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Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential.
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Neoplasias Colorretais , Ferroptose , Humanos , Animais , Camundongos , Piroptose , Fator 2 Relacionado a NF-E2/genética , Proteína Supressora de Tumor p53 , Caspase 1 , Glutationa , Camundongos Nus , Neoplasias Colorretais/tratamento farmacológico , Fator de Transcrição STAT3RESUMO
BACKGROUND: Paclitaxel induced fatigue still remains underrecognized and undertreated, partly because of limited understanding of its pathophysiology and lack of effective treatments. This study is aim to evaluate the anti-fatigue effects and mechanism of Bu-Zhong-Yi-Qi pill in murine 4 T1 breast cancer mice were treated with paclitaxel. METHODS: Breast cancer mice established with murine 4 T1 cells were randomly and repectively divided into five groups: negative control group (NC), tumor control group (TC), paclitaxel group (PTX), Bu-Zhong-Yi-Qi pill group (BZYQ) and Bu-Zhong-Yi-Qi pill plus paclitaxel group (BZYQ + PTX). The mice were administered for 21 days. During this period, the tumor volume, body weight and the weight-loaded swimming time were measured. After the last administration, all mice were sacrificed, weighted the tumor, measured immune cell cytokines and oxidative stress indicator. The remaining 10 mice in each group were observed for survival analysis. RESULTS: Treatments with BZYQ + PTX and PTX significantly reduced the rates of tumor volume in comparison with TC starting on the 9th day and the 18th day respectively (P < 0.05-0.01), and presented decreased tumor weight compared to TC (P < 0.05-0.01). Compared with mice in TC group, the median survival time and the average survival time in BZYQ + PTX group, BZYQ group and PTX group were significantly prolonged (P < 0.05-0.01). The swimming time of the BZYQ + PTX group gradually increased, which is longer than the PTX group on Day 14 and Day 21 (P < 0.01). The level of TNF-α was lower in BZYQ + PTX group than PTX group (P < 0.01). The level of SOD activity in BZYQ + PTX group was lower than the NC group (P <0.01), but much higher than the PTX group (P < 0.01). The level of MDA of BZYQ + PTX group was higher than the NC group (P < 0.01), but significant lower than the PTX group (P < 0.01). CONCLUSIONS: BZYQ has the potential of alleviating paclitaxel chemotherapy-related fatigue in 4 T1 breast cancer mice by reducing the serum levels of TNF-α and modulating the level of MDA and the SOD activity.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/complicações , Medicamentos de Ervas Chinesas/uso terapêutico , Fadiga/tratamento farmacológico , Magnoliopsida , Paclitaxel/efeitos adversos , Fitoterapia , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Fadiga/induzido quimicamente , Fadiga/metabolismo , Feminino , Humanos , Malondialdeído/metabolismo , Camundongos , Paclitaxel/uso terapêutico , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Cisplatin is a widely used anticancer drug in clinic, but it has a damaging effect on skeletal muscle cells. Clinical observation showed that Yiqi Chutan formula (YCF) had a alleviating effect on cisplatin toxicity. METHODS: In vitro cell model and in vivo animal model were used to observe the damage effect of cisplatin on skeletal muscle cells and verify that YCF reversed cisplatin induced skeletal muscle damage. The levels of oxidative stress, apoptosis and ferroptosis were measured in each group. RESULTS: Both in vitro and in vivo studies have confirmed that cisplatin increases the level of oxidative stress in skeletal muscle cells, thus inducing cell apoptosis and ferroptosis. YCF treatment can effectively reverse cisplatin induced oxidative stress in skeletal muscle cells, thereby alleviating cell apoptosis and ferroptosis, and ultimately protecting skeletal muscle. CONCLUSIONS: YCF reversed cisplatin-induced apoptosis and ferroptosis of skeletal muscle by alleviating oxidative stress.
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Cisplatino , Ferroptose , Animais , Cisplatino/farmacologia , Apoptose , Estresse Oxidativo , Músculo EsqueléticoRESUMO
Background: The incidence of cancer-related fatigue (CRF) is increasing, but its lack of clear pathogenesis makes its prevention and treatment difficult. Therefore, it is of great significance to clarify the pathogenesis of CRF and find effective methods to treat it. Methods: The CRF model was established by intraperitoneal injection of LLC cells in ICR mice to explore the pathogenesis of CRF and verify the therapeutic effect of the Yifei-Sanjie pill (YFSJ). The active components of YFSJ were found by LC/MS, the in vitro inflammatory infiltration model of skeletal muscle was constructed by TNF-α and C2C12 myoblasts, and the results of in vivo experiments were verified by this model. Results: Behavioral analysis results showed that YFSJ alleviated CRF; histological examination results showed that YFSJ could reverse the tumor microenvironment leading to skeletal muscle injury; ELISA and RNA-seq results showed that the occurrence of CRF and the therapeutic effect of YFSJ were closely related to the tumor inflammatory microenvironment; IHC and WB results showed that the occurrence of CRF and the therapeutic effect of YFSJ were closely related to the Stat3-related signaling pathway and autophagy. Conclusions: YFSJ can reduce the level of inflammation in the tumor microenvironment in vivo, inhibit the abnormal activation of the Stat3/HIF-1α/BNIP3 signaling pathway induced by tumor-related inflammation, thereby inhibiting the overactivation of mitophagy in skeletal muscle, and finally alleviate CRF. Quercetin, one of the components of YFSJ, plays an important role in inhibiting the phosphorylation activation of Stat3.
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Objectives. To assess the efficacy and safety of Liu Jun Zi Tang (LJZT) and Xiang Sha Liu Jun Zi Tang (XSLJZT) for treating functional dyspepsia. Methods. Literature searches were carried out on Medline database, Cochrane Library, CNKI database, Chinese Biomedical Literature database, Wanfang database, and VIP database up to July 2012. Hand search for further references was conducted. Study selection, data extraction, quality assessment, and data analyses were performed according to the Cochrane standards. Results. Fifteen publications in total were suitable for inclusion. There was evidence that LJZT compared with prokinetic drugs increased symptom improvement (odds ratio 1.96, 95% CI 1.15 to 3.36). There was also evidence that XSLJZT compared with prokinetic drugs increased symptom improvement (odds ratio 2.63, 95% CI 1.72 to 4.03). No adverse events were reported in LJZT or XSLJZT group in any of these randomized controlled trials. Conclusion. LJZT and XSLJZT might be more effective compared with prokinetic drugs in the treatment of functional dyspepsia, and no side effects are identified in the included trials. However, due to poor methodological quality in the majority of included studies, the potential benefit from LJZT and XSLJZT need to be confirmed in rigorously designed, multicentre, and large-scale trials.
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Luteolin, which is a natural flavonoid, has anti-inflammatory, antioxidant, and anticancer properties. Numerous studies have proven that luteolin inhibits the growth of many types of cancer cells by promoting apoptosis, autophagy, and cell cycle arrest in tumour cells. However, in vivo research on this topic has been limited. In addition, other studies have shown that luteolin exerts a good inhibitory effect on apoptosis-resistant cancer cells. While existing studies have not completely elucidated the mechanism underlying this phenomenon, we assume that luteolin, which is a natural compound that exerts its effects through various mechanisms, may have the potential to inhibit tumour growth. In our study, we proved that luteolin exerted a good inhibitory effect on the proliferation of colon cancer cells according to CCK8 and EdU fluorescence assays, and the same conclusion was drawn in animal experiments. In addition, we found that luteolin, which is an antioxidant, unexpectedly promoted oxidative stress as shown by measuring the levels of oxidative balance-related indicators, such as reactive oxygen species (ROS), SOD, H2O2 and GSH. However, the decreased oxidation of luteolin-treated HT-29 cells after treatment with the active oxygen scavenger NAC did not reverse the inhibition of cell growth. However, the Caspase1 inhibitor VX765 did reverse the inhibition of cell growth. Western blotting analysis showed that luteolin treatment increased the expression of Caspase1, Gasdermin D and IL-1ß, which are members of the pyroptosis signalling pathway, in colon cancer cells. We further intuitively observed NLRP3/Gasdermin D colocalization in luteolin-treated HT-29 cells and mouse tumour tissues by immunofluorescence. These results suggest that luteolin inhibits the proliferation of colon cancer cells through a novel pathway called pyroptosis. This study provides a new direction for the development of natural products that inhibit tumour growth by inducing pyroptosis.
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Chemotherapy-related fatigue (CRF), one of the most severe adverse effects observed in cancer patients, has been theoretically related to oxidative stress, and antioxidant treatment might be one of the most valuable therapeutic approaches. However, there are still few effective pharmacological therapies. Yifei Sanjie pills (YFSJ), a classical formula used to treat lung cancer as complementary and alternative medicine, have been proved to alleviate CRF of lung cancer patients in clinical practices. However, the underlying mechanisms have not been clarified. In this study, our data showed that YFSJ alleviated CRF presented as reversing the decline of swimming time and locomotor activity induced by cisplatin (DDP). Moreover, YFSJ significantly reduces the accidence of mitophagy and mitochondrial damage and reduces apoptosis in skeletal muscle tissues caused by DDP. It probably works by decreasing the oxidative stress, inhibiting the activation of the AMPK/mTOR pathway, decreasing protein expression levels of Beclin1 and other autophagy-related proteins, and attenuating the activation of Cytochrome c (cyto. C), Cleaved Caspase-9 (c-Casp 9), and other apoptosis-related proteins. Furthermore, YFSJ enhanced DDP sensitivity by specifically promoting oxidative stress and activating apoptosis and autophagy in the tumor tissues of mice. It was also found that YFSJ reduced the loss of body weight caused by DDP, reversed the ascent of serum concentrations of alanine aminotransferase (ALT), aminotransferase (AST), and creatinine (CREA), increased the spleen index, and prolonged the survival time of mice. Taken together, these results revealed that YFSJ could alleviate CRF by reducing mitophagy and apoptosis induced by oxidative stress in skeletal muscle; these results also displayed the effects of YFSJ on enhancing chemotherapy sensitivity, improving quality of life, and prolonging survival time in lung cancer mice received DDP chemotherapy.
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Colorectal cancer (CRC) is a severe threat to human health. Ginsenosides such as ginsenoside Rh4 have been widely studied in the antitumor field. Here, we investigated the antiproliferative activity and mechanism of Rh4 against CRC in vivo and in vitro. The CRC xenograft model showed that Rh4 inhibited xenograft tumor growth with few side effects (p < 0.05). As determined by MTT colorimetric assays, Western blotting, and immunohistochemical analysis, Rh4 effectively inhibited CRC cell proliferation through autophagy and ferroptosis (p < 0.05). Rh4 significantly upregulated autophagy and ferroptosis marker expression in CRC cells and xenograft tumor tissues in the present study (p < 0.05). Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed Rh4-induced ferroptosis (p < 0.05). Moreover, the autophagy inhibitor 3-methyladenine (3-MA) also reversed Rh4-induced ferroptosis (p < 0.05). These results indicate that Rh4-induced ferroptosis is regulated via the autophagy pathway. In addition, Rh4 increased reactive oxygen species (ROS) accumulation, leading to the activation of the ROS/p53 signaling pathway (p < 0.05). Transcriptome sequencing also confirmed this (p < 0.05). Moreover, the ROS scavenger N-acetyl-cysteine (NAC) reversed the inhibitory effect of Rh4 on CRC cells (p < 0.05). Therefore, this study proves that Rh4 inhibits cancer cell proliferation by activating the ROS/p53 signaling pathway and activating autophagy to induce ferroptosis, which provides necessary scientific evidence of the great anticancer potential of Rh4.
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OBJECTIVE: This study explored the potential therapeutic effect and possible mechanism of Kai-Xin-San (KXS) on doxorubicin-induced cognitive impairment in 4T1 breast cancer mice. METHODS: A model of chemotherapy-induced cognitive impairment (CICI) was established with the injection of doxorubicin (DOX, 5 mg/kg) at a 7-day interval in a 4T1 breast cancer mouse. KXS was given (1 g/kg) daily by gavage over three weeks starting at the first week while giving DOX. The Morris water maze task was performed to measure the CICI-like behaviors. Oxidative stress markers in the hippocampus, inflammatory cytokines in the serum and hippocampus, Nissl staining, immunofluorescence staining, and analysis for Glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 of the hippocampus were examined to explore the effect and mechanism of KXS on DOX-induced CICI. Meanwhile, tumor growth and survival time were tested in this study. RESULTS: CICI-like behaviors induced by DOX occurred earlier and were severer than the cognitive impairment induced by the tumor, and the effect of KXS on improving the cognitive impairment was obvious. KXS protected against DOX-induced neuroinflammation by decreasing levels of proinflammatory cytokines interleukin-6, interleukin-12p70, and tumor necrosis factor-alpha in both serum and brain and interleukin-1ß in the brain, increasing the anti-inflammatory cytokines interleukin-4 in the serum and interleukin-10 in the hippocampus, and inhibiting the astrocytic hyperplasia and microglial polarization in the hippocampus. KXS reduced neural degeneration and protected against DOX-induced oxidative stress according to decreased malondialdehyde level, increased glutathione level, and enhanced activities of superoxide dismutase, catalase, and glutathione peroxidase. Moreover, KXS recovered the lost body weights after DOX administration and prolonged the survival times of mice. CONCLUSIONS: KXS may attenuate DOX-induced cognitive impairment by regulating inflammatory responses and reducing oxidative stress and neural degeneration. These findings also presented the role of KXS in improving the quality of life and prolonging survival time in breast cancer mice that received chemotherapy.
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The weight-loaded swimming capability, tumor growth, survival time and biochemical markers of Ganoderma lucidum polysaccharides (GLPs) in a chemotherapy-related fatigue mouse model were tested in the present study. The results showed that the middle-dose GLPs (GLP-M) and the high-dose GLPs (GLP-H) could increase the exhausting swimming time, which was observed to decrease in the cisplatin control group(PCG) and the tumor control group (TCG).The GLP-M and the GLP-H had reduced serum levels of tumor necrosis factor-αand interleukin-6, which were up-regulated by cisplatin. Cisplatin and the presence of tumor significantly enhanced the malondialdehyde (MDA) content and inhibited the activity of superoxide dismutase (SOD) in the muscle. Administration of GLPs at a high dose decreased the levels of MDA and up-regulated the SOD activity. The high-dose GLPs+cisplatin group presented a decreased tendency of tumor volume and a lower tumor weight compared with PCG. Moreover, the mice in the GLP-M and GLP-H groups had longer survival times compared with the mice in the TCG and PCG.The levels of creatinine and serum blood urea nitrogen, which are up-regulated by cisplatin, were significantly reduced by GLP-M and GLP-H. Therefore, these results suggest that GLPs might improve chemotherapy-related fatigue via regulation of inflammatory responses, oxidative stress and reduction of nephrotoxicity.
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Tratamento Farmacológico , Fadiga/induzido quimicamente , Fadiga/tratamento farmacológico , Polissacarídeos/uso terapêutico , Reishi/química , Células A549 , Animais , Nitrogênio da Ureia Sanguínea , Cisplatino/efeitos adversos , Creatinina/sangue , Fadiga/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Superóxido Dismutase/metabolismo , Análise de Sobrevida , Natação , Fator de Crescimento Transformador alfa/sangue , Carga Tumoral/efeitos dos fármacosRESUMO
The anti-fatigue effects of the Radix Rehmanniae Preparata polysaccharides (RRPP) were studied in mice. The RRPP were orally administered at doses of 50, 100 and 200 mg/kg for 4 weeks and the anti-fatigue activity was evaluated using a weight-loaded swimming test, along with the determination of serum urea nitrogen (SUN), hepatic glycogen and blood lactic acid (BLA) contents. The results showed that there was no significant difference in the body weight of mice in the three RRPP groups compared with the negative control group during initial, intermediate and terminal stages in the experiment (p>0.05). The ratio of exhausting swimming time was obviously increased 31.48% (p<0.05) and 61.51% (p<0.01) in the middle-dose group and the high-dose RRPP group, respectively. The BLA and SUN levels were decreased in middle-dose and high-dose RRPP groups (p<0.01). Hepatic glycogen level was increased in three RRPP treated groups (p<0.01). Therefore, RRPP may be responsible for the pharmacological effect of anti-fatigue of Radix Rehmanniae Preparata. The mechanism was related to the increase of the storage of hepatic glycogen and the decrease of the accumulation of SUN and BLA.