INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Xiaohui Yang,Jie Li,Yilang Zhong,Yuanjiayi Shen,Chenqin Xu,Zhouyu Nie,He Wang,Rui Cao,Miaomiao Wang,Jinyu Zhang,Chao Ma,Tongkai Cai,Chenglin Jia,Ruilian Wang,Hao Yin,Jian Chen,Yongbing Cao
Background Candida auris ( C. auris ) is an emerging multidrug-resistant fungal pathogen. Current antifungals are often insufficient, creating a need for host-directed strategies. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that regulates redox homeostasis, but its role in antifungal macrophage defense is not well defined. We examined how SIRT3 shapes macrophage responses to C. auris . We also evaluated ethyl caffeate (EC) as a host-directed modulator. Methods We used murine macrophages with Sirt3 knockdown or overexpression. We quantified phagocytosis, intracellular fungal survival, mitochondrial ROS dynamics, and macrophage cell integrity using imaging, flow cytometry, CFU assays, and LDH release. We profiled infection-induced transcriptional programs by RNA-seq and performed pathway analyses. We tested EC both in vitro and in systemic infection models in Drosophila and mice. We assessed pathway markers by immunoblotting and immunofluorescence. We used the SIRT3 inhibitor 3-TYP to test inhibition sensitivity. Results SIRT3 deficiency impaired macrophage antifungal function and was accompanied by redox imbalance. mtROS regulation was disrupted in a biphasic pattern, with an early spike followed by late depletion. Transcriptomics linked SIRT3-dependent programs to FOXO and PI3K–AKT signaling. In macrophages, SIRT3 status tracked with FOXO3A acetylation and AKT phosphorylation. EC showed weak direct antifungal activity in vitro but improved outcomes in systemic infection models. EC treatment increased SIRT3 abundance and was associated with reduced FOXO3A acetylation and restrained infection-associated AKT activation. These functional and signaling effects were largely sensitive to SIRT3 inhibition by 3-TYP. Conclusion This study connects SIRT3-dependent redox control to FOXO3A–AKT signaling during C. auris infection. It also supports EC as a host-directed candidate that improves antifungal defense in vivo while limiting inflammatory injury.
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Frontiers in Immunology
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2026
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IF 7
Yadan Dong,Yuchen Ma,Qun Yu,Zhengmei Shi,Caiyi Wang,Yihao Che,Heng Liu,Desheng Wan,Weizai Shao,Huai Xiao
Introduction Colorectal cancer (CRC) represents one of the most common malignancies of the digestive tract, with colorectal cancer liver metastasis (CRLM) constituting a major cause of CRC-related mortality, for which therapeutic options remain limited. Methods This study examined the inhibitory role of inosine in CRLM and its molecular mechanisms using in vitro and in vivo approaches. CRC cell invasion was measured in transwell assays following direct inosine treatment or incubation with conditioned medium from inosine-exposed macrophage co-cultures. A CRLM mouse model generated by intrasplenic MC-38 injection was evaluated for hepatic metastasis. Histopathological examination of liver tissues was performed using HE staining to evaluate metastatic infiltration. Furthermore, flow cytometry and ELISA were utilized to analyze macrophage polarization markers and cytokine expression levels. Through transcriptomic sequencing and analysis, potential target genes and signaling pathways were predicted and subsequently validated by RT-qPCR. Results Inosine directly suppressed the invasive abilities of MC-38, CT-26, and HT-29 cells. This inhibitory effect on MC-38 cells was further enhanced under co-culture conditions with M1-polarized macrophages. In vivo , inosine reduced the formation of hepatic metastatic nodules, downregulated TNF-α and IL-1β, increased M1 macrophage proportions, and suppressed M2 polarization. Transcriptomics and RT-qPCR indicated that inosine upregulates CYP26A1 and CYP39A1, downregulates BCL-2, PTGS2, and OLFM1, and modulates PI3K/AKT signaling pathway. Inosine inhibits the activation of the PI3K/AKT signaling pathway. Discussion Inosine exerted an inhibitory effect on colorectal cancer liver metastasis by skewing macrophages toward an M1 phenotype, dampening pro-inflammatory cytokine release, and regulating key genes via the PI3K/AKT pathway.
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FASEB JOURNAL
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2026
·Vol. 40
·期 4
·e71580
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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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BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2026
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IF 2.9
Qing-Mei Wang,Xue-Ying Wang,Fei Lin,Wei-Qun Guan,Wei-Hui Chen
Objective This study aimed to examine the mechanisms by which Interleukin-27 (IL-27) contributes to the pathogenesis of oral squamous cell carcinoma (OSCC) through focal adhesion-induced stemness protein 1 (FSIP1)-mediated activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. Methods The effects of IL-27 on cellular proliferation, apoptosis, and migration were examined in human OSCC cell lines [squamous cell carcinoma cell line-27 (CAL-27) and squamous cell carcinoma-4 (SCC-4)] using Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays. Western blot (WB) analysis was performed to determine the expression of epithelial-mesenchymal transition (EMT) markers. High-throughput sequencing was used to identify differentially expressed genes and enriched pathways, while quantitative Polymerase Chain Reaction (qPCR) and WB validated the expression of FSIP1 and PI3K-Akt pathway-related proteins. An oral carcinogenesis mouse model was established using 4-nitroquinoline-1-oxide (4NQO). Following IL-27 treatment, histopathological alterations in tongue tissue were examined with Hematoxylin-Eosin (HE) staining, while IL-27, IL-27 receptor subunit alpha (IL-27RA), FSIP1, and PI3K-Akt pathway proteins were measured through immunohistochemistry and WB. In addition, FSIP1 overexpression vectors and interfering constructs were utilized to examine the regulatory role of FSIP1 in the presence of IL-27. Results Expression levels of IL-27 and IL-27RA were significantly elevated in OSCC. Treatment with IL-27 enhanced proliferation and migration, suppressed apoptosis, upregulated mesenchymal markers [Neural cadherin (N-cadherin), Vimentin], and downregulated the epithelial marker E-cadherin. Sequencing analysis identified FSIP1 as a key differentially expressed gene enriched in the PI3K-Akt pathway. IL-27 upregulated FSIP1 expression and elevated phosphorylation of PI3K and Akt (p-PI3K/PI3K, p-Akt/Akt). In the murine model, oral carcinogenesis was characterized by epithelial dysplasia, squamous epithelial thickening, and inflammatory cell infiltration. IL-27 treatment intensified these histopathological features and further upregulated protein expression. Overexpression of FSIP1 produced effects comparable to IL-27 treatment by enhancing malignant phenotypes and activating related pathways, while FSIP1 interference mitigated IL-27-induced cellular and molecular changes. Conclusion IL-27 promotes OSCC progression by upregulating FSIP1, leading to PI3K-Akt pathway activation, enhanced proliferation and migration, and reduced apoptosis. FSIP1 represents a central mediator of the oncogenic activity of IL-27 and may serve as a potential therapeutic target in OSCC.
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Animal Models and Experimental Medicine
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2026
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IF 3.3
Yijia Wang,Xing Feng,Shuhui Zhao,Yuchong Fu,Ao Zhang,Xiaofeng Shen,Bowen Yu,Yihao Wang,Jiahui Lin,Bing Zhang,Weiping Ji,Lianpin Wu,Xiaoling Guo
Background Oxidative stress plays a pivotal role in the pathogenesis of heart failure and is closely linked to myocardial remodeling, which includes myocardial hypertrophy and fibrosis. Chrysin (CHR) has multiple medicinal effects such as antioxidant, anti-inflammatory, and anti-apoptosis. This research seeks to investigate whether CHR can protect against pressure overload–induced myocardial remodeling and to explore the underlying mechanism. Methods Transverse aortic constriction (TAC) surgery was conducted to establish a model of cardiac hypertrophy on male C57BL/6J mice. A model of cardiomyocyte hypertrophy in H9C2 cells induced by angiotensin II (Ang II) was also established. Results The results showed that CHR significantly improved survival and cardiac function, reduced myocardial hypertrophy and fibrosis, inhibited the expression of inflammatory mediators TNF-α and IL-1β, suppressed cell apoptosis rate, downregulated the levels of Bcl-2 Associated X protein (BAX) and Cleaved-Caspase-3, and upregulated B-cell lymphoma/leukemia 2 (BCL-2) expression in TAC surgical mice or Ang II-treated H9C2 cells. CHR could also upregulate the levels of antioxidant enzymes SOD1 and HO-1 by mediating the nuclear translocation and expression of NRF2 to counteract oxidative stress response. The further mechanism investigation utilizing bioinformatics analysis and western blot revealed that the disease of heart failure is associated with the phosphatidylinositol‑3‑kinase (PI3K)/serine/threonine-protein kinase B (AKT) signaling pathway. Conclusions Collectively, our findings demonstrated that CHR might exert the improvement effects on pressure overload–induced myocardial remodeling with hypertrophy and fibrosis through regulating the PI3K/AKT/NRF2 pathway–mediated oxidative stress response to alleviate myocardial cell inflammation and apoptosis, suggesting that CHR may be a promising therapeutic agent for cardiac diseases induced by pressure overload.
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APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
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2026
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IF 3.5
Awang Danzeng,La Zong,Baima Kangzhuo,Xie Hongjun,Wang Li,Liu Xinyao,Wang Yueying,Shi Yan,Zhao Yicheng,Gongga Lanzi
Hypoxia-related myocardial injury is characterized by oxidative stress, mitochondrial dysfunction, and apoptosis, ultimately resulting in impaired cardiac structure and function. Salidroside (SAL), a major bioactive component of Rhodiola, has been shown to have antioxidant and cardioprotective effects, but its role in hypoxia-related myocardial injury remains incompletely understood. In this study, we combined network pharmacology, molecular docking, and experimental validation to investigate the protective effect of SAL in CoCl 2 -induced hypoxia-mimetic models. In vitro, SAL improved cell viability, reduced ROS accumulation, restored mitochondrial membrane potential and ATP production, and attenuated apoptosis in CoCl 2 -treated H9C2 cells. In vivo, SAL alleviated electrocardiographic abnormalities, myocardial histopathological injury, cardiomyocyte hypertrophy, and associated lung and liver damage in CoCl 2 -treated rats. Mechanistically, SAL modulated the Akt/GSK-3β signaling axis under CoCl 2 -induced stress. Notably, Akt inhibition experiments revealed that SAL promotes protective GSK-3β phosphorylation and exerts its anti-apoptotic effects through a largely Akt-independent mechanism. Collectively, these findings indicate that SAL alleviates hypoxia-induced myocardial injury through the attenuation of oxidative stress, the preservation of mitochondrial function, the suppression of apoptosis, and the robust, Akt-independent regulation of GSK-3β. Graphical The alternative text for this image may have been generated using AI.
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MOLECULAR IMMUNOLOGY
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2026
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IF 3.7
Na Mi,Lili Ma,Jing Zhao,Xinxin Bu,Jing Xu,Jia Fu,Chao Zhang,Yali Zhang,Lifen Yao
Discovery of the "Gut Microbiota-BCAA" metabolic dysregulation in PD. • BCAA supplementation promotes propionate production via microbiota remodeling. • Propionate alleviates neurodegeneration via anti-inflammatory and anti-apoptotic mechanisms. • Identification of the PI3K/Akt/mTORC1 axis as the mediator of propionate’s protection. Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and systemic inflammation, with increasing evidence implicating the gut–brain axis in its pathogenesis. Altered gut microbiota composition and reduced levels of neuroprotective microbial metabolites, such as short-chain fatty acids (SCFAs), have been reported in patients with PD. Branched-chain amino acids (BCAAs), essential nutrients influenced by microbial metabolism, may contribute to neuroimmune regulation through SCFA production, particularly propionate, and modulation of PI3K/Akt/mTORC1 signaling. In this study, we investigated whether dietary BCAA supplementation influences neurodegenerative processes in PD through gut microbiota remodeling and microbial propionate production, and examined the potential involvement of the PI3K/Akt/mTORC1 signaling pathway. We combined human clinical observations with mechanistic studies in MPTP-induced PD mouse models and MPP⁺-treated SH-SY5Y neuronal cells. Gut microbiota composition was profiled using 16S rRNA sequencing, and fecal and serum metabolites were analyzed by GC–MS. Neurobehavioral performance, dopaminergic neuron integrity, apoptosis-related markers, and PI3K/Akt/mTORC1 pathway activation were evaluated using immunohistochemistry, Western blotting, and cellular assays with or without pharmacological inhibition. PD patients exhibited gut dysbiosis, reduced BCAA levels, and depletion of SCFA-producing taxa. In mice, BCAA supplementation partially restored microbial composition and enhanced predicted propionate biosynthesis pathways. Propionate administration improved motor performance, preserved dopaminergic neurons, mitigated neuroinflammatory responses, and reduced apoptosis in vivo and in vitro. Mechanistically, propionate restored PI3K, Akt, and mTORC1 phosphorylation, upregulated Bcl-2, and suppressed cleaved caspase-3, effects that were abolished by PI3K inhibition. Collectively, these findings identify a gut microbiota–BCAA–propionate axis that may influence neurodegenerative processes through modulation of PI3K/Akt/mTORC1 signaling, highlighting microbial metabolites as potential modulators of gut–brain communication in PD.
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Pharmaceutics
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2026
·Vol. 18
·期 7
·869
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IF 6.9
Jiangtao Zhou,Yuhui Ge,Ran Li,Zhuoyang Cheng,Jianping Gao,Bin Zheng
Background: Skin photoaging, primarily induced by chronic ultraviolet (UV) radiation exposure, is characterized by dryness, wrinkle formation, pigmentation abnormalities, and reduced skin elasticity, resulting from oxidative stress, inflammation, and degradation of the extracellular matrix. Codonopsis pilosula , a traditional food–medicine homologous plant, is recognized for its anti-aging properties. However, its lipophilic components (designated as CP-L) remain insufficiently explored. Methods: Herein, we developed a thermosensitive nanogel encapsulating CP-L-loaded transferosomes (CP-L nanogel) to enhance topical delivery and evaluated its effects in both a UV-induced photoaging mouse model and UVB-irradiated HaCaT keratinocytes. Results: In UV-induced mice, topical application of the nanogel markedly reduced skin wrinkling and epidermal hyperplasia, with epidermal thickness decreased by 83.2% compared to the model group ( p < 0.01), and restored skin elasticity and collagen deposition, as evidenced by a 35.5% increase in collagen area fraction ( p < 0.01). Correspondingly, in UVB-irradiated HaCaT cells, it significantly increased cell viability from 53.0 ± 9.6% to 89.4 ± 1.0% ( p < 0.01) and suppressed apoptosis from 30.1 ± 0.48% to 12.4 ± 0.66% ( p < 0.01). Furthermore, the CP-L nanogel consistently attenuated oxidative stress, with SOD, CAT, and GSH-Px activities increased by 73.1%, 188.1%, and 18.2%, respectively ( p < 0.01), and MDA levels reduced by 71.0% ( p < 0.01), while inflammatory responses were suppressed, as TNF-α, IL-1α, IL-1β, and IL-6 levels decreased by 28.3%, 22.6%, 12.8% and 31.9%, respectively ( p < 0.01). Mechanistically, transcriptomic and molecular analyses revealed that the nanogel potently inhibited the UV-induced activation of the FGFR/PI3K/AKT/mTOR/p70S6K signaling cascade at both transcriptional and protein levels, with the phosphorylation levels of FGFR, PI3K, AKT, mTOR, and p70S6K significantly reduced by 43.9%, 30.9%, 38.8%, 34.9%, and 57.3%, respectively ( p < 0.01). Molecular docking and dynamics simulations identified isofuranodienone and aromadendrene oxide-(2) as key constituents with high-affinity, stable binding to FGFR1 and AKT1. The cytoprotective effect of the nanogel was completely abolished by co-treatment with the FGFR inhibitor PD173074 , confirming functional reliance on this pathway. Enhanced cellular delivery of the formulation was directly demonstrated by flow cytometry, showing an approximately 1.8-fold increase in cellular uptake compared to the free drug ( p < 0.01). Conclusions: Collectively, these results demonstrated that the CP-L nanogel alleviated skin photoaging through a multi-faceted mechanism involving enhanced cellular delivery, potent antioxidant and anti-inflammatory activities, and specific inhibition of the FGFR/PI3K/AKT/mTOR signaling cascade, highlighting its potential as a multitargeted topical agent derived from an edible plant.
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Biomaterials Research
·
2025
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IF 9.6
Jian Wu,Minghui Liu,Meng Gao,Yongchao Li,Youjie Zhang,Liang Tang,Hao Yu,Zhangcheng Liao,Yu Cui,Feng Zeng,Hequn Chen,Zewu Zhu
Although tea consumption has been suggested to affect kidney stone formation, epidemiological evidence remains inconsistent, and the underlying molecular mechanisms are unclear. To assess the association between tea intake and kidney stone risk, we initially conducted a prospective cohort analysis of 481,393 participants from the UK Biobank and a 2-sample Mendelian randomization (MR) analysis. Our findings revealed that heavy tea drinkers (>5 cups/day) had a significantly reduced risk of kidney stones (hazard ratio: 0.79, 95% confidence interval [CI]: 0.72 to 0.86, P < 0.001), and MR analyses confirmed a causal association (inverse variance weighted OR: 0.45, 95% CI: 0.32 to 0.62, P < 0.001). We next explored the effect of epigallocatechin gallate (EGCG), the main bioactive component in tea, on calcium oxalate (CaOx) stone formation. EGCG was found to inhibit the glucose-regulated protein 94/phosphatidylinositol 3-kinase/protein kinase B (GRP94/PI3K/AKT) pathway in human proximal renal tubular epithelial cells, thereby attenuating CaOx crystal-induced oxidative stress and inflammation, and inhibiting crystal-cell adhesion. This finding aligned with the observation that the activated GRP94/PI3K/AKT pathway was positively associated with inflammation-related molecules in renal papillary tissues of CaOx stone formers. Moreover, to enhance renal targeting and therapeutic potential, we synthesized cell membrane-coated EGCG-loaded poly(lactic-co-glycolic acid) (TP-EGCG) nanoparticles, which enhanced renal EGCG delivery and substantially reduced CaOx crystal deposition in a mouse model of CaOx nephrolithiasis. In conclusion, tea consumption protects against kidney stone formation, an effect exerted by EGCG through the GRP94/PI3K/AKT axis, and our novel TP-EGCG nanoparticles show strong potential for targeted prevention and treatment.
研究领域:
肾脏病学
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分子生物学
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药理学
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营养流行病学
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纳米医学
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信号转导
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ACS Omega
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2026
·
IF 4.3
Xianghuai Zheng,Yue Zou,Qinkai Xie,Hao Dong,Jiating Lin,Xianxian Zhuang,Ruoting Xian,Shaobing Li
Oral squamous cell carcinoma (OSCC) presents significant therapeutic challenges due to chemoresistance and limited treatment modalities. Black phosphorus nanosheets (BPNSs), a novel two-dimensional nanomaterial, have shown promising antitumor effects. However, their role in inducing ferroptosis in OSCC and the underlying mechanisms remain to be elucidated. In this study, BPNSs were prepared via liquid-phase exfoliation, and their effects on the OSCC CAL-27 cells were subsequently evaluated. In vitro, BPNSs dose-dependently inhibited CAL-27 cell proliferation, induced G2/M phase arrest, and triggered ferroptosis, indicated by increased intracellular Fe2+, ROS, and lipid peroxidation, along with decreased glutathione (GSH) levels and altered expression of ferroptosis-related proteins (ACSL4, NCOA4, and GPX4). These effects were attenuated by ferroptosis inhibitor ferrostatin-1. In vivo, BPNSs suppressed CAL-27 xenograft growth without systemic toxicity, with elevated tumor malondialdehyde (MDA) and Fe2+ confirming ferroptosis. Mechanistic studies indicated that BPNSs inhibited the PI3K-AKT pathway, leading to the downregulation of SREBP1. Overexpression of SREBP1 attenuated BPNS-induced ferroptosis, confirming its critical role. These findings suggest that BPNSs induce ferroptosis in OSCC via the PI3K-AKT-SREBP1 signaling pathway, providing a novel therapeutic strategy for OSCC treatment.
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JOURNAL OF MOLECULAR HISTOLOGY
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2026
·Vol. 57
·期 1
·30
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IF 2.2
Xiang Shouyu,Liu Wei,Tang Cheng,Xie Chuhai,Hu Hailan,Zhou Jianhui,Cao Yanming,Ling Long
Bone marrow mesenchymal stem cells (BMSCs) play a significant role in bone defect repair. Currently, the limited survival and function of transplanted BMSCs pose major obstacles to tissue repair mediated by these cells. Therefore, the exploration of BMSCs transplantation activity has become an urgent clinical problem. In this experiment, we constructed lentiviral vectors with overexpression and silencing of miR-19b-3p and utilized a rat fracture model. The effects of BMSCs proliferation were examined using CCK-8, the Annexin V-FITC apoptosis kit and TUNEL assay, the effects of BMSCs osteogenic differentiation were detected using ALP and Alizarin red staining. Furthermore, Western blotting and qRT-PCR were employed to examine the expression of key proteins in the PTEN/Akt/mTOR signaling pathway and autophagy-related proteins. Moreover, the impact of miR-19b-3p on bone microstructure was assessed using Micro CT, HE, Safranin O/Fast Green, as well as Masson staining, and Immunohistochemistry analysis examined PTEN, p62 and Runx2 expression levels on fracture site. By constructing lentiviral vectors with overexpression and silencing of miR-19b-3p, we found that silencing miR-19b-3p significantly promoted the proliferation as well as the osteogenic differentiation of BMSCs under hypoxia. Western blotting and qRT-PCR results showed that silencing miR-19b-3p significantly increased PTEN, LC3, and Beclin1 expression while decreasing p-Akt, p-mTOR, and p62 expression. Furthermore, by constructing the fracture rats and administering hypoxia-treated BMSCs transfected with miR-19b-3p via tail vein injection, we found that silencing miR-19b-3p obviously increased the formation of trabecular and promoted the healing of the fractures. Immunohistochemistry analysis showed that silencing miR-19b-3p upregulated PTEN and Runx2 expression levels and suppressed p62 expression with statistical significance. In summary, these findings suggest that miR-19b-3p may regulate BMSCs’ autophagy and osteogenic differentiation under hypoxia via the PTEN/Akt/mTOR signaling pathway, thereby promoting fracture healing and providing a potential target for the treatment of fractures.
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Molecular Pain
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2025
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IF 2.8
Yu-Na Cheng,Ming-Zhu Zhang,Cui-Qing Xie,Zhi-Qi Li,You-Feng Ge,Zhao-Hui Jin,Zhi-Hua Luo,Chen-Yang Zheng,Liang Chen,dong fang,Chen-Guang Niu,Jin-Jin He
Bone cancer pain (BCP), one of the most intractable symptoms in patients with cancer, remains poorly understood and lacks effective therapeutic interventions. In this study, we employed an established rat model of BCP induced by intratibial injection of MRMT-1 mammary carcinoma cells. Transcriptomic profiling of the L4-L6 dorsal root ganglia (DRGs) revealed an upregulation of the amino acid transporter SLC38A3. This finding was further confirmed by time-dependent increases in both its mRNA and protein levels. Immunofluorescence co-localization indicated that SLC38A3 was expressed in NF200-, CGRP-, and IB4-positive neurons within the L4-L6 DRGs, and its expression was upregulated in the BCP model. Concomitantly, the transient receptor potential vanilloid 1 (TRPV1) expression in BCP rat DRGs was dynamically upregulated at both the mRNA and protein levels, aligning temporally with pain hypersensitivity. Lentivirus-mediated overexpression or knockdown of SLC38A3 in the DRGs led to a corresponding upregulation or downregulation of TRPV1-expression. Activation of the PI3K/AKT signaling pathway corresponds with BCP-related pain behaviors and expression patterns of SLC38A3 and TRPV1. Bexarotene alleviates BCP in rats by suppressing the aberrant overexpression of SLC38A3, thereby blocking the PI3K/AKT signaling pathway-mediated upregulation of TRPV1. These findings indicate that SLC38A3, through its downstream PI3K/AKT-TRPV1 axis, may serve as a potential molecular mechanism for analgesia in BCP.
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