BIOFACTORS
·
2024
·
IF 5
Yining Lei,Manqin Li,Xinran Liu,Lu Zhang,Ruyi Zhang,Fei Cai
Despite the observation of diabetes-induced brain tissue damage and impaired learning and memory, the underlying mechanism of damage remains elusive, and effective, targeted therapeutics are lacking. Notably, the NLRP3 inflammasome is highly expressed in the hippocampus of diabetic individuals. Nerolidol, a naturally occurring compound with anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic option for metabolic disorders. However, the ameliorative capacity of nerolidol on diabetic hippocampal injury and its underlying mechanism remain unclear. Network pharmacology and molecular docking was used to predict the signaling pathways and therapeutic targets of nerolidol for the treatment of diabetes. Then established a diabetic rat model using streptozotocin (STZ) combined with a high-fat diet and nerolidol was administered. Morris water maze to assess spatial learning memory capacity. Hematoxylin and eosin and Nissl staining was used to detect neuronal damage in the diabetic hippocampus. Transmission electron microscopy was used to detect the extent of damage to mitochondria, endoplasmic reticulum (ER) and synapses. Immunofluorescence was used to detect GFAP, IBA1, and NLRP3 expression in the hippocampus. Western blot was used to detect apoptosis (Bcl-2, BAX, and Cleaved-Caspase-3); synapses (postsynaptic densifying protein 95, SYN1, and Synaptophysin); mitochondria (DRP1, OPA1, MFN1, and MFN2); ER (GRP78, ATF6, CHOP, and caspase-12); NLRP3 inflammasome (NLRP3, ASC, and caspase-1); inflammatory cytokines (IL-18, IL-1β, and TNF-α); AKT (P-AKT); and mitogen-activated protein kinase (MAPK) pathway (P-ERK, P-p38, and P-JNK) related protein expression. Network pharmacology showed that nerolidol's possible mechanisms for treating diabetes are the MAPK/AKT pathway and anti-inflammatory effects. Animal experiments demonstrated that nerolidol could improve blood glucose, blood lipids, and hippocampal neuronal damage in diabetic rats. Furthermore, nerolidol could improve synaptic, mitochondrial, and ER damage in the hippocampal ultrastructure of diabetic rats by potentially affecting synaptic, mitochondrial, and ER-related proteins. Further studies revealed that nerolidol decreased neuroinflammation, NLRP3 and inflammatory factor expression in hippocampal tissue while also decreasing MAPK pathway expression and enhancing AKT pathway expression. However, nerolidol improves hippocampal damage in diabetic rats cannot be shown to improve cognitive function. In conclusion, our study reveals for the first time that nerolidol can ameliorate hippocampal damage, neuroinflammation, synaptic, ER, and mitochondrial damage in diabetic rats. Furthermore, we suggest that nerolidol may inhibit NLRP3 inflammasome and affected the expression of MAPK and AKT. These findings provide a new experimental basis for the use of nerolidol to ameliorate diabetes-induced brain tissue damage and the associated disease.
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高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 3
·e70379
·
IF 4.2
Jiancheng Yang,Qinghua Tang,Siyu Li,Lei Yang,Ming Yang,Qingmei Li,Yan Feng,Mingming Pan,Yuhong Zeng
The accumulation of intracellular reactive oxygen species (ROS) is widely recognized to stimulate the development of osteoclasts, a crucial factor in the onset of osteoporosis. The ROS scavenging capability of Prussian blue nanoparticles (PBNPs) is exceptional, and they possess excellent biocompatibility. However, the effects of PBNPs on osteoporosis remain unknown. Present study aimed to investigate whether PBNPs could inhibit osteoclast differentiation and prevent ovariectomy (OVX)-induced bone loss by suppressing ROS. In vitro experiments demonstrated that PBNPs attenuated osteoclastogenesis and downregulated the expression of osteoclast-related genes. Mechanistically, PBNPs reduce cellular ROS by blocking RANKL-induced ROS generation and increasing the expression of ROS scavenging enzymes, which in turn block the NF-κB, ERK, JNK, and p38 pathways, thereby reducing NFATc1 signaling. According to in vivo experimental results, OVX caused a significant rise in ROS in the bone marrow, an increase in osteoclastic number on the bone surface, and substantial bone loss; however, PBNPs significantly reduced ROS and successfully protected OVX-induced bone damages. In conclusion, this study showed for the first time that PBNPs prevented OVX-induced bone loss and attenuate osteoclastogenesis, indicating that PBNPs may be a viable alternative therapy for the management of osteoclast-associated bone disorders. Graphical Once RANKL binds to RANK on the cell membrane of BMMs, the NF-κB and MAPK pathways become activated, resulting in the amplification of NFATc1, which upregulates the expression of osteoclast-specific genes such as CTSK , Integrin αV , Atp6v0d2 , and MMP9 . These signaling events are mediated by the RANKL-induced ROS signaling. PBNPs decreased levels of ROS and mitigated these signaling pathways by decreasing ROS production and enhancing the expression of antioxidant enzymes. Consequently, PBNPs prevented osteoclastogenesis.
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Drug Design Development and Therapy
·
2025
·
IF 5.1
Fangbin Liu,Jiyuan Chen,Chunai Gong,Minyan Chen,Gang Yang,Chun Chen,Ru Yao,Shengnan Li,Rong Wang,Yongfang Yuan
Introduction Xerostomia, commonly caused by Sjögren disease (SjD) or head and neck radiotherapy, significantly impairs patients’ quality of life, yet effective treatments remain limited. Traditional Chinese Medicine (TCM) offers promising alternatives due to its favourable efficacy and low toxicity. Shatai Heji (STHJ), a compound TCM formulation designed to nourish yin and invigorate qi, shows therapeutic potential for xerostomia. This study aimed to establish quality control standards for STHJ and evaluate its pharmacodynamics, safety, and mechanisms of action in models of xerostomia.Methods A qualitative identification method was developed for the twelve herbal components of STHJ, with quantification of active constituents, focusing on quality markers for Astragalus and Rehmannia. Xerostomia was induced in Sprague–Dawley (SD) rats using a muscarinic receptor antagonist, and in BALB/c mice with SjD. Histological examination of major organs and salivary glands was performed, and aquaporin-5 (AQP5) expression in submandibular glands was assessed via Western blotting and immunohistochemistry. Therapeutic effects were evaluated through salivary secretion, glandular weight, and biochemical markers. In SjD mice, submandibular gland immunofluorescence and ELISA were used to assess inflammatory cytokines (TNF-α, TNF-β, IFN-γ, IL-6) and autoantibodies (anti-SSA/Ro, anti-SSB/La). Western blotting was used to analyse NF-κB and MAPK p38 pathway activation. Acute toxicity was assessed in SD rats.Results STHJ significantly improved xerostomia symptoms, increased salivary output, upregulated AQP5, and preserved glandular morphology. It reduced fibrosis, suppressed inflammatory cytokine expression, and inhibited immune cell infiltration. Mechanistically, STHJ attenuated activation of NF-κB and MAPK p38 pathways. No acute toxicity was observed.Conclusion This is the first study to establish quality control standards for STHJ and to demonstrate its anti-inflammatory and immunomodulatory effects in xerostomia models. The findings suggest that STHJ may serve as a safe and effective therapeutic option for xerostomia associated with SjD and other conditions.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Wei Wei,Siting Pu,Chengxin Yan,Hongzao Yang,Hongwei Chen
The rapid growth of lithium (Li)-related industrial activities and the application of Li-containing products have become an emerging human health concern. Li has been employed to treat human mental disorders; however, excessive Li salt accumulation can lead to brain damage. The mechanism of toxicity of long-term exposure to Li in the brain warrants further investigation. This research study established a network toxicology strategy to evaluate the molecular mechanisms and putative toxicity of lithium chloride (LiCl). The analysis of online databases identified 80 intersection targets for LiCl-induced neurotoxicity. Further refinements via STRING and Cytoscape software highlight 10 core targets. Furthermore, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), apoptosis pathways, and mitogen-activated protein kinase (MAPK) were enriched. Molecular docking validated the robust interaction of core targets with Li + . In vivo analyses of mice brains revealed substantial pathological alterations, neuronal degeneration, and nerve cell apoptosis. LiCl elevated the mRNA level of core genes. Further, the phosphorylation status of core proteins was primarily modulated by LiCl. Our investigation employs novel strategies for assessing the environmental pollutant toxicity and gives theoretical basis for elaborating the LiCl-induced neurotoxicity-related molecular mechanism. This may be employed to guide risk assessment of environmental Li exposure.
研究领域:
毒理学
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神经科学
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分子生物学
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Veterinary Sciences
·
2025
·Vol. 12
·期 5
·428
·
IF 2.3
Yanbing Lou,Tingting Yang,Chenglong Xia,Shijun Yang,Huidan Deng,Yanqiu Zhu,Jing Fang,Zhicai Zuo,Hongrui Guo
Simple SummaryYak, as a unique species of plateau cattle, is highly susceptible to Cu deficiency, which is further exacerbated by poor soil conditions and low nutrient content in yak feed, which is associated with the decline of yak performance. Hormones synthesized by granulosa cells of yak follicles play an indispensable role in reproductive function. In this study, we investigated the effects of different concentrations of copper on the hormone secretion of cultured granulosa cells of yak follicles and the related molecular mechanisms. The above results showed that copper could positively promote the hormone secretion of female yaks, which provided a strategy direction with potential value for improving the fertility of yaks under the condition of copper deficiency.Yak (Bos grunniens) is the main economic animal growing in the Qinghai–Tibet Plateau. Because of its poor growing environment, copper deficiency is common. Studies have shown that appropriate copper supplementation can improve the reproductive performance of heifers. In this study, the primary granulosa cells of yak were isolated, and different copper levels were established by adding copper chelator and copper sulfate. Biochemical, Western blot and transcriptome methods were used to reveal the mechanism of copper on the hormone secretion function of granulosa cells. The results showed that copper promoted hormone secretion by regulating the expression of steroid synthase such as StAR, CYP19A1 and CYP11A1. Transcriptome analysis showed that copper ion levels significantly affected the function of cells, and changes in copper ion level affected genes related to protein phosphorylation, lipid metabolism, lipid biosynthesis, steroid hormone synthesis and the MAPK pathway. In conclusion, copper can promote steroid hormone synthesis in the granulosa cells of yak follicles, and the MAPK signaling pathway may be involved.
研究领域:
动物科学
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生殖生物学
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分子生物学
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营养学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Xinglishang He,Wanfeng Xu,Linzi Li,Xiaofeng Jiang,Yingjie Dong,Kun Liu,Xiaojie Feng,Jie Su,Bo Li,Guiyuan Lv,Suhong Chen
Ethnopharmacological relevance Polygonatum Rhizoma Ginseng Formula (HJRS) is a traditional Chinese medicine preparation commonly used to enhance immunity. Traditionally, it is believed to “moisten dryness and nourish yin, tonify the spleen, and benefit qi.” However, a systematic evaluation of its efficacy and mechanism of action is still lacking. Aim of the study To explore the pharmacodynamic effects and underlying mechanisms of HJRS in cyclophosphamide (CTX)-induced immunocompromised model mice. Method To explore the immunomodulatory effects of HJRS, we used cyberpharmacology combined with in vivo experiments. An immunocompromised mouse model was established using CTX, and different doses of HJRS were administered by gavage during the modeling period. The efficacy of HJRS was evaluated by assessing immune-related parameters, including body weight, heat pain threshold, and behavioral activity. Biochemical markers (acid phosphatase, total nitric oxide synthase, and lactate dehydrogenase), immune function indicators (C3, C4, secretory immunoglobulin A [sIgA]), and immune organ indices (spleen and thymus coefficients) were measured. Additionally, intestinal mucosal immunity (Peyer’s patches, sIgA, and IgM), cellular immunity (delayed-type hypersensitivity [DTH]), and humoral immunity (serum hemolysin, hemolysin, and IgM) were analyzed in the model mice. To further investigate the underlying mechanisms, we used 16S RNA sequencing, western blotting, gas chromatography-mass spectrometry, and other techniques to examine the intestinal microbiota, the short-chain fatty acids–G protein-coupled receptor 41 (SCFAs-GPR41) pathway, and the downstream mitogen-activated protein kinase (MAPK) signaling pathway. Result Network pharmacology analysis identified 34 active compounds and predicted 154 potential targets in HJRS that may regulate immune function by interacting with multiple targets (tumor-necrosis factor [TNF], PIK3CG, JUN, AKT1, and MAPK) and immune-related signaling pathways (MAPK and TNF-signaling pathway). Experimental validation demonstrated that HJRS alleviated symptoms of weakness and reduced behavioral activity in the model mice. It significantly enhanced the DTH response, elevated serum hemolysin levels, and restored the balance of white blood cells, lymphocytes, red blood cells, and hemoglobin percentages. HJRS also rebalanced the serum CD3 + CD4 + /CD3 + CD8 + ratio and increased C3 and C4 levels. Furthermore, it improved immune organ function by raising the thymus and spleen coefficients and increasing serum IgA, IgA, and IgM levels. Histopathological examination revealed that HJRS ameliorated CTX-induced pathological damage in the thymus, spleen, and intestines. HJRS regulated gut microbiota composition by enhancing the richness of Bacteroidetes and increasing the Firmicutes/Bacteroidetes ratio, while reducing the abundance of Firmicutes . It decreased the relative abundance of harmful genera, such as Bacteroides and Enterorhabdus , and promoted the growth of beneficial genera, including Muribaculaceae , Clostridia , and Alloprevotella . Additionally, HJRS increased the fecal acetic acid, propionic acid, hexanoic acid, and total SCFA levels in the model mice. It activated the SCFAs-GPR41 pathway and downstream MAPK signaling, thereby enhancing intestinal mucosal immune function. Conclusion HJRS effectively improved immune function in CTX-induced immunocompromised mice. Its mechanism of action may be associated with the regulation of intestinal microbiota dysbiosis, activation of the intestinal “SCFA-GPR41” pathway, and modulation of the downstream MAPK signaling pathway.
研究领域:
民族药理学
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免疫学
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分子生物学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Xin-Yao Li,Bang-Yin Tan,Yue Zhang,Yan-Lin Lv,Yun-Li Zhao,Xiao-Dong Luo
Ethnopharmacological relevance Stemona sessilifolia (Miq.) Miq. has been employed in traditional medicine for its potential renal benefits, including anti-edema, diuretic, and anti-jaundice properties. However, the renoprotective effects related to these traditional uses remain to be fully elucidated. Aim of the study : To investigate the therapeutic efficacy of S . sessilifolia against hyperuricemic nephropathy and elucidate its underlying signaling pathway. Materials and methods A hyperuricemic nephropathy mouse model, induced by potassium oxonate and hypoxanthine, was employed to evaluate the renal protection of the extract of S. sessilifolia through biochemical tests and histopathological observation. Transcriptomic analysis was applied to explore potential signaling pathways. Subsequently, bioassay-guided isolation was conducted during phytochemical investigation. Uric acid-induced HK-2 cells were then employed to validate the renal cytoprotective effects of the isolated compounds. Results Treatment with S. sessilifolia extract significantly reduced serum uric acid, creatinine, and urea nitrogen levels by 65.15%, 47.95%, and 49.1%, respectively. Additionally, it decreased urinary protein excretion, and ameliorated renal injury and fibrosis in mice. The protective effects might be exerted by inhibiting the c-Myc/c-Fos/MAPK signaling pathway to maintain the homeostasis of renal tissue. Moreover, the bioactive compound stemoninine protected HK-2 cells against uric acid-induced oxidative stress, inflammatory response, proliferation, migration, and apoptosis. Conclusion The S. sessilifolia extract and its major bioactive compound, stemoninine, protected against hyperuricemic nephropathy by suppressing the c-Myc/c-Fos/MAPK signaling pathway.
研究领域:
民族药理学
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肾病学
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植物化学
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分子生物学
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信号转导
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ACS Infectious Diseases
·
2025
·
IF 3.8
Hengxiu Wang,Hongchen Wang,Yue Yang,Tianming Wang,Changzhong Wang,Daqiang Wu,Caixia Zheng,Wenfan Wei
Berberine (BER), a natural isoquinoline alkaloid, exhibits broad-spectrum antifungal activity, yet its mechanism against Aspergillus fumigatus─a leading cause of invasive fungal infections─remains poorly understood. Here, we aim to unveil the mechanism of BER against the pathogenicity of A. fumigatus through mitochondrial dynamics and related pathways. In vitro assays revealed that berberine treatment triggered mitochondrial fragmentation, resulting in reactive oxygen species (ROS) overaccumulation. Subsequent proteomic analyses identified Hog1-MAPK as the central signaling hub activated by ROS stress. Upon activation, Hog1 localizes to the nucleus. ROS scavenging (N-acetylcysteine (NAC) treatment) abolished BER’s antifungal effects, confirming the ROS-Hog1-cell cycle axis. Crucially, in a murine invasive aspergillosis model, BER reduced the fungal burden in lungs and improved survival rates. Thus, we demonstrate that berberine suppresses A. fumigatus growth by disrupting mitochondrial dynamics, elevating reactive ROS, and activating the Hog1-MAPK signaling cascade, ultimately inducing cell cycle arrest. Our findings unveil a previously unrecognized mechanism linking mitochondrial morphology dysregulation to cell cycle control in fungi and establish BER as a promising therapeutic agent targeting mitochondrial-ROS-Hog1 signaling in A. fumigatus infections.
研究领域:
微生物学
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真菌致病机制
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分子生物学
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抗真菌治疗
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线粒体动力学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2020
·Vol. 47
·期 1
·243-255
·
IF 3.098
Qiumei Shi,Wuying Lang,Shiyong Wang,Guangyu Li,Xue Bai,Xijun Yan,Haihua Zhang
Acute kidney injury (AKI) is often accompanied by inflammation. Echinacea polysaccharide (EP) is an active ingredient that has been demonstrated to possess anti‑oxidative, anti‑inflammatory, antimicrobial and immunomodulatory functions. However, the role of EP in AKI has not been examined. The present study investigated the effects of EP on lipopolysaccharide (LPS)‑induced AKI. Western blotting, immunohistochemistry and immunofluorescence analyses were performed to detect protein expression levels. Administration of EP significantly attenuated LPS‑induced renal tissue injury, along with a decrease in blood urea nitrogen and creatinine levels. EP decreased the levels of inducible nitric oxide synthase and cyclo‑oxygenase‑2 in LPS‑treated mice. Furthermore, LPS‑induced inflammation was inhibited by EP in renal tissues and HBZY‑1 cells, as demonstrated by the downregulation of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6, nitric oxide and prostaglandin E2 levels. Similarly, EP administration decreased oxidative stress (OS) via decreasing reactive oxygen species, malondialdehyde and oxidized glutathione levels, and increasing superoxide dismutase, catalase, glutathione reductase and reduced glutathione activity. Notably, EP induced a marked decrease in the expression levels of phospho‑extracellular signal‑regulated protein kinase (p‑ERK), phospho‑c‑Jun N‑terminal kinase (p‑JNK) and p‑p38 in vivo and in vitro. In addition, in LPS‑treated HBZY‑1 cells, EP enhanced cell viability and inhibited nuclear translocation of p‑ERK, p‑JNK and p‑p38. Overall, the present findings demonstrated that EP alleviated LPS‑induced AKI via the suppression of inflammation, OS and the mitogen‑activated protein kinase signaling pathway, providing insight into potential avenues for the treatment of AKI.
研究领域:
药理学
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免疫学
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肾病学
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高影响因子
ONCOLOGY REPORTS
·
2016
·Vol. 36
·期 1
·315-323
·
IF 2.486
Qiang Liu,Lei Dong,Hong Li,Jia Yuan,Yuping Peng,Shejiao Dai
Bone marrow (BM) suppression (also known as myelosuppression) is the most common and most severe side-effect of therarubicin (THP) and thereby limits the clinical application of this anticancer agent. Lentinan (LNT), a glucan extracted from dried shiitake mushrooms (Lentinula edodes), exhibits a variety of pharmacological activities. The objectives of the present study were to determine the effect of LNT on the myelosuppression of THP-treated mice and to examine the pharmacological mechanism of these effects. In vivo experiments indicated that non-cytotoxic levels of LNT strongly increased blood myeloperoxidase (MPO) activity; improved BM structural injuries; increased the numbers of leukocytes and neutrophils in the blood and BM; elevated the blood levels of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF); and reduced the self-healing period in THP-treated mice. In vitro experiments indicated that LNT increased the viability of BM-derived macrophages (BMDMs) in a time- and dose-dependent manner without toxic side-effects and markedly increased the release of G-CSF, GM-CSF and M-CSF by BMDMs. Further analyses revealed that LNT activated the NF-κB and MAPK signalling pathways and promoted the nuclear import of p65 and that BAY 11-7082 (a specific inhibitor of NF-κB) suppressed the release of G-CSF, GM-CSF and M-CSF. Furthermore, we found that U0126, SB203580 and SP600125 (specific inhibitors of ERK, p38 and JNK, respectively) markedly inhibited the IKK/IκB/NF-κB-dependent release of G-CSF, GM-CSF and M-CSF. In conclusion, LNT induces the production of G-CSF, GM-CSF and M-CSF by activating the MAPK/NF-κB signalling pathway in BM cells, thereby mitigating THP-induced myelosuppression.
研究领域:
肿瘤学
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药理学
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免疫学
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细胞生物学
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
·
IF 3.671
Jing-yi Zhang,Ying Guo,Jin-ping Si,Xiao-bo Sun,Gui-bo Sun,Jing-jing Liu
Dendrobium officinale is one valuable traditional Chinese medicine, which has skyscraping medicinal value. Polysaccharide is the main active ingredient in D. officinale ; its antioxidant activity is a hot research topic nowadays. Oxidative stress plays an important role in the pathological progress of a variety of cardiovascular disease, as one of key factors of cardiomyocyte apoptosis. This research adopts a model of H 2 O 2 induction-H9c2 cardiomyocytes apoptosis, aiming to study the effect of Dendrobium officinale Polysaccharide (DOP-GY) for cardiomyocyte apoptosis caused by oxidative stress and its possible mechanism. Our results showed that pretreatment of DOP-GY (low dose: 6.25 μg/mL, medium dose: 12.5 μg/mL, high dose: 25 μg/mL) followed by a 2 h incubation with 200 μM H 2 O 2 elevated the survival rate, cutted the LDH leakage, reduced lipid peroxidation damage, improved the activity of the endogenous antioxidant enzymes. In addition, the pretreatment of DOP-GY significantly inhibited the production of ROS, declined of the mitochondrial membrane potential, down-regulated pro-apoptosis protein and up-regulated anti-apoptosis protein. The protective effect was correlated with the PI3K/Akt and MAPK signal pathway. Collectively, these observations suggest that DOY-GY has the potential to exert cardioprotective effects against H 2 O 2 -induced H9c2 cardiomyocyte apoptosis.
研究领域:
药理学
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心脏病学
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分子生物学
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高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 4
·e71580
·
IF 4.3
Liujie Zheng,Yinhua Ni,Suyao Xie,Yitian Ji,Jiahong Dong,Lanjun Fu,Zhengwei Fu,Juan Jin,Qiang He
Acute kidney injury (AKI) is a serious complication of cisplatin chemotherapy, requiring new preventive therapies. Germacrone, a sesquiterpenoid derived from Rhizoma Curcuma , has multiple pharmacological effects, including anti-inflammatory, antiapoptotic, and antioxidant effects. The current study aimed to investigate the effect and mechanism of germacrone on AKI. Single high-dose and multiple low-dose cisplatin-induced AKI and AKI-chronic kidney disease (CKD) transition mouse models were used to determine the preventive effect of germacrone, with the mechanism explored in HK-2 and Raw264.7 cells. A breast cancer tumor-bearing model was developed to determine whether the nephron-protective effects of germacrone affect the anticancer properties of cisplatin. Here, we found that germacrone significantly alleviated AKI and fibrosis in cisplatin-treated mice, as demonstrated by decreased serum creatinine and blood urea nitrogen (BUN) levels and improved renal pathology. Germacrone attenuated cisplatin-induced apoptosis and inflammation in vivo and in vitro. RNA sequencing revealed that germacrone restored cisplatin-induced gene dysregulation and regulated inflammation and apoptosis through the PI3K/AKT and Ras/MAPK pathways. Inhibition of these pathways abrogated the renoprotective effect of germacrone in vitro. Moreover, germacrone reduced macrophage activation and induced an M2-dominant shift in macrophage polarization in the kidneys and Raw264.7 cells via similar pathways. Furthermore, germacrone protected the kidneys without affecting the chemotherapeutic effects of cisplatin on a mouse model of breast cancer. Therefore, germacrone is expected to have universal renoprotective effects across different AKI models and a tumor-bearing model through similar signaling pathways, suggesting its potential as a clinical adjuvant therapy for reducing nephrotoxicity in patients receiving cisplatin chemotherapy. Graphical Germacrone alleviates inflammation and apoptosis in cisplatin-injured kidneys by activating PI3K/AKT and suppressing Ras/MAPK signaling, thereby protecting against acute kidney injury (AKI) in mice. This renoprotection is reinforced by its ability to drive an M2-dominant macrophage shift both in vivo and in vitro, ultimately restoring tubular integrity and renal function.
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