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Objective: To investigate the therapeutic effect and mechanism of lenvatinib on regorafenib-resistant hepatocellular carcinoma cells. Methods: CCK-8 and clone formation assay were used to observe the inhibitory effect of lenvatinib on the growth of hepatocellular carcinoma cells. Flow cytometry was used to detect the apoptosis of regorafenib-resistant hepatocellular carcinoma cells treated with lenvatinib. The expression levels of related proteins were detected by western blot and immunohistochemical staining. The inhibitory effect of lenvatinib on the tumor formation ability of regorafenib-resistant hepatocellular carcinoma cells in vivo was observed by subcutaneous tumor formation experiment in mice. Results: CCK-8 and clone formation assay showed that lenvatinib could inhibit the proliferation of regorafenib-resistant hepatocellular carcinoma cells. The number of clones of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group (120.67±11.06, 53.00±11.14, 55.00±9.54, 78.67±14.64) were all lower than those in control group (478.00±24.52, 566.00±27.87, 333.67±7.02, 210.00±12.77, all P<0.05). Flow cytometry showed that lenvatinib could promote apoptosis of regorafenib-resistant hepatocellular carcinoma cells, the apoptosis rates of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group [(12.30±0.70)%, (9.83±0.38)%, (15.90±1.32)%, (10.60±0.00)%] were all higher than those in control group [(7.50±0.87)%, (5.00±1.21)%, (8.10±1.61)%, (7.05±0.78)%, all P<0.05]. The apoptosis-related protein levels suggested that apoptosis was increased in the treatment of lenvatinib. The animal study showed that lenvatinib can inhibit the growth of regorafenib-resistant cells in vivo. Immunohistochemistry and western blot results showed that lenvatinib could down-regulate the abnormally activated IGF1R/Mek/Erk signaling pathway in regorafenib-resistant cells. Conclusion: Lenvatinib can reverse regorafenib resistance in hepatocellular carcinoma, possibly by down-regulating IGF1R/Mek/Erk signaling pathway.
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Animals , Mice , Humans , Apoptosis , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation , Liver Neoplasms/pathology , Signal TransductionABSTRACT
Objective:To explore whether esketamine (ESK) can inhibit the proliferation and induce apoptosis of breast cancer cells, and explore the mechanism.Methods:CCK-8 assay was used to detect the inhibitory effect of ESK on the proliferation of breast cancer cells. Annexin V/PI staining was used to detect the morphological changes of cells; Apoptosis and reactive oxygen species were detected by flow cytometry. Western blot was used to detect apoptosis and pathway expression.Results:CCK-8 experiment results proved that ESK could inhibit the proliferation of breast cancer cells in a time-dependent manner. The survival rate of MDA-MB-468 cells treated with ESK at 20 μM was (35.47±2.61) %, which was statistically different from that treated with vinorelbine at the same concentration ( P<0.05). The IC50 value of ESK on MDA-MB-468 cells was (14.54±2.12) μM. After treatment with ESK, the mitochondrial membrane potential was significantly reduced. In the protein level, the expression of Cytochrome C, Bax and Caspase-3 was up-regulated, and the expression of Bcl-2 was down regulated, which induced the mitochondrial dependent apoptosis of MDA-MB-468 cells. ESK could up regulate the level of reactive oxygen species in MDA-MB-468 cells and regulate the expression of PI3K/AKT signaling pathway. Conclusions:ESK can inhibit the proliferation and migration of breast cancer cells and induce them to play a mitochondrial dependent apoptosis. Its mechanism is achieved by up regulating the level of ROS in breast cancer cells, thereby regulating the PI3K/AKT signaling pathway, which provides a theoretical basis for the development and utilization of Aln.
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Objective:To probe into Rab25 Gene’s Effect on TGF-β inhibition of proliferation, invasion and epithelial mesenchymal transformation (EMT) of breast cancer MDA-MB-231 cells and explore its molecular mechanism.Methods:The experiment was divided into three groups: control group,TGF-β Group and si-Rab25 group. TGF-β induced MDA-MB-231 cell model of EMT was built. CCK-8 assay was used to detect cell proliferation. Transwell assay was used to detect the ability of cell invasion and migration.Western blot was used to detect the changes of related proteins in each group.Results:After stimulating MDA-MB-231 cells with TGF-β, Rab25 gene was highly expressed. Compared with TGF-β group (57.48±%3.62%), the migration ability and invasion ability of cells in si-Rab25 group (33.49%±2.93%) decreased by 41.7%, with a significant difference ( P<0.05). Compared with TGF-β group (153.21%±4.17%), the proliferation ability of cells in si-Rab25 group (115.32%±5.69%) decreased by 24.73%, with a significant difference ( P<0.05). The expression of MDA-MB-231 fine EMT related protein in si-Rab25 group was significantly different from that in TGF-β group ( P<0.05). The expression of p-AKT and Snail protein in si-Rab25 group was significantly lower than that in TGF-β group ( P<0.05) . Conclusions:Rab25 gene is highly expressed in MDA-MB-231 cells. Silencing Rab25 gene can activate AKT signal pathway, inhibit Snail protein expression, regulate EMT related protein expression, and inhibit EMT transformation.
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Theaflavins are a class of natural products extracted from black tea or green tea, with significant anti-tumor effects on gastric cancer, liver cancer, breast cancer and other tumors. Theaflavins were once considered as the new products for anticancer therapy. However, the anti-tumor mechanism of theaflavins involves a variety of biological processes, and the regulation is complex. Therefore, this article summarizes the role of theaflavins in promoting tumor cell apoptosis, inducing tumor cell mitotic arrest and regulating tumor immunity, and reviews the inhibition of tumorigenesis and growth through MAPK, PI3K/AKT, Hedgehog, NF-κB, JAK/STAT and Wnt/β-Catenin signal pathways, in order to provide new ideas for cancer treatment and anti-cancer drug development.
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Background Brachial plexus root avulsion (BPRA) can cause motor neuron death, nerve degeneration andupper limb motor dysfunction. The molecular mechanisms of motor neuron death and nerve degeneration arelargely unknown and there are no effective therapies to increase the functional recovery after BRPA.Aim: To detect the early pathway changes in spinal cord tissues after brachial plexus root avulsion.Methods A mouse brachial plexus avulsion and re-implantation model was constructed, and the C5-C7segments of the spinal cords were dissected three days after the surgery. We used RNA-seq to identify theexpression changes of genes and gene networks in spinal cord tissues.Results A total of 2253 differentially expressed genes were found significantly changed with 1852 upregulatedand 401 downregulated at 3 days after BPRA. Gene ontology (GO) enrichment analysis showed thatdifferentially expressed genes were most enriched in immune system process, regulation of immune systemprocess, defense response, plasma membrane part, extracellular region part, cell surface, protein binding,receptor binding, glycosaminoglycan binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathwayanalysis showed that the most enriched pathways included osteoclast differentiation, NF-kappa B, cytokinecytokine receptor interaction, TNF, hematopoietic cell lineage, complement and coagulation cascades, PI3KAkt, ECM-receptor interaction, NOD-like receptor, Toll-like receptor signaling pathway.Conclusions This study systematically identified the critical genes and signaling pathways in BPRA pathology.These results expand our understanding of the complex molecular mechanisms involved in BPRA and provide afoundation for future research of spinal cord tissue injury and repair.
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@#In the progress of retinal angiogenesis, sprouting angiogenesis plays an important role in retinal normal development and neovascular diseases. The structural and functional integrities of vascular endothelial cells are essential condition of sprouting angiogenesis. Vascular endothelial cells possess various subtypes, each of which plays a different role in sprouting angiogenesis. Many mechanisms participate in the regulation of endothelial cells under physiological and pathological conditions, such as biological signaling pathway, metabolism, immune inflammation and non-coding RNA. In this review, we provided a brief overview of the role and the related regulatory mechanisms of vascular endothelial cells in retinal sprouting angiogenesis.
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Muhidrug resistance (MDR) is one of the important reasons for the failure of clinical anticancer drugs,involving multiple mechanisms.Among them,the classical MDR mechanism mediated by P-glycoprotein (P-gp) is closely related to the formation of MDR,which can excrete intracellular chemotherapeutic drugs through the "drug pump" effect and significantly reduce the therapeutic effect.Curcumin is mainly extracted from the underground rhizome of Chinese medicine turmeric,with a wide range of pharmacological activity.Recent studies have found that curcumin also has a role in reversing the MDR of the tumor,by inhibiting both P-gp function and expression,and this process involves a variety of signal paths.
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Aim To explore the effects of Nrf2-ARE signal path on levrtiracetam anti-epileptic and levrtiracetam on learning and memorizing ability.Methods Thirty-six SD rats were divided into normal saline group, levrtiracetam group, model group and treatment group.Each group recruited nine rats.Tests of Morries water maze were given to the rats to evaluate their learning and memorizing ability.The protein expression of nuclear factor (erythroid-derived2)-like2 (Nrf2), heme oxygenase 1(HO-1) and NAD(P)H quinone oxidoreductase(NQO1) were examined by Western blot.Results Compared with model group, levrtiracetam could shorten the plateau period in epileptic rats (P<0.05), and increase the expression of Nrf2 protein, HO-1 protein and NQO1 protein in hippocampus(P<0.05).Conclusions Levrtiracetam could improve the learning and memorizing ability in epileptic rats.Levrtiracetam may increase the expression of HO-1 protein and NQO1 protein through the Nrf2-ARE pathway and play a part in antiepileptic effects.
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Objective To explore the effect of Quercetin on the long-term memory and PARP-1/AIF signal path in neonatal rats with hypoxic-ischemic brain damage (HIBD). Methods Fifty-six 7-day-old SD rats were randomly divided into sham-operation group, HIBD group, low dose of Quercetin group (20 mg/kg), and high dose of Quercetin group (40 mg/kg), each of 14 rats. Except for sham-operation group, in the other groups HIBD model were made by right common carotid artery ligation and anoxiate. The Quercetin groups were injected with the corresponding doses of Quercetin immediately once a day continuously for 7 days after the model was made,. Sham-operation group and HIBD group were intraperitoneally injected with normal saline at the same time. Neural function was evaluated by Hanging wire test and Vertical pole test at 21 days old. The capacity of learning and memory was detected by Morris water maze at 28 days old, and then rats were killed and brains were taken. HE was used to observe the pathological changes of hippocampus. Western blot were used to detect the expression of PARP-1 and AIF in hippocampus. Results Compared with sham-operation group, the neural function and learning and memory ability decreased significantly in HIBD group. Those ability in both low dose and high dose of Quercetin groups were remarkably increased in comparison with HIBD group, and there were statistic differences (P??0.05). Conclusion Quercetin could improve long-term learning memory in newborn rats with HIBD, and the mechanism may be down-regulation of PARP-1/AIF cell apoptosis signaling pathway, inhibition of neuronal apoptosis, and thus play a role in protection of brain.
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Objective To investigate the effects of HO/CO pathway on inflammation cytokines in a rat model of incisional pain. Methods Thirty-six rats were executed to collect ipsilateral spinal cord tissues for HO-1 detection by Western blot assay, and cytokines tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6 and high mobility group box (HMGB)1 were detected by ELISA before and at 1, 4, 8, 12 and 24 h after establishing incisional pain model. Additionally, 36 rats without establishment of incisional pain model were used as control group. A total of 144 model rats of incisional pain were divided into incisional pain (IP) group, IP+hemin group (100 mg/kg hemin was injected by i.p. before operation), IP+Znpp-IX group (45μmoL/kg Znpp-IX was injected by i.p. before operation) and IP+CORM-2 group (10 mg/kg CORM-2 was injected by i.p. before operation). Values of paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were detected, and expressions of TNF-a, IL-1 b, IL-6 and HMGB1 were measured by ELISA before and at 1, 4, 8, 12 and 24 h after operation. Results Compared with pre-operation of incisional pain in rats, expression levels of HO-1 protein and cytokines TNF-a, IL-1 b, IL-6 and HMGB1 were increased at 1, 4, 8, 12 and 24 h after operation (P PWTL were decreased and cytokines TNF-α, IL-1β, IL-6 and HMGB1 were increased in IP+Znpp-IX group (P<0.05). Conclusion Incisional pain can increase the expression of HO-1, and HO-1/CO pathway exists the regulatory effect on inflammatory cytokines in the rat model of incisional pain.
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Objective To observe the effect of crocin pretreatment on the learning memory ability, the ultrastructure and SIRT1/PGC-1α expression in hippocampus under hypoxia at high altitude in rats. Methods 96 male SD rats were randomly divided into Hypoxia model group and Hypoxia treatment group with 48 in each.The group rats in treatment group were injected with Crocin once daily(50 mg/kg) and the model group were injected with the same dose of 0.9%NaCl for 3 days,and then they were shifted to high al-titude under hypoxic environment and then the samples were taken at 1 d,3 d,5 d,7 d.Morris water maze test was used to observe learning and memory behaviors of rats.The level of SIRT1/PGC-1αprotein was detected by Western blot and the level of mRNA was detected by RT-PCR.Results Compared with the model group (1d(37.55±1.34)s,3d(46.51±6.19)s,5d(42.12±2.73)s),treatment group showed significant less time in looking for platform in Morris water maze experiment at (1d(33.58±2.23)s,3d(30.19±3.35)s and 5d (37.10±1.48)s;all P0.05). Western blot showed that the protein expression levels of SIRT1 and PGC-1α in hippocampus of rats were higher in treatment group (1d(0.72±0.02),(0.72±0.02);3d(0.76±0.03),(0.75±0.021);5d(0.54± 0.03),(0.74±0.01)) than those in control group (1d(0.53±0.04),(0.62±0.04);3d(0.15±0.02),(0.13± 0.02);5d(0.23±0.03),(0.21±0.02);all P0.05).Conclusion Crocin pretreatment can ameliorate mitochondrial damage and improve the a-bility of learning and memory under hypoxia at high altitude in rats,which may be achieved through increased expression of SIRT1 and PGC-1α in the hippocampus.
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Liver fibrosis occurs as compensatory responses to tis-sue repairing process in a wide range of chronic liver injures.It is characterized by excessive deposition of extracellular matrix (ECM)in liver tissues.The new discovery shows that suppres-sor of cytokine signaling (SOCS-3)is strictly associated with fi-brogenic progression of chronic liver diseases.Recent basic and clinical investigations also demonstrate that liver fibrogenesis is accompanied by SOCS-3,which critically determines the patho- genesis and prognosis of liver fibrosis.This review summarizes current knowledge on SOCS-3 and the relationships between SOCS-3 and liver fibrosis.On the other hand,it also presents the different strategies that have been used in experimental mod-els to counteract excessive SOCS-3 and the role of SOCS-3 in the prevention and treatment of liver fibrosis.
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Endoplasmic reticulum plays a key role in both basic structure formation and function performance of microenviron-ment. Endoplasmic reticulum homeostasis unbalance caused by endoplasmic reticulum stress has become a hot research topic in recent years. This paper focuses on the role of endoplasmic retic-ulum stress in ischemic stroke. Research progress of related sig-naling pathways were reviewed, especially mechanisms through which endoplasmic reticulum stress trigger the inflammatory reac-tion, so as to provide a new research method for prevention of is-chemic stroke.
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Salivary gland adenoid cystic carcinoma is one of the most common malignant salivary gland tumors.Its invasion and metastasis are multi-stage and multifactorial processes,in which complex mechanisms and multiple signaling pathways are involved.Here,this article reviews the research progress in signaling pathways of salivary gland adenoid cystic carcinoma.
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Objective This study was designed to investigate influence of resveratrol on serum lipid and antioxidant enzyme lev‐els in atherosclerotic rabbit model ,and to explore its influence on NF‐κB and MAPKs signal pathway .Methods Rabbits were as‐signed to five groups :control (group A) ,high fat diet group (group B) ,resveratrol group (group C ,D and E) .The contents of lip‐ids level (TC ,TG ,LDL‐C ,HDL‐C) and antioxidant enzyme (GSH ,GSH‐PX ,GST ,γ‐GCS ,CAT ,SOD ,MDA) levels in the serum were measured respectively and the difference was studied .Phosphorylation levels of MAPKs cascades ,NF‐κB were measured by Western blot .Results Compared with group A ,group B had elevated levels of blood lipids ,antioxidant enzymes were on the de‐cline ,the MDA content increased ,MAPKs and the NF‐κB protein phosphorylation enhanced .C ,D ,E group can reduce levels of blood lipids ,increases HDL‐C ,improve antioxidant enzyme activity and reduce MDA content ,inhibit MAPKs ,NF‐κB protein phos‐phorylation .Conclusion Resveratrol could reduce the atherosclerotic rabbit blood lipid levels ,increase antioxidant enzyme activity , reduce the MDA level and this effect is likely to inhibit NF‐κB and MAPKs signaling pathway activation .
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Objective To explore the dynamic change and meaning of JAK/STAT signal path in the invasive course of collagen-induced arthritis(CIA).Methods Forty-eight rats were divided into 6 groups ran- domly,eight rats served as the control group,the rest were for the development of CIA models.Rats were sac- rificed at the 2nd,3rd,4th,5th and 6th week after the initial immunity respectively.Then HE staining,im- munohistochemistry and immunoblotting were used to detect the pathological changes of synovium in different st ages and the expression of p-STAT1 and p-STAT3.Results On the second week after initial immunity,the rats had arthritis,and the inflammation achieved its peak at the 4th week,then gradually relieved,and a few joints developed rigidity,synovium hyperplasia and inflammatory cell infiltration could be seen at the second week of initial immunity,and pannus could be seen at the 4th week as well as cartilage destroy at the 6th week by HE staining.In the invasive course of CIA,STAT1 and STAT3 were all in activated state detected by im- munohistochemistry and immunoblotting,which were significantly different from those of control group and they had a positive correlation with arthritis index,the Pearson's value of them were 0.798 and 0.873 respectively. However,there was some difference on time.STAT3 kept at activated state and had positive correlation with pathology score of synovium,and the Pearson's value was 0.622.On the contrary,the activation of STAT1 was obviously delayed and only confined to the middle and advanced stage of the disease.Conclusion JAK/STAT signal pathway participates the pathological course of CIA,and blocking the different point of JAK/STAT path- way'activation process may reach the goal of reversing the RA's pathological course.