INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xinyu Zhang,Haojie Liu,Yumeng Shi,Zhenhao Liu,Yan Wang,Simai Chen,Xingzhi Yan,Rongyao Xu,Junqing Ma,Qiang Chen,Shuyu Guo
Aims Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease linked to disrupted chondrocyte activity and cartilage homeostasis. This study aimed to clarify the protective role of optineurin (OPTN) in preventing chondrocyte apoptosis during TMJ OA progression. Materials and Methods Using bioinformatics analysis, Optn was identified as a key gene in chondrocyte regulation. We employed a unilateral anterior crossbite (UAC) model in vivo and Tunicamycin (TM) in vitro to investigate OPTN's role in TMJ OA. Makin scores and histological staining assessed cartilage degeneration, while flow cytometry measured chondrocyte apoptosis, mitochondrial, and endoplasmic reticulum (ER) calcium levels. Key Findings We demonstrated that OPTN deficiency accelerates arthritis progression by intensifying endoplasmic reticulum stress (ERS) and chondrocyte apoptosis both in vivo and in vitro. Mechanistically, in vitro data showed that OPTN interacted with glycogen synthase kinase 3 beta (GSK3β), modulating the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (GRP75)/voltage-dependent anion channel 1 (VDAC1) complex. This interaction affected ER-mitochondrial calcium transfer, elevating mitochondrial calcium, and promoting apoptosis. Inhibiting this calcium channel with SB216763 and 2-APB effectively reduced mitochondrial Ca 2+ overload and apoptosis. Significance These findings reveal the crucial role of OPTN deficiency in TMJ OA pathogenesis and propose that targeting the IP3R-GRP75-VDAC1 complex to alleviate mitochondrial calcium could offer new therapeutic strategies for TMJ OA.
研究领域:
医学
·
分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2025
·
IF 4.7
Meizhu Wu,Yuting Zhou,Zhi Guo,Dawei Lian,Hong Chen,Renfeng Li,Jing Lin,Farman Ali,Aling Shen,Jun Peng
Isoliensinine, a bioactive alkaloid derived from Nelumbo nucifera Gaertn , has antihypertension effects. This study investigated its antihypertensive effect and molecular mechanism. Spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (n=6 per group) were treated with 2.5, 5 or 10 mg/kg isoliensinine or 7 mg/kg valsartan for 10 weeks. Ultrasonography, histology, immunohistochemistry, RNA-sequencing analysis, vascular tension, calcium imaging, and virtual docking were performed. Isoliensinine effectively attenuated the elevation of blood pressure, pulse wave velocity, and medial thickness of the abdominal aortas in SHRs. It reversed 253-upregulated and 161-downregulated differentially expressed transcripts in the abdominal aorta of SHRs, with enrichment in vascular smooth muscle contraction and calcium signaling pathways. Isoliensinine significantly attenuated the vasoconstriction induced by angiotensin II (Ang II), norepinephrine (NE), or potassium chloride (KCl) and maintained its inhibitory effects across increasing calcium concentrations. It promotes vasodilation in the abdominal aorta rings induced by NE or KCl independent of the endothelium and potassium ion channels but is associated with the modulation of L-type calcium channels. Isoliensinine also suppressed calcium release in vascular smooth muscle cells after KCl, Ang II, or NE stimulation. Isoliensinine upregulated the expression of MLCP but downregulated that of p-MLC2 in the abdominal aorta of SHRs. Virtual docking analysis revealed lower binding energy values for isoliensinine with MLCP, suggesting a potential interaction. Isoliensinine lowers blood pressure by regulating vascular smooth muscle contraction and relaxation, and its effects are potentially mediated by regulating calcium signaling pathways.
研究领域:
药理学
·
心血管生物学
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DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2025
·Vol. 52
·期 4
·e70033
·
IF 2.5
Xin Zhang,Xinliu Wang,Yuanyuan Wang,Xingyou Ma,Yunyun Geng,Shuxian Zang,Ziyun Ban,Yugai Jia,Yonggang Gao
Norisoboldine (NIB) displays beneficial effects on cardiovascular diseases, although its protective role and underlying mechanisms in myocardial ischemia (MI) injury remain elusive. The aim of this study is to explore the potential cardioprotective mechanism of NIB on MI injury caused by isoproterenol (ISO). We administered NIB to SD rats at 20 and 40 mg/kg daily for 7 days in this study; this was followed by an ISO injection to induce MI injury. Parameters such as electrocardiogram readings, heart rate, serum concentrations of creatine kinase (CK) and creatine kinase-MB (CK-MB), levels of inflammatory markers, some histopathological assessments and oxidative stress markers were evaluated. We conducted Western blot analyses to evaluate protein expression related to apoptosis and the TLR4–MyD88-mediated NF-κB activation pathway. The L-type Ca 2+ current (ICa-L) and contraction of isolated ventricular cells from rats were identified using patch-clamp methods and the IonOptix detection system. The treatment with NIB resulted in improvements in heart rate and ST-segment changes, a reduction in CK and CK-MB levels, the restoration of superoxide dismutase, catalase and glutathione levels and a decrease in malondialdehyde accumulation. Furthermore, NIB reduced the expression of inflammatory markers, lowered Ca 2+ levels and reactive oxygen species production and improved myocardial tissue morphology. It also countered ISO-induced alterations in apoptosis and the TLR4–MyD88-dependent NF-κB activation pathway. Additionally, NIB considerably attenuated ICa-L and reduced the contractile function of cardiomyocytes. These results suggest that NIB effectively mitigates ISO-induced MI injury through anti-inflammatory, antioxidative, and anti-apoptotic mechanisms, potentially involving the TLR4–MyD88-dependent NF-κB activation pathway and calcium balance.
研究领域:
药理学
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心血管疾病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
·
2024
·
IF 5.5
Jing Wang,Yue Wu,Huishan Li,Wenjue Kang,Wenhao Li,Shijia Fu
Nano hydroxyapatite (nHA) has been acknowledged for its inhibition efficiency on tumor cells and its excellent biocompatibility for normal tissue and cells. However, the low inhibitory efficiency of tumor cells and the ambiguous inhibitory mechanism limited its further application. In this work, four kinds of nHA with different sizes was prepared, and the one with the highest inhibition efficiency on 4T1 cells was screened as a substrate for developing the nanoparticles coated with polydopamine (PDA) coating, which was named nHA-PDA. Both in vivo and in vitro experiments were employed, and the results showed significantly higher inhibitory activity against 4T1 cells and 4T1-bared tumors by nHA-PDA. Further investigation revealed that the oxidative stress induced by PDA results in a large Reactive Oxygen Species (ROS) accumulation, thus triggering the mitochondria-dependent apoptosis pathway ROS-JNK/MAPK and inducing the cascade reaction of inhibiting the anti-apoptosis protein-Bcl-2 expression and activating the expression of the critical genes in apoptosis signaling pathway (caspase 3 and caspase 9). Besides, the significant increase of intracellular [Ca 2+ ] may also be an essential reason for the damage of mitochondria, eventually leading to apoptosis.
研究领域:
肿瘤学
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生物材料科学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PLANTA MEDICA
·
2016
·Vol. 83
·期 07
·624-630
·
IF 1.99
Yi-Lin Zhang,Jia-Wen Xu,Xiong-Hao Wu,Peng-Xiao Chen,Fang Wei,Dong-Dong Gao,Xiao-Wen Chen,Yu-Li Luo,Yun-Xin Zhu,Jiehong Huang,Ya-Xia Tan,Lei Zhao,Wen-Liang Zhou
Sodium tanshinone IIA sulphonate, a water-soluble derivative of tanshinone IIA, has been proven to possess versatile biological properties, but its pharmacological effect on tracheal smooth muscle remains elusive. This paper presents a study on the relaxant effect and underlying mechanisms of sodium tanshinone IIA sulphonate on mouse tracheal smooth muscle. The relaxant effect of sodium tanshinone IIA sulphonate was evaluated in mouse tracheal rings using a mechanical recording system. Intracellular Ca2+ concentration was measured in primary cultured tracheal smooth muscle cells using confocal imaging system. The results showed that sodium tanshinone IIA sulphonate induced dose-dependent relaxation of mouse tracheal rings in a β-adrenoceptor- and epithelium-independent manner. Pretreatment with the ATP-sensitive K+ channel blocker glibenclamide partly attenuated the relaxation response. Administration of sodium tanshinone IIA sulphonate notably inhibited the extracellular Ca2+-induced contraction. High KCl or carbachol-evoked elevation in the intracellular Ca2+ concentration was also abrogated by sodium tanshinone IIA sulphonate in tracheal smooth muscle cells. In conclusion, the tracheal relaxant effect of sodium tanshinone IIA sulphonate was independent of β-adrenoceptor and airway epithelium, mediated primarily by inhibition of extracellular Ca2+ influx via L-type voltage-dependent Ca2+ channels and partially by activation of the ATP-sensitive K+ channel. These results indicate the potential therapeutic value of sodium tanshinone IIA sulphonate for asthma treatment.
研究领域:
药理学
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呼吸系统研究
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DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
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IF 19
Linghui Song,Panpan Chen,Baimei Shi,Aihua Qu,Chuanlai Xu,Hua Kuang,Maozhong Sun
Autophagy is a key regulator in a diverse range of human diseases. Here, chiral copper sulfide (CuS) nanoparticles (NPs) modified with penicillamine are fabricated, which exhibited a circular dichroism (CD) spectrum between 300 and 1000 nm and a fluorescence peak at 680 nm. The experimental data showed that D -CuS NPs exhibited chirality-dependent autophagy induction, outperforming L -CuS NPs, and targeted breast cancer cells with 228.4 times higher affinity for CD81 receptor. The mechanism is revealed that chiral NPs specifically bound to CD81 receptor to open mechanosensitive calcium channels and motivated the calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK pathway, which enhanced Atg1/Unc-51-like autophagy activating kinase 1 (ULK1) activity to promote autophagy. In vivo experiments confirmed the selective accumulation of D -CuS NPs in tumors, induction of autophagy, and successful treatment of the tumor. Therefore, chiral CuS NPs show great potential for modulating biological processes and improving tumor treatment.
研究领域:
纳米医学
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肿瘤学
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分子生物学
·
细胞自噬
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生物材料
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转化医学
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产品关联
DOI
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
·
2017
·
IF 3.498
Zhuo Fan,Nanying Lv,Xiao Luo,Wen Tan
Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level.
研究领域:
药理学
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心血管病学
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DOI
PubMed
高影响因子
KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY
·
2023
·Vol. 27
·期 1
·39-48
·
IF 2
Qiru Wang,#,Yang Zhang,#,Qiong Du,Xinjie Zhao,Wei Wang,Qing Zhai,Ming Xiang
Spinal nerve injury causes mechanical allodynia and structural imbalance of neurotransmission, which were typically associated with calcium overload. Store-operated calcium entry (SOCE) is considered crucial elements-mediating intracellular calcium homeostasis, ion channel activity, and synaptic plasticity. However, the underlying mechanism of SOCE in mediating neuronal transmitter release and synaptic transmission remains ambiguous in neuropathic pain. Neuropathic rats were operated by spinal nerve ligations. Neurotransmissions were assessed by whole-cell recording in substantia gelatinosa. Immunofluorescence staining of STIM1 with neuronal and glial biomarkers in the spinal dorsal horn. The endoplasmic reticulum stress level was estimated from qRT-PCR. Intrathecal injection of SOCE antagonist SKF96365 dose-dependently alleviated mechanical allodynia in ipsilateral hind paws of neuropathic rats with ED 50 of 18 μg. Immunofluorescence staining demonstrated that STIM1 was specifically and significantly expressed in neurons but not astrocytes and microglia in the spinal dorsal horn. Bath application of SKF96365 inhibited enhanced miniature excitatory postsynaptic currents in a dosage-dependent manner without affecting miniature inhibitory postsynaptic currents. Mal-adaption of SOCE was commonly related to endoplasmic reticulum (ER) stress in the central nervous system. SKF96365 markedly suppressed ER stress levels by alleviating mRNA expression of C/EBP homologous protein and heat shock protein 70 in neuropathic rats. Our findings suggested that nerve injury might promote SOCE-mediated calcium levels, resulting in long-term imbalance of spinal synaptic transmission and behavioral sensitization, SKF96365 produces antinociception by alleviating glutamatergic transmission and ER stress. This work demonstrated the involvement of SOCE in neuropathic pain, implying that SOCE might be a potential target for pain management.
研究领域:
神经科学
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药理学
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疼痛研究
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DOI
高影响因子
CURRENT BIOLOGY
·
2022
·
IF 10.9
Jingda Qiao,Shengxi Yang,Hongyan Geng,Wing-Ho Yung,Ya Ke
Summary Aversive olfactory conditioning in Drosophila is a valuable model for elucidating the mechanism of associative learning . Much effort has centered around the role of neuroplasticity at the mushroom body (MB)-mushroom body output neuron (MBON) synapses in mapping odors to specific behaviors . By electrophysiological recordings from MB neurons, we discovered a form of input-timing-dependent plasticity at the incoming synapses from projection neurons that controls the efficacy of aversive olfactory memory formation. Importantly, this plasticity is facilitated by the neural activity of PPL1, the neuronal cluster that also modulates MB-MBON connections at the output stage of MB. Unlike the MB-MBON synapses that probably utilize dopamine D1-like receptors, this neuroplasticity is dependent on D2-like receptors that are expressed mainly by γ Kenyon cells noticeably in their somato-dendritic region. The D2-like receptors recruit voltage-gated calcium channels , leading to calcium influx in the soma and dendrites of γ neurons. Together, our results reveal a previously unrecognized synaptic component of the MB circuit architecture that not only could increase the salience of a conditioning odor but also couples the process of memory encoding and valency mapping to drive-associative learning.
研究领域:
神经科学
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行为生物学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
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IF 4.8
Jinzhao Yang,Hailun Xia,Qingqing Li,Ruibin Li,Lu Cao,Congrong Tang
The aim of this study was to investigate the impact of calcium channel blockers (CCBs) and antihypertensive traditional Chinese medicine (TCM) on the metabolism of quetiapine. In vitro, two incubation systems of rat liver microsomes (RLM) and human liver microsomes (HLM) were established and optimized to explore potential interactions between five kinds CCBs (nicardipine, dilthiazem, lercanidipine, nimodipine, nitrendipine), five kinds antihypertensive TCM (quercetin, fangchinoline, apigenin, tetrandrine, and berberine) and quetiapine, and to evaluate their underlying inhibition mechanisms. In vivo, Sprague-Dawley rats were used to assess the interaction between quetiapine and nicardipine. The results showed that nicardipine had the highest inhibition rate (79.22%) against quetiapine metabolism among those drugs screened. The half-maximal inhibitory concentration (IC50) values for the inhibition of quetiapine metabolism by nicardipine in RLM and HLM were similar, at 10.29 ± 0.06 μM and 13.23 ± 0.37 μM, respectively. In RLM, nicardipine exhibited a mixed mechanism of competitive and non-competitive inhibition, while in HLM, it displayed a non-competitive and un-competitive inhibition mechanism. In vivo results indicated that nicardipine could significantly increase the main pharmacokinetic parameters AUC(0-t), AUC0−∞, and Cmax of quetiapine, but decrease the AUC(0-t) of its metabolite N-desalkylquetiapine. The findings of this study suggested that nicardipine had inhibited the metabolism of quetiapine, suggesting the dose adjustment or therapeutic drug monitoring of quetiapine should be conducted to achieve individualized therapy.
研究领域:
药物代谢
·
临床药理学
·
肝脏药理学
·
药物相互作用
·
分子药理学
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转化医学
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心血管药理学
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产品关联
DOI
PubMed
高影响因子
BMC Medicine
·
2025
·Vol. 23
·期 1
·1-16
·
IF 8.3
Li Yinyan,Yang Sizu,Jiang Feng,Luo Siqi,Liang Jinlong,Jiang Linrui,Chen Zhixuan,Chen Xin,Yang Jie
Background Influenza A virus (IAV) is a major cause of seasonal and global pandemics, posing serious health risks. Repositioning approved drugs offers an efficient antiviral strategy, particularly as calcium (Ca 2 ⁺) is crucial for IAV infection, making Ca 2 ⁺ channel blockers (CCBs) promising candidates for antiviral agents. Methods The in vitro antiviral activity of cilnidipine was evaluated using MTT assays, qRT-PCR, plaque assays, and western blotting. Mechanistic studies involved time-of-addition, viral internalization, pseudovirus neutralization, and HA (hemagglutinin) syncytium assays. For in vivo analysis, BALB/c mice were intranasally infected to evaluate the effects of cilnidipine on viral titer, lung index, pulmonary inflammatory mediators, and survival rate. Results In vitro, cilnidipine exhibits antiviral activity against IAV during the early stages of infection. It disrupts clathrin- and caveolin-mediated endocytosis to inhibit the internalization of IAV and interacts with the viral HA2 subunit to impede virus membrane fusion. Additionally, cilnidipine suppresses the PI3K-AKT and p38 MAPK pathways activated by IAV infections. In vivo, cilnidipine reduces virus titers and lung index, ameliorates lung pathology, and inhibits pulmonary inflammatory mediator expression, improving survival rates. Conclusions These findings highlight the promising anti-IAV properties of cilnidipine both in vitro and in vivo, suggesting its potential as a clinical agent for emergencies against influenza outbreaks.
研究领域:
病毒学
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药理学
·
分子生物学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
CELL PROLIFERATION
·
2020
·Vol. 54
·期 1
·e12955
·
IF 5.753
Jun Ma,Lei Zhu,Zhibin Zhou,Tengfei Song,Lei Yang,Xu Yan,Aimin chen,Tian Wen Ye
Objectives Calcium ion signals are important for osteoclast differentiation. Transient receptor potential vanilloid 6 (TRPV6) is a regulator of bone homeostasis. However, it was unclear whether TRPV6 was involved in osteoclast formation. Therefore, the aim of this study was to evaluate the role of TPRV6 in bone metabolism and to clarify its regulatory role in osteoclasts at the cellular level. Materials and methods Bone structure and histological changes in Trpv6 knockout mice were examined using micro-computed tomography and histological analyses. To investigate the effects of Trpv6 on osteoclast function, we silenced or overexpressed Trpv6 in osteoclasts via lentivirus transfection, respectively. Osteoclast differentiation and bone resorption viability were measured by tartrate-resistant acid phosphatase (TRAP) staining and pit formation assays. The expression of osteoclast marker genes, including cathepsin k, DC-STAMP, Atp6v0d2 and TRAP, was measured by qRT-PCR. Cell immunofluorescence and Western blotting were applied to explore the mechanisms by which the IGF-PI3K-AKT pathway was involved in the regulation of osteoclast formation and bone resorption by Trpv6. Results We found that knockout of Trpv6 induced osteoporosis and enhanced bone resorption in mice, but did not affect bone formation. Further studies showed that Trpv6, which was distributed on the cell membrane of osteoclasts, acted as a negative regulator for osteoclast differentiation and function. Mechanistically, Trpv6 suppressed osteoclastogenesis by decreasing the ratios of phosphoprotein/total protein in the IGF–PI3K–AKT signalling pathway. Blocking of the IGF–PI3K–AKT pathway significantly alleviated the inhibitory effect of Trpv6 on osteoclasts formation. Conclusions Our study confirmed the important role of Trpv6 in bone metabolism and clarified its regulatory role in osteoclasts at the cellular level. Taken together, this study may inspire a new strategy for the treatment of osteoporosis.
研究领域:
骨骼生物学
·
细胞信号传导
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
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