DEVELOPMENTAL CELL
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2021
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IF 12.27
Cansu Karabiyik,Mariella Vicinanza,Sung Min Son,David C. Rubinsztein
Summary Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated. Here, we reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P 2 . ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels. Our study has identified how ULK1 upregulates autophagy upon glucose starvation and induces the formation of PI(5)P-containing autophagosomes by activating PIKfyve.
研究领域:
细胞生物学
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分子生物学
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生物化学
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PubMed
高影响因子
Biomedicines
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2026
·Vol. 14
·期 2
·403
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IF 4.5
Rui Ye,Qianqian Wang,Le Du,Li Li,Fan Hu
Background:Mitochondrial dysfunction is a fundamental driver of skin aging, making the enhancement of cellular bioenergetics an important strategy in dermocosmetic innovation.Cornus officinalisfruit extract (COFE), standardized for iridoid glycosides, was investigated for its ability to modulate mitochondrial function and counteract photo-oxidative stress associated with skin aging.Methods:Human dermal fibroblasts were treated with COFE to evaluate mitochondrial bioactivation. Transcriptomic changes were assessed using RNA sequencing (RNA-seq), with key mitochondrial genes validated by qPCR. AMPK phosphorylation, intracellular ATP content, NAD+/NADH ratio, and mitochondrial membrane potential (ΔΨm) were quantified as functional indicators of mitochondrial performance. To examine anti-aging relevance, a reconstructed human epidermis model was challenged with UVA and retinol to induce photo-oxidative stress. COFE’s effects on inflammatory (IL-1α), hydration (AQP3), proliferation (Ki67), and barrier-related (PKCα) markers were subsequently analyzed.Results:COFE was associated with activation of AMPK signaling and coordinated upregulation of OXPHOS-related genes in dermal fibroblasts, increasing ATP by 30.00%, the NAD+/NADH ratio by 158.71%, and ΔΨm by 158.82%. It also reduced IL-1α and upregulated AQP3, Ki67, and PKCα in a UVA/retinol-challenged epidermis model. In vivo, a 1% COFE eye cream produced statistically significant improvements across hydration, barrier function, redness, skin tone, wrinkles, elasticity, and periorbital contour after 28 days.Conclusions:COFE functions as an AMPK-associated mitochondrial bioenergetic modulator that enhances cellular energy metabolism and mitigates photo-oxidative stress in skin-relevant experimental models. The concordance between mechanistic findings and clinical outcomes supports COFE as a promising anti-aging active ingredient for dermocosmetic applications.
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JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
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2026
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IF 4.9
Qingliu Li,Nan Hu,Limei Zhao,Shaoxuan Zhang,Lulu Meng,Jinyu Zhou,Qiujie Li,Fucheng Lei,Xiaotong Yang,Meiqin Hu,Hua Zhu,Pengzhou Hang,Jing Zhao
Transmembrane protein 175 (TMEM175) is a lysosomal proton-activated and proton-selective channel critical for regulating lysosomal membrane potential and acidity. However, its role in cardiomyocyte physiological and stress response remains unclear. Here, we investigated the function of TMEM175 in mitochondrial homeostasis using H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVMs) under physiological conditions and during hydrogen peroxide (H 2 O 2 )-induced oxidative stress. Under physiological conditions, genetic knockout of TMEM175 impaired mitochondrial respiration, reduced mitochondrial superoxide, and attenuated autophagic clearance. In contrast, under H 2 O 2 -induced stress, TMEM175 deletion significantly alleviated mitochondrial dysfunction and cell death, despite autophagic flux being primarily stalled at the degradation stage. Mechanistically, TMEM175 deficiency activated AMP-activated protein kinase (AMPK), and silencing AMPK reversed the cytoprotective effects of TMEM175 deletion against H 2 O 2 injury. Pharmacological inhibition of TMEM175 with 2-phenylpyridin-4-ylamine (2-PPA) in H9c2 and NRVMs recapitulated key phenotypes observed in genetic knockout models. Furthermore, 2-PPA improved cardiac function and attenuated histopathological injury in myocardial infarction mice. Together, these findings reveal a dual role for TMEM175: it maintains lysosomal-mitochondrial communication under basal conditions, yet its inhibition protects against oxidative stress primarily through AMPK activation. This study identifies TMEM175 as a novel lysosomal regulator of cardiac mitochondrial resilience and highlights its potential role in the cellular response to oxidative injury in cardiomyocytes.
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 5.4
Xing-lan Ye,Ling-shuai Zeng,Qiang Liu,Wen-cheng Xu,Hong Liu,Hong Cheng,Wen-xiao Zheng,Xiao-qin Wang,Xue Xue
Ethnopharmacological relevance Huaiqihuang granule (HQH) is a traditional Chinese herbal formula comprising Trametes robiniophila Murr. , Lycii Fructus ., and Polygonatum sibiricum Red. This granule can nourish Qi and Yin, improve blood circulation and remove blood stasis. HQH has been extensively used to improve immune-mediated kidney diseases, such as IgA vasculitis nephritis (IgAVN). However, its renal protective mechanism remains elusive. Aim of the study This study investigated whether HQH ameliorates IgAVN by modulating the AMPK/mTOR-mediated autophagy pathway. Materials and methods The IgAVN mouse model was established using gliadin sensitization and India ink-mediated reticuloendothelial blockade (n = 10/group). The model mice were then treated for 4 weeks with low/high-dose HQH (4/8 g/kg/day) or dexamethasone (2.5 mg/kg/day). For in vitro analyses, human mesangial cells (HMCs) were first stimulated with aggregated IgA1 (aIgA1, 25 μg/mL) and then treated with the optimal concentration of HQH-containing serum (40 %). Furthermore, biochemical indices assays, renal histopathology, and immunofluorescence analysis of IgA deposition were performed. Moreover, autophagy levels were evaluated by assessing the expression of autophagy-related proteins, MDC staining, and mCherry-EGFP-LC3 transfection. Western blot and immunofluorescence were carried out to assess the levels of the AMPK/mTOR pathway proteins and proliferation markers. Results The results showed that HQH treatment significantly reduced 24-h urinary protein and serum IgA levels, but improved renal histopathology in IgAVN mice. Furthermore, HQH activated autophagy by upregulating p-AMPKα, LC3-Ⅱ/LC3-Ⅰ, and Beclin1, while inhibiting p-mTOR/mTOR and p62. Moreover, in HMCs, 40 % HQH-containing serum optimally inhibited aIgA1-induced mesangial proliferation and increased autophagic levels, as evidenced by the quantitative increase in autophagy activity and mean fluorescence intensity of MDC. However, these effects were blocked by AMPK inhibition. Conclusion This study showed that HQH alleviates IgAVN by upregulating AMPK/mTOR-mediated autophagy, inhibiting mesangial cell proliferation, and mitigating renal injury. These findings suggest that HQH has therapeutic potential for IgAVN and link autophagy modulation to IgAVN treatment.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Yongsheng Fang,Han Liu,Fakun Jiang,Qian Lu,Bangrui Huang,Chuanjun Mao,Qian Long,Qixin Zhou,Xiaodong Yang,Jun Cao,Wenyong Xiong
Hepatic steatosis is a chronic progressive condition that leads to multiple severe liver disorders. However, current therapeutic options are limited for available drugs. Screening active natural products for curing hepatic steatosis provide novel chemical scaffolds for drug development and chemical probes to reveal novel mechanisms in the development of hepatic steatosis. Here, we established an in vitro cell model for measuring hepatic lipid content and screened a series of euphorane-type diterpenoids to identify active diterpenoids for decreasing hepatic lipids. Interestingly, among these diterpenoids, euphorbia factor L3 (EFL3) exhibited the most pronounced inhibition activity for lipid amount, both in cultured hepatocytes and in HFD-induced mice with hepatic steatosis. Mechanistic studies demonstrated that EFL3 activated the LKB1-AMPK signaling pathway in hepatocytes, leading to downregulation of the lipogenic factors SREBP-1c, ACC1, and FASN, and leading to upregulation of fatty acid oxidation-related proteins SIRT1, PGC-1α, PPARα, and CPT1A. These changes improved cellular lipid metabolism and ultimately ameliorated hepatic steatosis in mice. In summary, this study supports the key role of LKB1-AMPK pathway in regulation of hepatic steatosis and reveals that EFL3 could be considered as a novel compound for drug development against hepatic steatosis.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 24
·17280
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IF 5.6
Hui Li,Mingchao Wang,Kai Qu,Ruiming Xu,Haibo Zhu
It is widely recognized that macrophage cholesterol efflux mediated by the ATP-binding cassette transporter A1 (ABCA1) constitutes the initial and rate-limiting step of reverse cholesterol transport (RCT), displaying a negative correlation with the development of atherosclerosis. Although the transcriptional regulation of ABCA1 has been extensively studied in previous research, the impact of post-translational regulation on its expression remains to be elucidated. In this study, we report an AMP-activated protein kinase (AMPK) agonist called ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-((3-hydroxyphenyl) amino)-9H-purin-9-yl) tetrahydrofuran-2-yl) methyl dihydrogen phosphate (MP), which enhances ABCA1 expression through post-translational regulation rather than transcriptional regulation. By integrating the findings of multiple experiments, it is confirmed that MP directly binds to AMPK with a moderate binding affinity, subsequently triggering its allosteric activation. Further investigations conducted on macrophages unveil a novel mechanism through which MP modulates ABCA1 expression. Specifically, MP downregulates the Cav1.2 channel to obstruct the influx of extracellular Ca2+, thereby diminishing intracellular Ca2+levels, suppressing calcium-activated calpain activity, and reducing the interaction strength between calpain and ABCA1. This cascade of events culminates in the deceleration of calpain-mediated degradation of ABCA1. In conclusion, MP emerges as a potentially promising candidate compound for developing agents aimed at enhancing ABCA1 stability and boosting cellular cholesterol efflux and RCT.Keywords:ATP-binding cassette transporter A1;reverse cholesterol transport;AMP-activated protein kinase;MP;calpain-mediated degradation
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2023
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IF 5.6
Peng Cao,Yi Wang,Cong Zhang,Mitchell A. Sullivan,Wen Chen,Xiang Jing,Huifan Yu,Fei Li,Qu Wang,Zhongshi Zhou,Qi Wang,Wen Tian,Zhenpeng Qiu,Lianxiang Luo
The global incidence of nonalcoholic fatty liver disease (NAFLD) has been surging in recent years, however, no drug is currently approved to treat this disease. Quercetin, a natural flavonoid abundant in plants and fruits, has been reported to alleviate NAFLD, however, the exact molecular mechanism remains unclear. This study aims to further elucidate its potential mechanism of action. The beneficial effects and the underlying mechanism of quercetin in alleviating NAFLD were explored both in vitro and in vivo, by employing chemical inhibitors of autophagosomes (3-methyladenine, 3-MA), autolysosomes (chloroquine, CQ), AMPK (Compound C, CC) and SIRT1 (selisistat, EX-527). The levels of intracellular lipids, reactive oxygen species, mitochondria function, autophagy, and mitophagy were assessed by fluorescent labeling and examined using flow cytometry or confocal microscopy. Key protein expressions of autophagy, mitophagy, and inflammation were also determined. In vivo, quercetin was shown to dose-dependently effectively alleviate NAFLD, but intraperitoneal injection of 3-MA could block the beneficial effects of quercetin on body weight, liver weight, serum ALT/AST, hepatic ROS and inflammation. In vitro, quercetin could reduce intracellular lipids (Nile Red staining) and ROS/DHE accumulation, which could be also blocked by 3-MA or CQ. Furthermore, we found that CC could abrogate the protective effects of quercetin on lipid and ROS accumulation in vitro. Also, CC abolished the proautophagic and anti-inflammatory effects of quercetin, as shown by western blot determination and Lyso-Tracker labeling. Importantly, mitophagy, a specific form of mitochondria-targeted autophagy, was enhanced by quercetin, as demonstrated by PINK1/Parkin protein variation and immunofluorescence colocalization of autophagosomes and mitochondria, which could also be blocked by the intervention of CC. This study demonstrates that quercetin prevents NAFLD through AMPK-mediated mitophagy and suggests that promoting mitophagy via an upregulation of AMPK may be a promising therapeutic strategy against NAFLD.
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Frontiers in Nutrition
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2022
·
IF 6.59
Wang Chenlei,Yan Xinlei,Bai Yanping,Sun Lina,Zhao Lihua,Jin Ye,Su Lin
Sunit sheep are famous for their high meat quality, but the meat quality of them has declined due to the change in feeding methods. Lactobacillus has a variety of probiotic effects and is widely used in animal diets to optimize meat quality. This study aimed to investigate the effect of dietary supplementation with different levels of Lactobacillus on meat quality. A total of 24 3-month-old Sunit sheep with an average body weight of 19.03 ± 3.67 kg were randomly divided into control (C), 1% (L1), 2% (L2), and 3% Lactobacillus groups (L3), with 6 sheep in each group. Myofiber characteristics, meat quality, and metabolic enzyme activity were detected. Moreover, the regulatory mechanism of Lactobacillus on meat quality was explored by using Western blotting and real-time Quantitative polymerase chain reaction (RT-qPCR). The results showed that dietary addition of Lactobacillus decreased LDH activity in the Biceps femoris of Sunit sheep (P < 0.05). Compared to the other groups, the 1% Lactobacillus group showed the conversion of myofibers from the glycolytic to the oxidative type, and the increasing b* values (P < 0.05), decreasing shear force and cooking loss of meat (P < 0.05) and the relative gene and protein expression levels of AMPK, PGC-1α, NRF1, TFAM, and COX IV (P < 0.05) in the Biceps femoris were also increased in the 1% Lactobacillus group. Therefore, the addition of Lactobacillus to the diet of Sunit sheep could regulate the AMPK signaling pathway to promote myofiber type conversion, which improves meat quality. This study provided a theoretical and data basis for improving the meat quality of sheep and supplied a novel way of applying Lactobacillus.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Qi Liang,Rongjie Guo,Jia-Ruei Tsao,Yun He,Chenchen Wang,Jiaxuan Jiang,Di Zhang,Taige Chen,Tingting Yue,Kai Hu
Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata , in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Tianjiao Ma,Lei Yang,Binmei Zhang,Xin Lv,Feifei Gong,Wei Yang
Aims Doxorubicin is a drug widely used in clinical cancer treatment, but severe cardiotoxicity limits its clinical application. Autophagy disorder is an important factor in the mechanism of doxorubicin-induced cardiac injury. As the smallest molecule in nature, hydrogen has various biological effects such as anti-oxidation, anti-apoptosis and regulation of autophagy. Hydrogen therapy is currently considered to be an emerging therapeutic method, but the effect and mechanism of hydrogen on doxorubicin-induced myocardial injury have not been determined. The purpose of this study was to investigate the protective effect of hydrogen inhalation on doxorubicin-induced chronic myocardial injury and its effect and mechanism on autophagy. Methods In this study, we established a chronic heart injury model by intraperitoneal injection of doxorubicin in rats for 30 days, accumulating 20 mg/kg. The effect of hydrogen inhalation on the cardiac function in rats was explored by echocardiography, Elisa, and H&E staining. To clarify the influence of autophagy, we detected the expression of LC3 and related autophagy proteins in vivo and in vitro by immunofluorescence and western blot.In order to further explore the mechanism of autophagy, we added pathway inhibitors and used western blot to preliminarily investigate the protective effect of hydrogen inhalation on myocardial injury caused by doxorubicin. Results Hydrogen inhalation can improve doxorubicin-induced cardiac function decline and pathological structural abnormalities in rats. It was confirmed by immunofluorescence that hydrogen treatment could restore the expression of autophagy marker protein LC3 (microtubule-associated protein 1 light chain 3) in cardiomyocytes reduced by doxorubicin, while reducing cardiomyocyte apoptosis. Mechanistically, Western blot results consistently showed that hydrogen treatment up-regulated the ratio of p-AMPK (phosphorylated AMP-dependent protein kinase) to AMPK and down-regulated p-mTOR (phosphorylated mammalian target of rapamycin) and mTOR ratio. Conclusions These results suggest that hydrogen inhalation can activate autophagy through the AMPK/mTOR pathway and protect against myocardial injury induced by doxorubicin. Hydrogen inhalation therapy may be a potential treatment for doxorubicin-induced myocardial injury.
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ENVIRONMENT INTERNATIONAL
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2020
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IF 7.577
Miaoling Lin,Rui Hua,Jing Ma,Yao Zhou,Pei Li,Xiya Xu,Zhiqiang Yu,Song Quan
Background Bisphenol A (BPA) is a widespread endocrine-disrupting chemical with estrogen like effects, which could interfere with the human reproductive system by disrupting the normal function of granulosa cells (GCs) leading to abnormal ovarian function. However, the mechanism of its toxicity on human GCs has not been clearly described thus far. Methods 106 normogonadotropic infertile women undergoing their first in-vitro fertilization-embryo transfer (IVF-ET) cycle were recruited. Urinary BPA level and the early outcomes of IVF-ET were analysed. Patients were divided to low and high BPA exposure groups using the median urinary BPA concentration as the cut-off value. In-vivo and in-vitro studies were conducted using mice and human granulosa cell line (KGN cells). Female Kunming mice approximately 6–8 weeks of age were poisoned with BPA at different dosages (1, 10 or 100 μg/kg) by oral gavage once daily for 2 weeks, while KGN cells were exposed to BPA at the concentration of 1, 10 or 100 nM for 24 h, 48 h or 72 h. BPA-induced ovarian morphologic changes were analysed by histopathology investigation. Cell viability and apoptosis were evaluated using CCK-8, TUNEL and flowcytometric, respectively. Hormone levels were determined using ELISA and the molecular mechanism studies were conducted using immunofluorescence, RT-PCR and western blots. Results The oocyte retrieval rate, maturation rate and embryo implantation rate significantly decreased with the higher level of urinary BPA concentration. Peak E2 level was lower in high BPA group, but no statistical significance could be observed. In BPA treated mice, cystic dilation of the follicles with a decreased number of GCs could be observed histopathologically. Decreased E2, P4 and AMH level and GCs autophagy could be detected both in-vivo and in-vitro with the activation of AMPK/mTOR/ULK1 signalling pathway. As being confirmed in KGN cells, phosphorylated AMPK and ULK1 increased while phosphorylated mTOR decreased, and by inhibition autophagy using knockdown of AMPK or 3-MA, adverse effects of BPA exposure in-vitro could be reversed. Conclusion BPA exposure might abnormally influence human ovarian functions leading to abnormal folliculogenesis by activation of autophagy in GCs through AMPK/mTOR/ULK1 pathway.
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LIFE SCIENCES
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2020
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IF 3.647
Jing Yang,Yiwen Zhou,Jinsong Shi
Acute pancreatitis (AP) is a noninfectious inflammatory disease with high morbidity and mortality, which is characterized by severe inflammation and tissue necrosis. Cordycepin (CRD), derived from Cordyceps militaris , possesses anti-inflammatory effects and immunomodulation properties. Here, we investigated the protective effects of CRD on pancreatic injury and clarified potential mechanisms in AP model. There were established caerulein-induced AP and CRD pretreatment models in vivo and in vitro, as showed by serum enzymes, histopathological alterations and pro-inflammatory cytokines. Pretreatment with CRD notably downregulated the serum amylase and lipase levels and apparently reduced pancreatic histopathological alterations in AP mice. Meanwhile, the MPO staining confirmed that CRD pretreatment modulated the infiltration of neutrophils in AP mice. Furthermore, CRD markedly decreased the levels of pro-inflammatory factors (IL-6, IL-1β, and TNF-α) though inhibiting the activation of nuclear factor-κB (NF-κB) and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in AP mice. In pancreatic acinar cancer cell 266-6, CRD pretreatment decreased cholecystokinin(CCK)-induced inflammatory response was consistent with those in vivo. Mechanistically, CRD was also revealed to activate activated protein kinase (AMPK) and attenuated inflammation both in vivo and in vitro. On the whole, this study indicated that CRD protects mice from pancreatic inflammatory process and damage by suppressed NF-κB and NLRP3 inflammasome activation via AMPK, which probably contributed to the potential therapy for AP.
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