INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Zhidan Shi,Xinyi Cheng,Chu Zhang,Jiayi Hu,Xinqi He,Shuting Chen,Hao Wu,Meng Tian,Chuang Yan,Ling He
Alzheimer's disease (AD) is a neurodegenerative disorder with significant sex-related differences, exhibiting a higher incidence rate in elderly women. Tau pathology has been implicated in sex-associated differences in AD susceptibility and disease progression, contributing to differential pathological burden between males and females. Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi) used in cancer treatment, has shown potential therapeutic effects in various neurological and psychiatric disorders; however, the mechanisms underlying its regulation of tau-associated pathology remain poorly understood, with limited evidence regarding its effects in tau-related neurodegenerative conditions. In this study, we investigated the effects of SAHA treatment on an AAV-P301L-Tau-induced tauopathy model. In vivo, we observed that SAHA administration significantly improved p-Tau levels in the hippocampus and cortex of mice, reduced microglial activation and neuronal damage, and alleviated tauopathy-associated cognitive impairments. Our findings revealed sex-associated differences in Tau-related pathological alterations, with female mice exhibiting greater pathological changes and differential responses to SAHA treatment in several molecular and histological indicators. Further combined in vivo and in vitro experiments revealed that SAHA was associated with modulation of the PI3K/AKT/GSK3β signaling pathway, suppression of NF-κB activation, and attenuation of neuroinflammatory responses, including reductions in experimentally measured inflammatory markers such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α). These molecular alterations may represent important regulatory components contributing to the neuroprotective effects of SAHA, rather than acting as the sole determinants of its therapeutic efficacy. In summary, these results indicate that SAHA can improve Tau-associated pathological alterations in an AAV-P301L-Tau-induced tauopathy model. The potential mechanisms may involve coordinated regulation of multiple pathological processes, including modulation of Tau phosphorylation, neuroinflammatory responses, and aging-associated signaling pathways. The observed sex-dependent responses to SAHA provide additional insights into the potential influence of biological sex on HDACi-based therapeutic strategies, although the molecular mechanisms underlying these differences require further investigation.
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高影响因子
NEUROPHARMACOLOGY
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2020
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IF 4.431
Aijing Bi,Wenji An,Chunmei Wang,Yao Hua,Fang Fang,Xiaoliang Dong,Rong Chen,Zhengping Zhang,Lan Luo
Except for few symptoms-improved drugs for Alzheimer's disease (AD), no disease-modified drug has been developed, especially for AD in type 2 diabetes mellitus (T2DM). SCR-1693, a disease-mortified candidate for AD, which is now in Phase I clinical study in China, improves Aβ 25 – 35 -impaired cognitive function in rodent's models. Here we report the effect of SCR-1693 on regulation of tau phosphorylation and insulin resistance associated cognition, and illustrate its underlying mechanism. We found that in intracerebroventricular injection of streptozotcin (STZ) rats, oral administration of SCR-1693 dose-dependently improved the learning and memory in Morris water maze test, decreased tau hyperphosphorylation , astrogliosis and postsynaptic protein loss in hippocampus . In Neura-2a cells with stable transfection of full-length human tau (Neura-2a-tau), treatment of SCR-1693 concentration-dependently enhanced the activation of protein phosphatase (PP1) and protein phosphatase 2A (PP2A), decreased cellular tau phosphorylation, and increased insulin-induced cellular signaling to reverse insulin resistance. Pre-treatment with the inhibitor of PP1 and PP2A inhibited the effect of SCR-1693 on both of tau phosphorylation and insulin signaling in Neura-2a-tau cells. All data suggest that an increase of activity of tau phosphatase was involved in the mechanism of SCR-1693 on the regulation of tau phosphorylation and insulin signaling, and SCR-1693 is considerable candidate for insulin resistance associated sporadic AD.
研究领域:
神经科学
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药理学
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糖尿病
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阿尔茨海默病
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PubMed
高影响因子
Translational Andrology and Urology
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2022
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IF 2.479
Shujun Sun,Kehua Jiang,Jin Zeng
Background To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer. Methods We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related genes and the relationship between their expression and bladder cancer survival and prognostic indicators. Results The 5637 cell line showed the most significant sensitivity to chemoradiotherapy. The expression levels of DNA damage repair genes in 5637 cells did not significantly change after chemoradiotherapy. In contrast, the expression levels of BRCA1 and RBBP8 genes significantly increased in J82 and TCCSUP cells after chemoradiotherapy. After combination with olaparib, which is a poly (ADP-ribose) polymerase inhibitor that initiates DNA repair, 5637 cells were significantly inhibited by chemoradiotherapy. However, chemoradiotherapy inhibition on J82 cells was weakened when combined with olaparib. A high reactive expression of BRCA1 and RBBP8 after combination with olaparib suggested that olaparib was ineffective because it did not induce synthetic lethality in which inhibiting PARP by olaparib coincided with suppression of BRCA1/2 expression result in cancer cell death. Conclusions The expression levels of RBBP8 and BRCA1 genes were associated with sensitivity to radiotherapy and chemotherapy in bladder cancer, and an increase in reactive expression after treatment led to worse sensitivity. Therefore, the reactive expression levels of BRCA1 and RBBP8 after chemoradiotherapy may be useful in evaluating the efficacy of olaparib combination therapy.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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高影响因子
Translational Andrology and Urology
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2024
·Vol. 13
·期 9
·2055
·
IF 1.9
Shoubin Li,Chunhong Yu,Helong Xiao,Qingle Xu,Bo Gao,Liuxiong Guo,Zhanxin Sun,Junjiang Liu
Background Benign prostatic hyperplasia (BPH) is a common disease among older men characterized by non-malignant proliferation of epithelial cells and inflammation. Nitric oxide synthase traffic inducer (NOSTRIN) is a pleiotropic regulator of endothelial cell function and signaling and exerts anti-inflammatory, anti-proliferation, and modulating nuclear factor-kappa B (NF-κB) signaling effects. Its expression and function in BPH tissues and prostate epithelial cells are unknown. The study aims to investigate the expression and functions of NOSTRIN in BPH, and its possible molecular mechanism. Methods The BPH model was constructed in male Institute of Cancer Research (ICR) mice using 5 mg/kg/day testosterone propionate (TP) for 30 days, and the model was evaluated by detecting prostate index, prostate epithelial thickness, and prostate-specific antigen (PSA) expression. Dihydrotestosterone (DHT, 10 nM)-induced in vitro model of human prostate epithelial cells (RWPE-1) was established. We generated lentivirus-harboring human NOSTRIN . The mRNA expression was detected by real-time quantitative polymerase chain reaction (PCR) assay; the protein expression or localization was detected by western blot assay, immunohistochemistry, or immunofluorescence staining. Cell proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) staining. Reactive oxygen species (ROS) production was observed by dihydroethidium staining. Nitric oxide (NO) and malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were detected using commercial kits. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of interleukin 1 beta (IL1B), interleukin 6 (IL6), interferon gamma (IFNG), and tumor necrosis factor (TNF). Results NOSTRIN expression was significantly inhibited in the TP-induced ICR mouse BPH model and DHT-induced model of RWPE-1 proliferation. Protein expression of the BPH-related and proliferation markers PSA and proliferating cell nuclear antigen (PCNA) was suppressed in NOSTRIN-overexpressing RWPE-1 cells exposed to DHT. NOSTRIN overexpression notably inhibited the RWPE-1 cell proliferation in vitro , as evidenced by MTT and EdU staining. NOSTRIN overexpression significantly decreased the expression of cell cycle-related proteins cyclin dependent kinase 4 (CDK4) and cyclin D1 (CCND1) in vitro . The production of ROS, NO, and lipid peroxidation products MDA was inhibited by NOSTRIN overexpression in vitro , while the SOD activity was increased. NOSTRIN overexpression reduced the mRNA expression of inflammatory mediator nitric oxide synthase 2 (NOS2) and inhibited the mRNA expression and secretion of pro-inflammatory cytokines IL1B, IL6, IFNG, and TNF in vitro . The mechanistic studies revealed an increased phosphorylation of NF-κB p65 in vivo and in vitro . Remarkably, NOSTRIN overexpression notably inhibited the protein expression of phospho-NF-κB p65 in vitro . Conclusions NOSTRIN is involved in BPH by inhibiting proliferation, oxidative stress, and inflammation in prostate epithelial cells. These functions may act through the inhibition of NF-κB signaling.
研究领域:
泌尿学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Translational Andrology and Urology
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2024
·Vol. 13
·期 9
·1971
·
IF 1.9
Jiahao Jiang,Fei Xiao,Lanxin Yang,Yan Zeng,Jing Chen,Hengcheng Zhu,Lingqi Liu
Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain and various discomforts. Astaxanthin (AST) has multiple functions, including anti-inflammatory property, but it is unclear whether AST plays a key role in CP/CPPS and how it works. This study aimed to investigate the protective effect of AST on CP/CPPS in rats and the underlying mechanism. Methods A CP/CPPS rat model was induced by intraprostatic injection of carrageenan and the blood specimens and prostates were harvested for further research after oral administration of AST for 4 weeks. Results Tactile allodynia test showed that AST ameliorated chronic pelvic pain in a dose-depended manner. In addition, histological evaluation indicated that AST alleviated CP/CPPS rat prostate histological inflammation. Meanwhile, AST suppressed the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Besides, AST inhibited the activities of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). Furthermore, AST decreased the activation of the nuclear factor-κB (NF-κB) signaling pathway. Conclusions Our study has shown that AST exerts an anti-inflammatory and protective effect against CP/CPPS and the function is mediated at least through the suppression of NF-κB signaling pathway. These results provide evidence of AST as the potential agents for the treatment of CP/CPPS.
研究领域:
泌尿科
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药理学
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炎症研究
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PubMed
高影响因子
Translational Andrology and Urology
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2026
·Vol. 15
·期 3
·73
·
IF 1.9
Jiahao Jiang,Huajie Song,Jing Chen,Yan Zeng,Hengcheng Zhu,Mao Ding,Lingqi Liu
Background Chronic nonbacterial prostatitis (CNP) is the most common type of symptomatic prostatitis that afflicts men due to various discomforts. Owing to its anti-inflammatory and antioxidant properties, astaxanthin (AST) can be used in the treatment of various chronic inflammatory diseases. This study was conducted to assess the effects of AST and investigate the underlying mechanisms in a rat model of CNP. Methods A rat model of CNP was established by intraprostatic carrageenan (0.1 mL 1% λ-carrageenan saline solution) injection. AST (40 and 80 mg/kg/day) was administered orally for 4 weeks, and blood and prostate tissue samples were collected for examination. Results The prostate weight and index were lower in AST-treated rats than in rats with CNP. In prostate tissue and serum, AST increased superoxide dismutase and glutathione peroxidase activity. Meanwhile, AST reduced inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1β, and IL-6] expression in prostate tissue and serum. Besides, AST also reduced nerve growth factor expression in prostate tissue. Furthermore, AST inhibited mitogen-activated protein kinase (MAPK) pathway activation. Conclusions This study showed that AST exerts antioxidant and protective effects against CNP, mediated through MAPK signaling suppression. The study results provide evidence supporting the potential use of AST in the treatment of CNP.
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高影响因子
Translational Andrology and Urology
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2026
·Vol. 15
·期 2
·41
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IF 1.9
Li Xiaoxin,Sun Yang,Zhang Xinghao,Zhang Ziheng,Han Ziyang,Chen Yun
Background Erectile dysfunction (ED), which frequently occurs in individuals with hyperlipidemia, seriously affects quality of life. Lumbrokinase exhibits multiple pharmacological effects. There is currently a lack of evidence to support the use of lumbrokinase in treating ED. We investigated the effect and mechanism of lumbrokinase in a rat model of hyperlipidemia-induced erectile function (HLED). Methods There were 28 male Sprague-Dawley rats included. Eight rats received a standard diet as controls; 20 rats were fed a high-cholesterol diet to induce hyperlipidemia. After 8 weeks, the apomorphine test (APO) was used to confirm HLED. Fourteen rats were then allocated into two subgroups: one received lumbrokinase by oral gavage for 4 weeks, and the other received saline as the control group. Erectile function was assessed by intracavernous pressure (ICP) and mean arterial pressure (MAP) measurements. Histopathological and apoptotic changes in the corpus cavernosum were examined, and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway-related protein and gene expression were analyzed using Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR). Results ICP/MAP were significantly higher in the treatment group than in the model group. Abnormal lipid levels, imbalance between NO and ET-1 and multi-organ lesions observed in the model group were improved in the treatment group. Moreover, the model group showed a higher rate of apoptotic cells, which was also inhibited by the lumbrokinase treatment. Furthermore, lumbrokinase significantly upregulated the expression of Bcl-2, PI3K and Akt and downregulated the expression of cleaved Caspase-3. Conclusions Lumbrokinase improved erectile function in rats with HLED, likely by inhibiting apoptosis. These findings provide evidence of a potential treatment option for HLED.
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PubMed
高影响因子
Translational Andrology and Urology
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2023
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IF 2
Tianqin Deng,Xuemei Li,Bing Yao
Background In the pathological study of necrozoospermia—a form of sperm mortality—the underlying metabolic mechanism remains unclear. Thus, the aim of this study was to characterize metabolic alterations in the seminal plasma of necrozoospermic patients and to provide insights into the etiology of the disease. Methods Seminal plasma samples were collected from patients diagnosed with necrozoospermia (n=28) as well as normozoospermia (n=37). The samples were analyzed using nontargeted metabolomics based on liquid chromatography-mass spectrometry (LC-MS). The raw data were subjected to multivariate analysis to identify metabolites correlated with necrozoospermia. Differential metabolites were subjected to pathway analysis using MetaboAnalyst. Results The results of the metabolomic analysis showed that there were 194 differential metabolites between the two groups; 129 metabolites were upregulated and 65 metabolites were downregulated. Among the differential metabolites, the top ten differential metabolites were choline, benzaldehyde, pyrazinamide, 5-aminoimidazole-4-carboxamide, and dihydrothymine. The following differential metabolite pathways were identified, and the top five metabolite pathways were arachidonic acid metabolism, steroid hormone biosynthesis, alanine aspartate and glutamate metabolism, bile secretion, and prostate cancer. Conclusions The elevation of choline and 2-hydroxyglutarate levels in seminal plasma was an important finding, and the results also indicate that abnormalities in arachidonic acid metabolism and glutamate metabolism were an underlying pathological mechanism of necrozoospermia.
研究领域:
生殖医学
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代谢组学
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高影响因子
Natural Products Journal
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2025
·Vol. 16
·期 4
·E22103155343062
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IF 1.2
Dipender Kumari,Manjusha Choudhary,Prabhjeet Kaur Bamrah,Aditya Malan,Nitesh
Tau protein is found in abundance in brain. It is responsible for structural stabilization of neurons. It is a substrate of numerous protein kinases like glycogen synthase kinase-3 (GSK-3β), cyclin dependent protein kinase-5 (CDK5), and protein kinase A (PKA), which impel the deformation of its structure. In Alzheimer’s disease (AD), tau hyperphosphorylation entails the way to build-up neurofibrillary tangles (NFTs) inside the neurons. Lamentably, there are no such treatments that can reverse or halter the course of AD. The drugs approved by FDA, donepezil, galantamine, rivastigmine (cholinesterase inhibitors) and memantine (N-methyl D-aspartate receptors antagonists), provide only symptomatic relief from AD. An extensive literature survey from several databases like PubChem, Science Direct, and Web of Science was performed and it was concluded that naturally derived phytoconstituents can be a reliable alternative for AD treatment. The diverse spectrum of activity of the naturally occurring flavonoids may make them especially useful for preventing tau hyperphosphorylation by inhibiting the activity of various protein kinases like glycogen synthase kinase-3, cyclin-dependent protein kinase-5, and mitogen-activated protein kinases. The present review aims to identify the mechanisms of action and highlight the therapeutic benefits of different flavonoids in AD intervention.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Guoxing Chen,Keying Chen,Peitong Chen,Ru Yan,Jiali Qian,Yahui Liu,Yu Zhang,Huiming Wu,Guonian Zhu,Zhanyi Xu,Mengli Chen
Bactrocera tau(Walker) (Diptera: Tephritidae), a highly invasive horticultural pest, threatens more than 80 crop species. The environmentally friendly strategy based on behavioral response of flies to host plant volatiles is a promising alternative to chemical insecticides. Here, we found BtauOR74a, one antennae highly expressed odorant receptor of B. tau, was responsible for detecting six host volatiles in a dose-dependent manner. Among these, (E)-2-octen-1-ol or (Z)-6-nonen-1-ol exhibited significant attraction to female or male, respectively. Furthermore, the preference of female B. tau for (E)-2-octen-1-ol and that of male B. tau for (Z)-6-nonen-1-ol were significantly decreased after silencing of BtauOR74a by RNAi. Additionally, a significant reduction was observed in the EAG responses of B. tau to these host volatiles in both male and female. These results not only provide the molecular basis of the olfactory recognition mechanism of B. tau to host volatiles, but also offer the potential for development of eco-friendly management strategies.
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高影响因子
MOLECULAR PSYCHIATRY
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2026
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IF 10.4
Liao Kang,Xie Meng,Ibáñez Carlos F.
Therapeutic development in Alzheimer’s Disease (AD) has for the most part been focused on reducing β-amyloid load. Nevertheless, neurofibrillary tangles (NFTs), produced by aggregation of hyper-phosphorylated Tau protein, correlate with neurodegeneration and cognitive impairment significantly better than amyloid accumulation in AD patients. Here we report that P301S mice, a model of Tau-mediated neurodegeneration, carrying mutant variants of the p75 neurotrophin receptor (p75 NTR ) deficient in RhoA/ROCK signaling are protected from neurodegeneration and cognitive impairment. Both p75 ∆DD , lacking the death domain, and triple mutant p75 KKEA , unable to interact with RhoGDI, decreased insoluble Tau species, reduced gliosis, neurodegeneration and synapse loss, and improved spatial learning and memory in P301S mice. Intriguingly, p75 C259A , a variant unresponsive to neurotrophins but still competent for RhoA signaling induced by myelin-derived ligands, did not afford any neuroprotection. P301S neurons expressing p75 ∆DD or p75 KKEA , but not p75 C259A , showed reduced phospho-Tau and ROCK and GSK3β activity, the two main kinases responsible for Tau phosphorylation. In line with this, treatment with myelin-associated glycoprotein (MAG) enhanced Tau phosphorylation and ROCK activity in P301S neurons expressing wild type p75 NTR or p75 C259A , but not p75 ∆DD or p75 KKEA . Together, these results indicate that p75 NTR contributes to AD Tauopathy by enhancing the activity of the RhoA-ROCK pathway.
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高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·137
·
IF 7.4
Deng Lan,Yin Can,Zhou Xiaogang,Feng Chi,Wu Jianming,An Xiaobing,Mi Jianing,Huang Lufen,Qin Dalian,Yu Lu,Chen Ting,Wu Anguo
Background Alzheimer’s disease (AD) is characterized by Tau aggregation, mitochondrial dysfunction, and oxidative stress, yet effective interventions targeting these pathological cascades remain limited. Therapeutic strategies that enhance autophagic and mitophagic clearance, attenuate Tau toxicity, and restore mitochondrial homeostasis are crucial for AD management. Methods This study investigated the neuroprotective effects of Pulsatilla chinensis extract (PCE) in SH-SY5Y neuronal cells and Caenorhabditis elegans ( C. elegans ) models of Tauopathy. Autophagic flux was evaluated by GFP-LC3 puncta formation, LC3-II conversion, and p62 degradation. Mitochondrial function was assessed through reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and ultrastructural analysis. The roles of autophagy and mitophagy were examined using 3-methyladenine (3-MA) and the Parkin inhibitor AC220. In C. elegans , locomotion, Tau aggregation, oxidative stress, and mitophagosome formation were assessed, and pink-1 knockdown was used to confirm mitophagy dependence. Results PCE significantly enhanced autophagic flux, decreased total and phosphorylated Tau (p-Tau Ser404) levels, and improved neuronal viability. It significantly reduced ROS accumulation, maintained MMP, and preserved mitochondrial morphology under both Tau overexpression and H 2 O 2 -induced oxidative stress. Inhibition of autophagy or Parkin-mediated mitophagy negated these protective effects. In C. elegans , PCE ameliorated neuromuscular dysfunction, suppressed Tau inclusions, and reduced oxidative injury, while the loss of pink-1 abolished its benefits, underscoring the critical role of mitophagy. Conclusion PCE exerts potent neuroprotective effects by promoting mitophagy, reducing Tau phosphorylation and aggregation, and restoring mitochondrial integrity. These findings reveal a novel mechanism linking mitochondrial quality control with Tau proteostasis and highlight PCE as a promising natural therapeutic candidate for AD. Graphical
The alternative text for this image may have been generated using AI.
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高影响因子
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