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1.
J Ethnopharmacol ; 329: 118081, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38570148

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Liujunzi formula has been used to treat liver cancer in China for many years, but its underlying mechanism remains unclear. We previously found that decreased expression of miR-122-3p was associated with liver cancer. In this study, we aimed to explore the target of miR-122-3p and the effect of the Liujunzi formula on miR-122-3p and its downstream events in liver cancer. MATERIAL AND METHODS: Bioinformatics pinpointed potential targets of miR-122-3p. The actual target was confirmed by miRNA mimic/inhibitor transfections and a dual-luciferase reporter assay. RNA-seq looked at downstream genes impacted by this target. Flow cytometry checked for changes in T cell apoptosis levels after exposing them to liver cancer cells. Gene expression was measured by RT-qPCR, western blotting, and immunofluorescence staining. RESULTS: Cell experiments found the Liujunzi extract (LJZ) upregulated miR-122-3p and in a dose-dependent manner. Bioinformatics analysis found UBE2I was a potential target of miR-122-3p, which was validated through experiments using miRNA mimics/inhibitors and a dual-luciferase reporter assay. RNA-seq data implicated the NF-κB pathway as being downstream of the miR-122-3p/UBE2I axis, further confirmed by forcing overexpression of UBE2I. Bioinformatic evidence suggested a link between UBE2I and T cell infiltration in liver cancer. Given that the NF-κB pathway drives PD-L1 expression, which can inhibit T cell infiltration, we investigated whether PD-L1 is a downstream effector of miR-122-3p/UBE2I. This was corroborated through mining public databases, UBE2I overexpression studies, and tumor-T cell co-culture assays. In addition, we also confirmed that LJZ downregulates UBE2I and NF-κB/PD-L1 pathways through miR-122-3p. LJZ also suppressed SUMOylation in liver cancer cells and protected PD-1+ T cells from apoptosis induced by co-culture with tumor cells. Strikingly, a miR-122-3p inhibitor abrogated LJZ's effects on UBE2I and PD-L1, and UBE2I overexpression rescued the LJZ-mediated effects on NF-κB and PD-L1. CONCLUSIONS: miR-122-3p targets UBE2I, thereby suppressing the NF-κB signaling cascade and downregulating PD-L1 expression, which potentiates anti-tumor immune responses. LJZ bolsters anti-tumor immunity by modulating the miR-122-3p/UBE2I/NF-κB/PD-L1 axis in liver cancer cells.


Asunto(s)
Medicamentos Herbarios Chinos , Neoplasias Hepáticas , MicroARNs , Enzimas Ubiquitina-Conjugadoras , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Humanos , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Medicamentos Herbarios Chinos/farmacología , Apoptosis/efectos de los fármacos , FN-kappa B/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células Hep G2 , Tolerancia Inmunológica/efectos de los fármacos
2.
J Ethnopharmacol ; 329: 118115, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38580190

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi Decoction (SJZD), a traditional Chinese herbal remedy, is frequently employed in the treatment of various cancers, including colon cancer. Previous research suggests that SJZD plays a pivotal role in modulating the immune system and enhancing immunity against tumors. However, the precise role of SJZD in combating colon cancer and its potential molecular functions in regulating natural killer cells remain elusive. AIMS OF THE STUDY: To elucidate the potential mechanism underlying the anticolon cancer effects of SJZD in synergy with natural killer (NK) cells through both in vivo and in vitro experiments. MATERIALS AND METHODS: In vivo experiments: A subcutaneous tumor mouse model of colon cancer and in vivo NK cell depletion experiments were conducted to observe the anticolon cancer effects of SJZD. Flow cytometry assessed immune cell depletion in mouse spleens, while immunohistochemical (IHC) staining detected the expression of apoptotic genes in tumor tissues. In vitro experiments: The mechanism by which SJZD regulates the sensitization of colon cancer cells to NK cells was investigated using real-time polymerase chain reaction (RT-PCR), western blotting (WB), and co-culture experiments with NK cells. RESULTS: Sijunzi Decoction (SJZD) significantly impeded tumor growth in mice; however, NK cell depletion markedly attenuated the tumor-suppressive effect of SJZD. Immunohistochemical (IHC) results indicated that SJZD increased the expression of P53, death receptor 4 (DR4), and death receptor 5 (DR5) in tumor tissues. In vitro experiments, 24 h SJZD-pretreated colon cancer cells showed a substantial elevation in P53, DR4, and DR5 levels, and the activity of colon cancer cells significantly diminished after co-culture with NK cells. These effects of SJZD were reversed with the addition of the P53 inhibitor pifithrin-α (PFT-α), resulting in reduced inhibition of colon cancer cells by NK cells. CONCLUSION: SJZD enhances the levels of DR4 and DR5 through the modulation of P53 expression, consequently increasing the sensitivity of colon cancer cells to NK cell-mediated killing. These findings provide a theoretical foundation for the clinical application of SJZD in patients with colon cancer. In this study, we first investigated the effect of SJZD on subcutaneous tumor growth in mice with colon cancer using in vivo assays and assessed the impact of NK cells on the anticolon cancer effect of SJZD in vivo through NK cell depletion. In vitro experiments were conducted to explore the potential mechanism of action of SJZD in NK cell-mediated anticolon cancer effects.


Asunto(s)
Neoplasias del Colon , Medicamentos Herbarios Chinos , Células Asesinas Naturales , Proteína p53 Supresora de Tumor , Animales , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Proteína p53 Supresora de Tumor/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ratones , Humanos , Ratones Endogámicos BALB C , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico
3.
Med Oncol ; 41(5): 123, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652404

RESUMEN

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.


Asunto(s)
Apoptosis , Benzoquinonas , Supervivencia Celular , Neoplasias Colorrectales , Maleato de Dizocilpina , Mitocondrias , Receptores de N-Metil-D-Aspartato , Humanos , Benzoquinonas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Células HT29 , Maleato de Dizocilpina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Supervivencia Celular/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos
4.
J Ethnopharmacol ; 330: 118067, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38636574

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Jingfang Baidu Powder (JFBDP) is a classic traditional Chinese medicine prescription. Although Jingfang Baidu powder obtained a general consensus on clinical efficacy in treating pneumonia, there were many Chinese herbal drugs in formula, complex components, and large oral dosage, which brings certain obstacles to clinical application. AIM OF THE STUDY: Therefore, screening of the active fraction that exerts anti-pneumonia helps improve the pharmaceutical preparation, improve the treatment compliance of patients, and further contribute to the clinical application, and the screening of the new active ingredients with anti-pneumonia. The histopathological observation, real-time quantitative PCR, western blotting, and immunofluorescence were applied to evaluate the anti-pneumonia efficacy of active fractions from JFBDP. RESULTS: Three fractions from JFBDP inhibit the gene expression of IL-1ß, IL-10, CCL3, CCL5, and CCL22 in lung tissue infected by Klebsiella at various degrees, and presented a good dose-response relationship. JF50 showed stronger anti-inflammatory effects among three fractions including JF30, JF50, and JF75. Besides, JF50 significantly reduced the protein expression of TLR4 and Myd88 in lung tissue infected with Klebsiella, and it also significantly inhibited p-ERK and p-NF-κB p65. JF50 significantly inhibits the protein expression of Caspase 3, Caspase 8, and Caspase 9 in lung tissue infected with Klebsiella at the dose of 25 mg/kg and 50 mg/kg. CONCLUSION: JF50 improves lung pathological damage in Klebsiella pneumonia mice by inhibiting the TLR4/Myd88/NF-κB-ERK signaling pathway, and inhibiting apoptosis of lung tissue cells. These findings provide a reference for further exploring the active substance basis of Jingfang Baidu Powder in treating bacterial pneumonia.


Asunto(s)
Medicamentos Herbarios Chinos , Infecciones por Klebsiella , Factor 88 de Diferenciación Mieloide , Polvos , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Factor 88 de Diferenciación Mieloide/metabolismo , Ratones , Masculino , Infecciones por Klebsiella/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Klebsiella pneumoniae/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL
5.
Int J Mol Sci ; 25(7)2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38612399

RESUMEN

Osteosarcoma, which has poor prognosis after metastasis, is the most common type of bone cancer in children and adolescents. Therefore, plant-derived bioactive compounds are being actively developed for cancer therapy. Artemisia apiacea Hance ex Walp. is a traditional medicinal plant native to Eastern Asia, including China, Japan, and Korea. Vitexicarpin (Vitex), derived from A. apiacea, has demonstrated analgesic, anti-inflammatory, antitumour, and immunoregulatory properties; however, there are no published studies on Vitex isolated from the aerial parts of A. apiacea. Thus, this study aimed to evaluate the antitumour activity of Vitex against human osteosarcoma cells. In the present study, Vitex (>99% purity) isolated from A. apiacea induced significant cell death in human osteosarcoma MG63 cells in a dose- and time-dependent manner; cell death was mediated by apoptosis, as evidenced by the appearance of cleaved-PARP, cleaved-caspase 3, anti-apoptotic proteins (Survivin and Bcl-2), pro-apoptotic proteins (Bax), and cell cycle-related proteins (Cyclin D1, Cdk4, and Cdk6). Additionally, a human phosphokinase array proteome profiler revealed that Vitex suppressed AKT-dependent downstream kinases. Further, Vitex reduced the phosphorylation of PRAS40, which is associated with autophagy and metastasis, induced autophagosome formation, and suppressed programmed cell death and necroptosis. Furthermore, Vitex induced antimetastatic activity by suppressing the migration and invasion of MMP13, which is the primary protease that degrades type I collagen for tumour-induced osteolysis in bone tissues and preferential metastasis sites. Taken together, our results suggest that Vitex is an attractive target for treating human osteosarcoma.


Asunto(s)
Neoplasias Óseas , Flavonoides , Osteosarcoma , Humanos , Apoptosis , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt
6.
J Ethnopharmacol ; 330: 118223, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38642624

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.


Asunto(s)
Apoptosis , Hemorragia Cerebral , Leonurus , Simulación del Acoplamiento Molecular , Farmacología en Red , Neuronas , Animales , Apoptosis/efectos de los fármacos , Leonurus/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratones , Masculino , Hemorragia Cerebral/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Janus Quinasa 1/metabolismo , Factor de Transcripción STAT1/metabolismo , Modelos Animales de Enfermedad
7.
J Ethnopharmacol ; 330: 118228, 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-38643863

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Prostate cancer (PCa) is the most common malignancy of the male genitourinary system and currently lacks effective treatment. Semen Impatientis, the dried ripe seed of Impatiens balsamina L., is described by the Chinese Pharmacopoeia as a traditional Chinese medicine (TCM) and is used in clinical practice to treat tumors, abdominal masses, etc. In our previous study, the ethyl acetate extracts of Semen Impatientis (EAESI) was demonstrated to be the most effective extract against PCa among various extracts. However, the biological effects of EAESI against PCa in vivo and the specific antitumor mechanisms involved remain unknown. AIM OF THE STUDY: In this study, we aimed to investigate the antitumor effect of EAESI on PCa in vitro and in vivo by performing network pharmacology analysis, transcriptomic analysis, and experiments to explore and verify the underlying mechanisms involved. MATERIALS AND METHODS: The antitumor effect of EAESI on PCa in vitro and in vivo was investigated via CCK-8, EdU, flow cytometry, and wound healing assays and xenograft tumor models. Network pharmacology analysis and transcriptomic analysis were employed to explore the underlying mechanism of EAESI against PCa. Activating transcription factor 3 (ATF3) and androgen receptor (AR) were confirmed to be the targets of EAESI against PCa by RT‒qPCR, western blotting, and rescue assays. In addition, the interaction between ATF3 and AR was assessed by coimmunoprecipitation, immunofluorescence, and nuclear-cytoplasmic separation assays. RESULTS: EAESI decreased cell viability, inhibited cell proliferation and migration, and induced apoptosis in AR+ and AR- PCa cells. Moreover, EAESI suppressed the growth of xenograft tumors in vivo. Network pharmacology analysis revealed that the hub targets of EAESI against PCa included AR, AKT1, TP53, and CCND1. Transcriptomic analysis indicated that activating transcription factor 3 (ATF3) was the most likely critical target of EAESI. EAESI downregulated AR expression and decreased the transcriptional activity of AR through ATF3 in AR+ PCa cells; and EAESI promoted the expression of ATF3 and exerted its antitumor effect via ATF3 in AR+ and AR- PCa cells. CONCLUSIONS: EAESI exerts good antitumor effects on PCa both in vitro and in vivo, and ATF3 and AR are the critical targets through which EAESI exerts antitumor effects on AR+ and AR- PCa cells.


Asunto(s)
Acetatos , Factor de Transcripción Activador 3 , Ratones Desnudos , Farmacología en Red , Neoplasias de la Próstata , Receptores Androgénicos , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Animales , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Factor de Transcripción Activador 3/metabolismo , Factor de Transcripción Activador 3/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Acetatos/química , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Transcriptoma/efectos de los fármacos , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos
8.
Med Oncol ; 41(5): 106, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575697

RESUMEN

Recent advances in nanotechnology have offered novel ways to combat cancer. By utilizing the reducing capabilities of Lactobacillus acidophilus, silver nanoparticles (AgNPs) are synthesized. The anti-cancer properties of AgNPs have been demonstrated in previous studies against several cancer cell lines; it has been hypothesized that these compounds might inhibit AMPK/mTOR signalling and BCL-2 expression. Consequently, the current research used both in vitro and in silico approaches to study whether Lactobacillus acidophilus AgNPs could inhibit cell proliferation autophagy and promote apoptosis in HepG2 cells. The isolated strain was identified as Lactobacillus acidophilus strain RBIM based on 16 s rRNA gene analysis. Based on our research findings, it has been observed that this particular strain can generate increased quantities of AgNPs when subjected to optimal growing conditions. The presence of silanols, carboxylates, phosphonates, and siloxanes on the surface of AgNPs was confirmed using FTIR analysis. AgNPs were configured using UV-visible spectroscopy at 425 nm. In contrast, it was observed that apoptotic cells exhibited orange-coloured bodies due to cellular shrinkage and blebbing initiated by AgNP treatment, compared to non-apoptotic cells. It is worth mentioning that AgNPs exhibited remarkable selectivity in inducing cell death, specifically in HepG2 cells, unlike normal WI-38 cells. The half-maximum inhibitory concentration (IC50) values for HepG2 and WI-38 cells were 4.217 µg/ml and 154.1 µg/ml, respectively. AgNPs induce an upregulation in the synthesis of inflammation-associated cytokines, including (TNF-α and IL-33), within HepG2 cells. AgNPs co-treatment led to higher glutathione levels and activating pro-autophagic genes such as AMPK.Additionally, it resulted in the suppression of mTOR, MMP-9, BCL-2, and α-SMA gene expression. The docking experiments suggest that the binding of AgNPs to the active site of the AMPK enzyme leads to inhibiting its activity. The inhibition of AMPK ultimately results in the suppression of the mechanistic mTOR and triggers apoptosis in HepG2 cells. In conclusion, the results of our study indicate that the utilization of AgNPs may represent a viable strategy for the eradication of liver cancerous cells through the activation of apoptosis and the enhancement of immune system reactions.


Asunto(s)
Neoplasias Hepáticas , Nanopartículas del Metal , Humanos , Plata/farmacología , Plata/química , Proteínas Quinasas Activadas por AMP , Nanopartículas del Metal/química , Metaloproteinasa 9 de la Matriz , Apoptosis , Neoplasias Hepáticas/tratamiento farmacológico , Serina-Treonina Quinasas TOR , Proteínas Proto-Oncogénicas c-bcl-2 , Extractos Vegetales/química
9.
Aging (Albany NY) ; 16(8): 6937-6953, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38643461

RESUMEN

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.


Asunto(s)
Ácido Ascórbico , Autofagia , Lesiones Cardíacas , Miocardio , Sepsis , Animales , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificación , Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Autofagia/efectos de los fármacos , Lesiones Cardíacas/tratamiento farmacológico , Lesiones Cardíacas/etiología , Lesiones Cardíacas/metabolismo , Miocardio/metabolismo , Miocardio/patología , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo
10.
Transpl Immunol ; 84: 102044, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38663757

RESUMEN

BACKGROUND: Glutamine is crucial for the activation and efficacy of T cells, and may play a role in regulating the immune environment. This study aimed to investigate the potential role of glutamine in the activation and proliferation of induced regulatory T cells (iTregs). METHODS: CD4+CD45RA+T cells were sorted from peripheral blood mononuclear cells and cultured to analyze iTreg differentiation. Glutamine was then added to the culture system to evaluate the effects of glutamine on iTregs by determining oxidative phosphorylation (OXPHOS), apoptosis, and cytokine secretion. Additionally, a humanized murine graft-versus-host disease (GVHD) model was constructed to confirm the efficacy of glutamine-treated iTregs in vivo. RESULTS: After being cultured in vitro, glutamine significantly enhanced the levels of Foxp3, CTLA-4, CD39, CD69, IL-10, TGF-ß, and Ki67 (CTLA-4, IL-10, TGF-ß are immunosuppressive markers of iTregs) compared with that of the control iTregs (P < 0.05). Furthermore, the growth curve showed that the proliferative ability of glutamine-treated iTregs was better than that of the control iTregs (P < 0.01). Compared with the control iTregs, glutamine supplementation significantly increased oxygen consumption rates and ATP production (P < 0.05), significantly downregulated Annexin V and Caspase 3, and upregulated BCL2 (P < 0.05). However, GPNA significantly reversed the effects of glutamine (P < 0.05). Finally, a xeno-GVHD mouse model was successfully established to confirm that glutamine-treated iTregs increased the mice survival rate, delayed weight loss, and alleviated colon injury. CONCLUSION: Glutamine supplementation can improve the activity and immunosuppressive action of iTregs, and the possible mechanisms by which this occurs are related to cell proliferation, apoptosis, and OXPHOS.


Asunto(s)
Glutamina , Enfermedad Injerto contra Huésped , Linfocitos T Reguladores , Glutamina/farmacología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Ratones , Humanos , Células Cultivadas , Enfermedad Injerto contra Huésped/inmunología , Proliferación Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Terapia de Inmunosupresión , Citocinas/metabolismo
11.
Phytomedicine ; 129: 155534, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38583346

RESUMEN

BACKGROUND: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PURPOSE: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. STUDY DESIGN AND METHODS: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. RESULTS: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. CONCLUSION: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.


Asunto(s)
Lesión Pulmonar Aguda , Apoptosis , Subtipo H1N1 del Virus de la Influenza A , Infecciones por Orthomyxoviridae , Sirtuina 1 , Estilbenos , Animales , Estilbenos/farmacología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/virología , Ratones , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sirtuina 1/metabolismo , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Células RAW 264.7 , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Macrófagos/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por AMP/metabolismo , FN-kappa B/metabolismo , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/virología , Pulmón/efectos de los fármacos , Pulmón/virología , Pulmón/patología , Femenino
12.
Phytomedicine ; 129: 155596, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38626646

RESUMEN

BACKGROUND: Traditional Chinese medicine (TCM) is useful in disease treatment and prevention. Genipin is an active TCM compound used to treat diabetic retinopathy (DR). In this study, a network pharmacology (NP)-based approach was employed to investigate the therapeutic mechanisms underlying genipin administration in DR. METHODS: The potential targets of DR were identified using the gene expression omnibus (GEO) database. TCM database screening and NP were used to predict the potential active targets and pathways of genipin in DR. Cell viability was tested in vitro to determine the effects of different doses of glucose and genipin on Human Retinal Microvascular Endothelial Cells (hRMECs). CCK-8, CCK-F, colony formation, CellTiter-Lum, Annexin V-FITC, wound healing, Transwell, tube-forming, reactive oxygen species (ROS), and other assay kits were used to detect the effects of genipin on hRMECs during high levels of glucose. In vivo, a streptozotocin (STZ)-mouse intraocular genipin injection (IOI.) model was used to explore the effects of genipin on diabetes-induced retinal dysfunction. Western blotting was performed to identify the cytokines involved in proliferation, apoptosis, angiogenesis, ROS, and inflammation. The protein expression of the AKT/ PI3K/ HIF-1α and AGEs/ RAGE pathways was also examined. RESULTS: Approximately 14 types of TCM, and nearly 300 active ingredients, including genipin, were identified. The NP approach successfully identified the HIF-1α and AGEs-RAGE pathways, with the EGR1 and UCP2 genes, as key targets of genipin in DR. In the in vitro and in vivo models, we discovered that high glucose increased cell proliferation, apoptosis, angiogenesis, ROS, and inflammation. However, genipin application regulated cell proliferation and apoptosis, inhibited angiogenesis, and reduced ROS and inflammation in the HRMECs exposed to high glucose. Furthermore, the retinal thickness in the genipin-treated group was lower than that in the untreated group. AKT/ PI3K/ HIF-1α and AGEs/ RAGE signaling was increased by high glucose levels; however, genipin treatment decreased AKT/ PI3K and AGEs/ RAGE pathway expressions. Genipin also increased HIF-1α phosphorylation, oxidative phosphorylation of ATP synthesis, lipid peroxidation, and the upregulation of oxidoreductase. Genipin was found to protect HG-induced hRMECs and the retina of STZ-mice, based on; 1 the inhibition of UCP2 and Glut1 decreased intracellular glucose, and glycosylation; 2 the increased presence of HIF-1α, which increased oxidative phosphorylation and decreased substrate phosphorylation; 3 the increase in oxidative phosphorylation from ATP synthesis increased lipid peroxidation and oxidoreductase activity, and; 4 the parallel effect of phosphorylation and glycosylation on vascular endothelial growth factor (VEGF), MMP9, and Scg3. CONCLUSION: Based on NP, we demonstrated the potential targets and pathways of genipin in the treatment of DR and confirmed its effective molecular mechanism in vitro and in vivo. Genipin protects cells and tissues from high glucose levels by regulating phosphorylation and glycosylation. The activation of the HIF-1α pathway can also be used to treat DR. Our study provides new insights into the key genes and pathways associated with the prognosis and pathogenesis of DR.


Asunto(s)
Diabetes Mellitus Experimental , Retinopatía Diabética , Células Endoteliales , Productos Finales de Glicación Avanzada , Subunidad alfa del Factor 1 Inducible por Hipoxia , Iridoides , Ratones Endogámicos C57BL , Transducción de Señal , Retinopatía Diabética/tratamiento farmacológico , Animales , Iridoides/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratones , Células Endoteliales/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Retina/efectos de los fármacos , Apoptosis/efectos de los fármacos , Glucosa/metabolismo
13.
Phytomedicine ; 129: 155633, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38640859

RESUMEN

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Cardiotoxicidad , Cirsium , Doxorrubicina , Ratones Endogámicos C57BL , Miocitos Cardíacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Extractos Vegetales , Superóxido Dismutasa , Animales , Humanos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Extractos Vegetales/farmacología , Ratas , Miocitos Cardíacos/efectos de los fármacos , Cirsium/química , Cardiotoxicidad/tratamiento farmacológico , Superóxido Dismutasa/metabolismo , Ratones , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Masculino , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
14.
Phytomedicine ; 129: 155652, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38663118

RESUMEN

BACKGROUND: Autoimmune hepatitis (AIH) is a prevalent liver disease that can potentially lead to hepatic fibrosis and cirrhosis. The prolonged administration of immunosuppressive medications carries significant risks for patients. Purple sweet potato polysaccharide (PSPP), a macromolecule stored in root tubers, exhibits anti-inflammatory, antioxidant, immune-enhancing, and intestinal flora-regulating properties. Nevertheless, investigation into the role and potential mechanisms of PSPP in AIH remains notably scarce. PURPOSE: Our aim was to explore the possible protective impacts of PSPP against concanavalin A (Con A)-induced liver injury in mice. METHODS: Polysaccharide was isolated from purple sweet potato tubers using water extraction and alcohol precipitation, followed by purification through DEAE-52 cellulose column chromatography and Sephadex G-100 column chromatography. A highly purified component was obtained, and its monosaccharide composition was characterized by high performance liquid chromatography (HPLC). Mouse and cellular models induced by Con A were set up to investigate the impacts of PSPP on hepatic histopathology, apoptosis, as well as inflammation- and oxidative stress-related proteins in response to PSPP treatment. RESULTS: The administration of PSPP significantly reduced hepatic pathological damage, suppressed elevation of ALT and AST levels, and attenuated hepatic apoptosis in Con A-exposed mice. PSPP was found to mitigate Con A-induced inflammation by suppressing the TLR4-P2X7R/NLRP3 signaling pathway in mice. Furthermore, PSPP alleviated Con A-induced oxidative stress by activating the PI3K/AKT/mTOR signaling pathway in mice. Additionally, PSPP demonstrated the ability to reduce inflammation and oxidative stress in RAW264.7 cells induced by Con A in vitro. CONCLUSION: PSPP has the potential to ameliorate hepatic inflammation via the TLR4-P2X7R/NLRP3 pathway and inhibit hepatic oxidative stress through the PI3K/AKT/mTOR pathway during the progression of Con A-induced hepatic injury. The results of this study have unveiled the potential hepatoprotective properties of purple sweet potato and its medicinal value for humans. Moreover, this study serves as a valuable reference, highlighting the potential of PSPP-1 as a drug candidate for the treatment of immune liver injury.


Asunto(s)
Concanavalina A , Ipomoea batatas , Estrés Oxidativo , Polisacáridos , Animales , Estrés Oxidativo/efectos de los fármacos , Ipomoea batatas/química , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Masculino , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hígado/efectos de los fármacos , Células RAW 264.7 , Hepatitis Autoinmune/tratamiento farmacológico , Receptor Toll-Like 4/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Antiinflamatorios/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Antioxidantes/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Tubérculos de la Planta/química , Proteínas Proto-Oncogénicas c-akt/metabolismo
15.
Fitoterapia ; 175: 105945, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38575091

RESUMEN

Four previously undescribed isoprenoid flavonoids (2-5) were isolated from Sophora davidii, along with five known analogues. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR, and absolute configurations determined by theoretical calculations, including ECD and NMR calculation. The cytotoxic effects of the isolated compounds on human HT29 colon cancer cells were evaluated using the MTT assay, compound 1 exhibited cytotoxicity against human HT29 colon cancer cells with an IC50 value of 8.39 ± 0.09 µM. Studies conducted with compound 1 in HT29 cells demonstrated that it may induce apoptosis and autophagy in HT29 by promoting the phosphorylation of P38 MAPK and inhibiting the phosphorylation of Erk MAPK.


Asunto(s)
Antineoplásicos Fitogénicos , Apoptosis , Autofagia , Flavonoides , Sophora , Humanos , Sophora/química , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células HT29 , Estructura Molecular , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , China , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Terpenos/farmacología , Terpenos/aislamiento & purificación , Fosforilación
16.
Fitoterapia ; 175: 105931, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38608733

RESUMEN

Pararorine A, a new isoindolinone alkaloid was isolated from Paramyrothecium roridum, an endophytic fungus from the medicinal plant Gynochthodes officinalis (F.C. How) Razafim. & B. Bremer. The structure of this compound was elucidated by extensive spectroscopic (UV, IR, MS, and NMR) analyses. In addition, the antitumor activity of pararorine A was evaluated against SF-268, MCF-7, HepG2, and A549 tumor cell lines. The results revealed that pararorine A exhibited potent antitumor activities with the IC50 values ranging from 1.69 to 8.95 µM. Moreover, the tumor cell inhibitory activity of pararorine A was evidenced by promoting cytochrome C release and cell cycle arrest as well as the induction of apoptosis by the up-regulation of the protein expressions of JNK and Bax through PARP-cleavage and caspase 3-cleavage.


Asunto(s)
Apoptosis , Humanos , Estructura Molecular , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Endófitos/química , Alcaloides/farmacología , Alcaloides/aislamiento & purificación , Alcaloides/química , Antineoplásicos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , China
17.
Fitoterapia ; 175: 105960, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38621426

RESUMEN

Five undescribed eremophilane-type sesquiterpenes, remophilanetriols E-I (1-5), along with seven known compounds (6-12) were isolated from the fresh roots of Rehmannia glutinosa. Their structures were characterized by extensive spectroscopic data analysis and their absolute configurations were determined by comparing their calculated electronic circular dichroism (ECD) spectra and experimental ECD spectra. The anti-pulmonary fibrosis activities of all compounds were evaluated in vitro by MTT methods, and compounds 2, 8, 10, and 12 exhibited excellent anti-pulmonary fibrosis activities. In addition, compound 2 can reduce the levels of ROS and apoptosis in TGF-ß1-induced BEAS-2B cells.


Asunto(s)
Fitoquímicos , Raíces de Plantas , Rehmannia , Raíces de Plantas/química , Estructura Molecular , Rehmannia/química , Humanos , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/química , Apoptosis/efectos de los fármacos , Línea Celular , Especies Reactivas de Oxígeno/metabolismo , China , Sesquiterpenos Policíclicos/farmacología , Sesquiterpenos Policíclicos/aislamiento & purificación , Sesquiterpenos Policíclicos/química
18.
Fitoterapia ; 175: 105966, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38631600

RESUMEN

Ficus altissima, also known as lofty fig, is a monoecious plant from the Moraceae family commonly found in southern China. In this study, we isolated and identified one new isoflavone (1), three new hydroxycoumaronochromones (2a, 2b and 3a) and 12 known compounds from the fruits of F. altissima. Their chemical structures were determined using spectroscopic analysis methods. We also tested all the isolated compounds for their anti-proliferative activities against eight human tumour cell lines (A-549, AGS, K562, K562/ADR, HepG2, HeLa, SPC-A-1 and CNE2) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Our experiments showed that compound 6 exhibited obvious anti-proliferative activity against the K562 cell line with an IC50 value of 1.55 µM. Additionally, compounds 8 and 9 showed significant anti-proliferative activities against the AGS and K562 cell lines, respectively. Moreover, compound 6 induced apoptosis in K562 cells through the caspase family signalling pathway.


Asunto(s)
Antineoplásicos Fitogénicos , Apoptosis , Ficus , Frutas , Isoflavonas , Humanos , Ficus/química , Frutas/química , Isoflavonas/farmacología , Isoflavonas/aislamiento & purificación , Estructura Molecular , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , China , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Células K562
19.
J Ethnopharmacol ; 329: 118127, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38583728

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Shugan Xiaozhi (SGXZ) decoction is a traditional Chinese medicine used for treating nonalcoholic steatohepatitis (NASH). It has been used clinically for over 20 years and proved to be effective; however, the molecular mechanism underlying the effects of SGXZ decoction remains unclear. AIM OF THE STUDY: We analyzed the chemical components, core targets, and molecular mechanisms of SGXZ decoction to improve NASH through network pharmacology and in vivo experiments. MATERIALS AND METHODS: The chemical components, core targets, and related signaling pathways of SGXZ decoction intervention in NASH were predicted using network pharmacology. Molecular docking was performed to verify chemical components and their core targets. The results were validated in the NASH model treated with SGXZ decoction. Mouse liver function was assessed by measuring ALT and AST levels. TC and TG levels were determined to evaluate lipid metabolism, and lipid deposition was assessed via oil red O staining. Mouse liver damage was determined via microscopy following hematoxylin and eosin staining. Liver fibrosis was assessed via Masson staining. Western blot (WB) and immunohistochemical (IHC) analyses were performed to detect inflammation and the expression of apoptosis-related proteins, including IL-1ß, IL-6, IL-18, TNF-α, MCP1, p53, FAS, Caspase-8, Caspase-3, Caspase-9, Bax, Bid, Cytochrome c, Bcl-2, and Bcl-XL. In addition, WB and IHC were used to assess protein expression associated with the TLR4/MyD88/NF-κB pathway. RESULTS: Quercetin, luteolin, kaempferol, naringenin, and nobiletin in SGXZ decoction were effective chemical components in improving NASH, and TNF-α, IL-6, and IL-1ß were the major core targets. Molecular docking indicated that these chemical components and major core targets might interact. KEGG pathway analysis showed that the pathways affected by SGXZ decoction, primarily including apoptosis and TLR4/NF-κB signaling pathways, interfere with NASH. In vivo experiments indicated that SGXZ decoction considerably ameliorated liver damage, fibrosis, and lipid metabolism disorder in MCD-induced NASH mouse models. In addition, WB and IHC verified the underlying molecular mechanisms of SGXZ decoction as predicted via network pharmacology. SGXZ decoction inhibited the activation of apoptosis-related pathways in MCD-induced NASH mice. Moreover, SGXZ decoction suppressed the activation of TLR4/MyD88/NF-κB pathway in MCD-induced NASH mice. CONCLUSION: SGXZ decoction can treat NASH through multiple targets and pathways. These findings provide new insights into the effective treatment of NASH using SGXZ decoction.


Asunto(s)
Apoptosis , Medicamentos Herbarios Chinos , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Enfermedad del Hígado Graso no Alcohólico , Transducción de Señal , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Ratones , Transducción de Señal/efectos de los fármacos , Deficiencia de Colina/complicaciones , Inflamación/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Modelos Animales de Enfermedad , Farmacología en Red , Antiinflamatorios/farmacología , Metabolismo de los Lípidos/efectos de los fármacos
20.
J Ethnopharmacol ; 329: 118107, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38599475

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall. (PLP), a traditional Chinese medicine, is recognized for its antioxidative and anti-apoptotic properties. Despite its potential medicinal value, the mechanisms underlying its efficacy have been less explored, particularly in alleviating acute liver injury (ALI) caused by excessive intake of acetaminophen (APAP). AIM OF THE STUDY: This study aims to elucidate the role and mechanisms of PLP in mitigating oxidative stress and apoptosis induced by APAP. MATERIALS AND METHODS: C57BL/6 male mice were pre-treated with PLP for seven consecutive days, followed by the induction of ALI using APAP. Liver pathology was assessed using HE staining. Serum indicators, immunofluorescence (IF), immunohistochemical (IHC), and transmission electron microscopy were employed to evaluate levels of oxidative stress, ferroptosis and apoptosis. Differential expression proteins (DEPs) in the APAP-treated and PLP pre-treated groups were analyzed using quantitative proteomics. Subsequently, the potential mechanisms of PLP pre-treatment in treating ALI were validated using western blotting, molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) analysis. RESULTS: The UHPLC assay confirmed the presence of three compounds, i.e., albiflorin, paeoniflorin, and oxypaeoniflorin. Pre-treatment with PLP was observed to ameliorate liver tissue pathological damage through HE staining. Further confirmation of efficacy of PLP in alleviating APAP-induced liver injury and oxidative stress was established through liver function serum biochemical indicators, IF of reactive oxygen species (ROS) and IHC of glutathione peroxidase 4 (GPX4) detection. However, PLP did not demonstrate a significant effect in alleviating APAP-induced ferroptosis. Additionally, transmission electron microscopy and TUNEL staining indicated that PLP can mitigate hepatocyte apoptosis. PKC-ERK pathway was identified by proteomics, and subsequent molecular docking, molecular dynamics simulations, and SPR verified binding of the major components of PLP to ERK protein. Western blotting demonstrated that PLP suppressed protein kinase C (PKC) phosphorylation, blocking extracellular signal-regulated kinase (ERK) phosphorylation and inhibiting oxidative stress and cell apoptosis. CONCLUSION: This study demonstrates that PLP possesses hepatoprotective abilities against APAP-induced ALI, primarily by inhibiting the PKC-ERK cascade to suppress oxidative stress and cell apoptosis.


Asunto(s)
Acetaminofén , Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Ratones Endogámicos C57BL , Estrés Oxidativo , Paeonia , Animales , Acetaminofén/toxicidad , Paeonia/química , Estrés Oxidativo/efectos de los fármacos , Masculino , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ratones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Simulación del Acoplamiento Molecular , Antioxidantes/farmacología
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