXO1 reduced pancreatic β cell death, decreased ROS, iron and ACSL4 levels, and increased GPX4 levels. Conclusion 1,25D/VDR inhibited pancreatic β cell ferroptosis in T2DM by downregulating the expression of FOXO1. This study provides a new theoretical basis for basic research on T2DM and is expected to establish a new idea for the treatment of T2DM.
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FASEB JOURNAL
·
2024
·Vol. 38
·期 11
·e23681
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IF 4.4
Shi-shi Liao,Le-le Zhang,Yi-guo Zhang,Jie Luo,Tulanisa Kadier,Ke Ding,Rong Chen,Qing-tao Meng
Ischemia–reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia–reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 μg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.
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PHYTOTHERAPY RESEARCH
·
2024
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IF 6.1
Fan Wu,Fuer Lu,Hui Dong,Meilin Hu,Lijun Xu,Dingkun Wang
Oxyberberine (OBB), a natural metabolite of berberine, has been shown to exhibit inhibitory effects on gluconeogenesis in our previous work. This work was designed to investigate the potential effects and underlying mechanisms of OBB on hepatic gluconeogenesis. Our work found that OBB significantly inhibited the expressions of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), and decreased the glucose production in palmitic acid-induced HepG2 cells. Then, AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways were confirmed by transcriptomics and network pharmacology analyses. It was shown that AMPK activation may phosphorylate and promote nuclear exclusion of FoxO1 and CRTC2, two key regulators of hepatic gluconeogenesis transcriptional pathways, resulting in the inhibition of gluconeogenesis under OBB administration. Afterwards, AMPK/Akt/FoxO1, AMPK/CRTC2 signaling pathways were evidenced by western blot, immunoprecipitation and confocal immunofluorescence, and the targeted inhibitor (Compound C) and siRNA of AMPK were applied for further mechanism verification. Moreover, it was found that OBB treatment activated AMPK/Akt/FoxO1 and AMPK/CRTC2 signaling pathways to decrease hepatic gluconeogenesis in db/db mice. Similarly, the in vivo inhibitory effects of OBB on gluconeogenesis were also diminished by AMPK inhibition. Our work demonstrated that OBB can inhibit hepatic gluconeogenesis in vitro and in vivo, and its underlying mechanisms were associated with AMPK-mediated suppression of FoxO1 and CRTC2 signaling axes.
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MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·650
·
IF 5.5
Guo Yaoxue,Wang Xueyan,Zhang Lixiang,Liu Xing,Lu Pu,Liang Furu,Wu Jing,Zhao Junli,Hai Yan
Alzheimer’s disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ 25-35 oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD + /NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ 25-35 -injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.
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