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1.
J Orthop Surg Res ; 19(1): 198, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528538

RESUMO

PURPOSE: This study aimed to evaluate the protective effects of gentiopicroside against lipopolysaccharide-induced chondrocyte inflammation. METHODS: SW 1353 chondrosarcoma cells were stimulated with LPS (5 µg/ml) for 24 h and treated with different concentrations of gentiopicroside (GPS) for 24 h. The toxic effects of GPS on chondrocytes were determined using a CCK-8 assay and EdU staining. Western blotting, qPCR, and immunofluorescence analysis were used to examine the protective effect of GPS against the inflammatory response in chondrocytes induced by lipopolysaccharide (LPS). One-way ANOVA was used to compare the differences between the groups (significance level of 0.05). RESULTS: The CCK-8 results showed that 10, 20 and 40 µM GPS had no significant toxic effects on chondrocytes; GPS effectively reduced the production of IL-1ß and PGE2, reversed LPS-induced extracellular matrix degradation in cartilage by inhibiting the Stat3/Runx2 signaling pathway, and suppressed the hypertrophic transformation of SW 1353 chondrosarcoma cells. CONCLUSION: Our study demonstrated that GPS significantly inhibited the LPS-induced inflammatory response and hypertrophic cellular degeneration in SW 1353 chondrosarcoma cells and is a valuable traditional Chinese medicine for the treatment of knee osteoarthritis.


Assuntos
Condrossarcoma , Glucosídeos Iridoides , Osteoartrite , Humanos , Condrócitos/metabolismo , Lipopolissacarídeos/toxicidade , Osteoartrite/metabolismo , Sincalida/metabolismo , Sincalida/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Hipertrofia , Condrossarcoma/tratamento farmacológico , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo
2.
J Exp Clin Cancer Res ; 43(1): 62, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38419081

RESUMO

BACKGROUND: In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold­inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). METHODS: CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. RESULTS: Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)­like population. Moreover, hyperthermia substantially improved the sensitivity of radiation­resistant NPC cells and CSC­like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti­tumor­killing activity of hyperthermia against NPC cells and CSC­like cells, whereas ectopic expression of Cirbp compromised tumor­killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC­like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. CONCLUSION: Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.


Assuntos
Diterpenos do Tipo Caurano , Hipertermia Induzida , MicroRNAs , Neoplasias Nasofaríngeas , Animais , Humanos , Neoplasias Nasofaríngeas/patologia , Sincalida/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patologia , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica
3.
J Ethnopharmacol ; 322: 117577, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38104877

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Biejia Jianwan (M-BJJW), a Traditional Chinese Medicine (TCM) decoction, has exhibited great potential in treating hepatocellular carcinoma (HCC). However, its underlying functional mechanism still remains unknown. AIM OF THE STUDY: The study aimed to explore the anti-hepatocarcinogenic effects of M-BJJW, specifically its influence on PD-L1-mediated immune evasion in hypoxic conditions, and elucidate the related molecular mechanisms in HCC. MATERIALS AND METHODS: To investigate the therapeutic efficacy and mechanisms underlying M-BJJW's effects on HCC, we employed a diethylnitrosamine (DEN)-induced rat model maintained for 120 days. Following model establishment, flow cytometry was utilized to assess the distribution of immune cell populations in peripheral blood, spleens, and tumor tissues after M-BJJW administration. Simultaneously, enzyme-linked immunosorbent assays (ELISA) were conducted to analyze cytokine profiles in serum samples. Immunohistochemistry was employed to determine the expression levels of crucial proteins within tumor tissues. Furthermore, HCC cells exposed to CoCl2 underwent Western blot analysis to validate the expression levels of HIF-1α, PD-L1, STAT3, and nuclear factor kappa B (NF-κB) p65. The modulatory effects of STAT3 and NF-κB p65 were investigated using specific inhibitors and activators in wild-type cell lines. High-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) was utilized to identify the chemical constituents present in M-BJJW-medicated serum. The immunomodulatory properties and the anti-tumor activities of M-BJJW were evaluated by co-culturing with peripheral blood mononuclear cells (PBMC) and the CCK-8 assay. Additionally, we assessed M-BJJW's impact on hypoxia-induced alterations in HCC cell lines using immunofluorescence and Western blot assessments. RESULTS: M-BJJW exhibited substantial therapeutic advantages by effectively alleviating pathological deterioration within the HCC microenvironment. In the DEN-induced rat model, M-BJJW administration notably reduced tumor growth. Flow cytometry analyses revealed an increased proportion of Cytotoxic T lymphocytes (CTLs) accompanied by a simultaneous decrease in regulatory T cells (Tregs). ELISA data supported a marked decrease in pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor α (TNF-α). Immunohistochemistry confirmed the suppressive effect of M-BJJW on the expression of HIF-1α and PD-L1. Notably, western blotting unveiled the role of HIF-1α in regulating PD-L1 expression via the STAT3 and NF-κB signaling pathways in HCC cell lines, which was validated using activators and inhibitors of STAT3 and NF-κB. The CCK-8 assay and co-culture techniques demonstrated the anti-tumor activity of M-BJJW. Immunofluorescence and western blotting further confirmed that M-BJJW-containing serum dose-dependently inhibited HIF-1α, PD-L1, p-STAT3, and p-p65 in hypoxic HCC cell lines. CONCLUSIONS: M-BJJW demonstrates significant therapeutic potential against HCC by influencing the hypoxic microenvironment, thereby regulating the immunosuppressive milieu. Specifically, M-BJJW modulates the HIF-1α/STAT3/NF-κB signaling pathway, leading to reduced PD-L1 expression and an elevated ratio of cytotoxic T lymphocytes (CTLs), while concurrently decreasing T regulatory cells (Tregs) and immunosuppressive factors. These synergistic effects aid in countering PD-L1-mediated immune evasion, presenting compelling pharmacological evidence supporting the clinical application of M-BJJW as a therapeutic approach for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratos , Animais , NF-kappa B/metabolismo , Carcinoma Hepatocelular/metabolismo , Leucócitos Mononucleares/metabolismo , Neoplasias Hepáticas/patologia , Antígeno B7-H1/metabolismo , Evasão da Resposta Imune , Sincalida/farmacologia , Transdução de Sinais , Microambiente Tumoral
4.
Zhongguo Zhong Yao Za Zhi ; 48(17): 4702-4710, 2023 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-37802809

RESUMO

This study aimed to investigate the effect and molecular mechanism of sinomenine on proliferation, apoptosis, metastasis, and combination with inhibitors in human hepatocellular carcinoma HepG2 cells and SK-HEP-1 cells. The effect of sinomenine on the growth ability of HepG2 and SK-HEP-1 cells were investigated by CCK-8 assay, colony formation assay, and BeyoClick~(TM) EdU-488 staining. The effect of sinomenine on DNA damage was detected by immunofluorescence assay, and the effect of sinomenine on apoptosis of human hepatocellular carcinoma cells was clarified by Hoechst 33258 staining and CellEvent~(TM) Cystein-3/7Green ReadyProbes~(TM) reagent assay. Cell invasion assay and 3D tumor cell spheroid invasion assay were performed to investigate the effect of sinomenine on the invasion ability of human hepatocellular carcinoma cells in vitro. The effect of sinomenine on the regulation of protein expression related to the protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/signal transducer and activator of transcription 3(STAT3) signaling pathway in HepG2 and SK-HEP-1 cells was examined by Western blot. Molecular docking was used to evaluate the strength of affinity of sinomenine to the target cysteinyl aspartate specific proteinase-3(caspase-3) and STAT3, and combined with CCK-8 assay to detect the changes in cell viability after combination with STAT3 inhibitor JSI-124 in combination with CCK-8 assay. The results showed that sinomenine could significantly reduce the cell viability of human hepatocellular carcinoma cells in a concentration-and time-dependent manner, significantly inhibit the clonogenic ability of human hepatocellular carcinoma cells, and weaken the invasive ability of human hepatocellular carcinoma cells in vitro. In addition, sinomenine could up-regulate the cleaved level of poly ADP-ribose polymerase(PARP), a marker of apoptosis, and down-regulate the protein levels of p-Akt, p-mTOR, and p-STAT3 in human hepatocellular carcinoma cells. Molecular docking results showed that sinomenine had good affinity with the targets caspase-3 and STAT3, and the sensitivity of sinomenine to hepatocellular carcinoma cells was diminished after STAT3 was inhibited. Therefore, sinomenine can inhibit the proliferation and invasion of human hepatocellular carcinoma cells and induce apoptosis, and the mechanism may be attributed to the activation of caspase-3 signaling and inhibition of the Akt/mTOR/STAT3 pathway. This study can provide a new reference for the in-depth research and clinical application of sinomenine and is of great significance to further promote the scientific development and utilization of sinomenine.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Caspase 3/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Simulação de Acoplamento Molecular , Sincalida/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Células Hep G2 , Serina-Treonina Quinases TOR/metabolismo , Apoptose
5.
J Mol Histol ; 54(6): 645-654, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37740843

RESUMO

Prostate cancer (PC) is the most common malignancy in male reproductive system. Sennoside A (SA) is an anthraquinone active ingredient extracted from Rheum officinale Baill., which exerts anti-tumor activity on different tumors. In the present study, the toxicity of SA on PC3 and DU 145 cells was detected via CCK-8. The effects of SA on growth, apoptosis, and autophagy were determined through CCK-8, Hoechst stain, flow cytometry, western blot, and immunofluorescence examinations. An in vivo experiment was performed in xenografted mice with intraperitoneal introduction of 10 mg/kg SA and validated via TUNEL, immunohistochemistry and western blot. The results showed that SA inhibited the cell viability with a IC50 value of 52.36 and 67.48 µM in DU 145 and PC3 cells respectively, and enhanced the apoptosis of PC3 and DU 145 cells. Additionally, SA elevated the relative LC3B expression, and the relative protein expression of LC3II/LC3I and Beclin-1, but diminished the P62 protein expression. The relative protein level of p-PI3K/PI3K, p-AKT/AKT and p-mTOR/mTOR was reduced with SA treatment, which was verified by the 740 Y-P application. The 740 Y-P treatments also restored the SA-induced the cell viability, apoptosis rate and relative LC3B expression. Meanwhile, SA inhibited the growth of PC cell and the relative protein level of PI3K/AKT/mTOR axis in vivo. Taken together, SA regulated the proliferation, apoptosis and autophagy via inactivating the PI3K/AKT/mTOR axis in PC.


Assuntos
Neoplasias da Próstata , Proteínas Proto-Oncogênicas c-akt , Humanos , Masculino , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fosfatidilinositol 3-Quinases/metabolismo , Senosídeos/farmacologia , Sincalida/farmacologia , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/metabolismo , Apoptose , Autofagia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proliferação de Células
6.
Phytomedicine ; 118: 154924, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37393829

RESUMO

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous carcinoma characterized by the most aggressive phenotype among all breast cancer subtypes. However, therapeutic options for TNBC patients have limited clinical efficacy due to lack of specific target and efficient targeted therapeutics. AIM: To investigate the biological characteristics of a novel estrogen receptor (ER)-α splice variant ER-α30 in breast cancer cells, and its possible role in the anticancer effects of calycosin, a typical phytoestrogen derived from the herbal plant Astragalus membranaceus, against TNBC. This may also provide a better understanding of the inhibitory activity of calycosin on TNBC progression. METHODS: Breast cancer tissues and para-cancer tissues were collected and analyzed for the expression levels of ER-α30 using immunohistochemistry (IHC), and its expression in two TNBC cell lines (MDA-MB-231 and BT-549) was detected by western blot and qRT-PCR assays. Then the alteration of cell viability, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT) in response to overexpression or knockdown of ER-α30 was separately determined by CCK-8, Hoechst 33258, wound healing, transwell and western blot assays in two TNBC cell lines. Next, the anticancer effects of calycosin on MDA-MB-231 cells were evaluated through CCK-8, colony formation, flow cytometry, Hoechst 33258 and western blot assays, along with the role of ER-α30 in these effects and the possible downstream targets of ER-α30. In addition, the in vivo experiments were carried out using MDA-MB-231 xenograft model intraperitoneally treated with calycosin. The volume and weight of xenograft tumor were measured to evaluate the in vivo anticancer activities of calycosin, while the corresponding changes of ER-α30 expression in tumor tissues were detected by IHC. RESULTS: It was demonstrated that the novel ER-α splice variant ER-α30 was primarily distributed in the nucleus of TNBC cells. Compared with normal breast tissues, ER-α30 expression was found in significantly higher levels in breast cancer tissues of ER- and progesterone receptor (PR)-negative subtype, so did in TNBC cell lines (MDA-MB-231 and BT-549) when compared to normal breast cell line MCF10A. Moreover, ER-α30 overexpression strikingly enhanced cell viability, migration, invasion and EMT progression and reduced apoptosis in TNBC cells, whereas shRNA-mediated knockdown of ER-α30 revealed the opposite results. Notably, calycosin suppressed the expression of ER-α30 in a dose-dependent manner, accompanied with the inhibition of TNBC growth and metastasis. A similar finding was observed for the xenografts generated from MDA-MB-231 cells. The treatment with calycosin suppressed the tumor growth and decreased ER-α30 expression in tumor tissues. Furthermore, this inhibition by calycosin was more pronounced in ER-α30 knockdown cells. Meanwhile, we found a positive relationship between ER-α30 and the activity of PI3K and AKT, which could also be inactivated by calycosin treatment. CONCLUSION: For the first time, it is demonstrated that the novel estrogen receptor-α splice variant ER-α30 could function as pro-tumorigenic factor in the context of TNBC by participating in cell proliferation, apoptosis, invasion and metastasis, thus it may serve as a potential therapeutic target for TNBC therapy. Calycosin could reduce the activation of ER-α30-mediated PI3K/AKT pathway, thereby inhibited TNBC development and progression, suggesting that calycosin may be a potential therapeutic option for TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regulação para Baixo , Bisbenzimidazol/farmacologia , Sincalida/genética , Sincalida/metabolismo , Sincalida/farmacologia , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de Células , Movimento Celular
7.
J Ethnopharmacol ; 312: 116454, 2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37059246

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Polyrhachis vicina Roger (P. vicina), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis, hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia. Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. AIM OF THE STUDY: The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. METHODS: To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology, molecular docking, qRT-PCR, western blotting, CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. RESULTS: Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. CONCLUSION: According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC.


Assuntos
Neoplasias Colorretais , Necroptose , Animais , Simulação de Acoplamento Molecular , Sincalida , Neoplasias Colorretais/tratamento farmacológico , Carcinogênese
8.
J Ethnopharmacol ; 304: 116028, 2023 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-36529250

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Koumine, an indole alkaloid extracted from Gelsemium elegans Benth, exerts anti-inflammation and antioxidant activities. However, the effects of koumine on intestinal injury induced by H2O2 and its potential molecular mechanisms need larger studies. AIM OF THE STUDY: We established an IPEC-J2 cell damage model induced by H2O2 to explore the protective mechanism of koumine on intestinal injury. MATERIALS AND METHODS: In the experiment, cell damage models were made with hydrogen peroxide. To assess the protective effect of koumine on H2O2-induced IPEC-J2 cell injury, CCK-8, the release of LDH and ROS, transmission electron microscopy and Annexin V-FITC/PI were employed. Western Blot and Quantitative Real-time PCR were used to determine the potential alleviated mechanism of koumine on H2O2-trigged IPEC-J2 cell damage. RESULTS: The results of CCK-8 and LDH implied that koumine has a mitigative effect on H2O2-induced cell damage via upregulating cell viability and suppressing cell membrane fragmentation. Simultaneously, koumine notably inhibited the level of pro-inflammatory factors (IL-1ß, IL-6, IL-8, TNF-α and TGF-ß), the over-production of ROS along with decreasing the injury of mitochondrion, endoplasmic reticulum and lysosome induced by H2O2. Moreover, koumine dramatically attenuated H2O2-triggered IPEC-J2 cell apoptosis and autophagy. Subsequently, Western blot analysis identified NF-ΚB, PI3K and ERS as possible pathway responsible for the protective effect of koumine on H2O2-stimulated IPEC-J2 cell inflammation. CONCLUSIONS: This in vitro experimental study suggests that koumine suppresses the H2O2-induced activation of inflammatory pathways, oxidative injury, ER stress, apoptosis and autophagy, which provide a rationale for therapeutically use in major intestinal diseases.


Assuntos
Peróxido de Hidrogênio , NF-kappa B , NF-kappa B/metabolismo , Peróxido de Hidrogênio/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases , Sincalida/farmacologia , Linhagem Celular , Alcaloides Indólicos/farmacologia , Serina-Treonina Quinases TOR , Apoptose
9.
Life Sci ; 308: 120931, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36084760

RESUMO

AIMS: Recently, the European Association of Urology recommended hexane-extracted fruit of Serenoa repens (HESr) in their guidelines on management of non-neurogenic male lower urinary tracts symptoms (LUTS). Despite previously lacking recommendations, Permixon® is the most investigated HESr in clinical trials, where it proved effective for male LUTS. In contrast, underlying mechanisms were rarely addressed and are only marginally understood. We therefore investigated effects of Permixon® on human prostate and detrusor smooth muscle contraction and on growth-related functions in prostate stromal cells. MAIN METHODS: Permixon® capsules were dissolved using n-hexane. Contractions of human prostate and detrusor tissues were induced in organ bath. Proliferation (EdU assay), growth (colony formation), apoptosis and cell death (flow cytometry), viability (CCK-8) and actin organization (phalloidin staining) were studied in cultured human prostate stromal cells (WPMY-1). KEY FINDINGS: Permixon® inhibited α1-adrenergic and thromboxane-induced contractions in prostate tissues, and methacholine-and thromboxane-induced contractions in detrusor tissues. Endothelin-1-induced contractions were not inhibited. Neurogenic contractions were inhibited in both tissues in a concentration-dependent manner. In WPMY-1 cells, Permixon® caused concentration-dependent breakdown of actin polymerization, inhibited colony formation, reduced cell viability, and proliferation, without showing cytotoxic or pro-apoptotic effects. SIGNIFICANCE: Our results provide a novel basis that allows, for the first time, to fully explain the ubiquitous beneficial effects of HESr in clinical trials. HESr may inhibit at least neurogenic, α1-adrenergic and thromboxane-induced smooth muscle contraction in the prostate and detrusor, and in parallel, prostate stromal cell growth. Together, this may explain symptom improvements by Permixon® in previous clinical trials.


Assuntos
Hiperplasia Prostática , Serenoa , Actinas/metabolismo , Adrenérgicos/farmacologia , Endotelina-1/metabolismo , Hexanos/metabolismo , Hexanos/farmacologia , Hexanos/uso terapêutico , Humanos , Masculino , Cloreto de Metacolina/metabolismo , Contração Muscular , Músculo Liso , Faloidina/metabolismo , Faloidina/farmacologia , Faloidina/uso terapêutico , Extratos Vegetais/uso terapêutico , Próstata/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Sincalida/metabolismo , Células Estromais/metabolismo , Tromboxanos/metabolismo , Bexiga Urinária/metabolismo
10.
Toxins (Basel) ; 14(9)2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36136571

RESUMO

Pyrrolizidine alkaloids (PAs) are common constituents of plants and have serious hepatotoxicity. Intermedine (Im) and lycopsamine (La) are two monoesters of PAs that frequently coexist in the PA-containing plants (e.g., comfrey and tea). The present study aimed to explore the combined hepatotoxicity and toxicity mechanism of the Im and La mixture. In vitro, the combined cytotoxicity of the Im and La mixture on human hepatocytes (HepD) was examined by CCK-8, colony formation, wound healing, and Annexin V/PI staining assays. The combination of Im and La inhibited the ability of HepD cells to proliferate, colonize, and migrate and induced hepatocytes apoptosis in a dose-dependent manner. In addition to significantly causing a burst of intracellular reactive oxygen species (ROS), mitochondrial apoptosis, and endoplasmic reticulum (ER) stress, the Im and La mixture can also cause an increase in intracellular Ca2+, triggering the PERK/eIF2α/ATF4/CHOP apoptosis pathway. This study provided the first direct evidence that the combined PAs induced hepatotoxicity through ER-mediated apoptosis. These results supplemented the basic toxicity data for the combined PAs and provided a new perspective for the risk assessment of combined PA toxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Alcaloides de Pirrolizidina , Anexina A5 , Apoptose , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Estresse do Retículo Endoplasmático , Humanos , Alcaloides de Pirrolizidina/análise , Alcaloides de Pirrolizidina/toxicidade , Espécies Reativas de Oxigênio , Sincalida , Chá
11.
Elife ; 112022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36111780

RESUMO

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically carry a dismal prognosis. Given the insensitivity of these tumors to traditional chemotherapy and the absence of effective targeted drugs, new therapeutic strategies are urgently needed. Photothermal therapy (PTT) including near-infrared laser at the third biowindow (NIR-III) has demonstrated significant potential in cancer theranostics due to its minimally invasive nature and excellent therapeutic outcomes. However, the passive utilization of photothermal agents (PTAs) with poor target specificity and biocompatibility substantially hinders the clinical translation and application of this method. Methods: We evaluated the efficiency, safety, and underlying mechanisms of NIR-III without PTAs in the treatment of MPNSTs. The photothermal performance and tissue penetration capability of the NIR-III laser were evaluated in human MPNST cell lines using CCK-8, Calcein-AM and propidium iodide (PI) staining, and Annexin V-FITC/PI assays. The tumor xenografted mice model was used for evaluating the efficacy and biosafety of NIR-III photothermal ablation. Finally, the underlying mechanisms of NIR-III treatment, explored by whole-transcriptome sequencing, are further verified by RT-qPCR. Results: We found that although the NIR-III photothermal treatment efficiency varied among individuals, which was possibly influenced by different endoplasmic reticulum stress responses, the expected antineoplastic effect was ultimately achieved after adjustment of the power density and radiation duration. Conclusions: The present study provides an intriguing noninvasive therapy for MPNSTs that accelerates the clinical translation of PTT while avoiding the biocompatibility issues arising from PTAs. Funding: This work was supported by grants from National Natural Science Foundation of China (82102344; 82172228); Shanghai Rising Star Program supported by Science and Technology Commission of Shanghai Municipality (20QA1405600); Natural Science Foundation of Shanghai (22ZR1422300); Science and Technology Commission of Shanghai Municipality (19JC1413) ; "Chenguang Program" supported by Shanghai Education Development Foundation (SHEDF) (19CG18); Shanghai Municipal Key Clinical Specialty (shslczdzk00901); Innovative research team of high-level local universities in Shanghai (SSMU-ZDCX20180700).


Assuntos
Antineoplásicos , Hipertermia Induzida , Neoplasias , Neurofibrossarcoma , Animais , Linhagem Celular Tumoral , China , Humanos , Hipertermia Induzida/métodos , Camundongos , Neoplasias/terapia , Neurofibrossarcoma/terapia , Fototerapia/métodos , Propídio , Sincalida
12.
Sci Rep ; 12(1): 9215, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35654807

RESUMO

The cholecystokinin-2 receptor (CCK2R) is a G protein-coupled receptor (GPCR) that is expressed in peripheral tissues and the central nervous system and constitutes a promising target for drug development in several diseases, such as gastrointestinal cancer. The search for ligands of this receptor over the past years mainly resulted in the discovery of a set of distinct synthetic small molecule chemicals. Here, we carried out a pharmacological screening of cyclotide-containing plant extracts using HEK293 cells transiently-expressing mouse CCK2R, and inositol phosphate (IP1) production as a readout. Our data demonstrated that cyclotide-enriched plant extracts from Oldenlandia affinis, Viola tricolor and Carapichea ipecacuanha activate the CCK2R as measured by the production of IP1. These findings prompted the isolation of a representative cyclotide, namely caripe 11 from C. ipecacuanha for detailed pharmacological analysis. Caripe 11 is a partial agonist of the CCK2R (Emax = 71%) with a moderate potency of 8.5 µM, in comparison to the endogenous full agonist cholecystokinin-8 (CCK-8; EC50 = 11.5 nM). The partial agonism of caripe 11 is further characterized by an increase on basal activity (at low concentrations) and a dextral-shift of the potency of CCK-8 (at higher concentrations) following its co-incubation with the cyclotide. Therefore, cyclotides such as caripe 11 may be explored in the future for the design and development of cyclotide-based ligands or imaging probes targeting the CCK2R and related peptide GPCRs.


Assuntos
Ciclotídeos , Sequência de Aminoácidos , Animais , Ciclotídeos/química , Células HEK293 , Humanos , Ligantes , Camundongos , Extratos Vegetais , Receptor de Colecistocinina B , Sincalida
13.
Anticancer Agents Med Chem ; 22(18): 3172-3181, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35579132

RESUMO

BACKGROUND AND PURPOSE: Osteosarcoma is the most commonly seen type of primary malignant bone tumors in children and adolescents. Partial patients with osteosarcoma cannot tolerate the side effects of chemotherapy drugs. Hence, it is urgent to find anti-osteosarcoma drugs with low side effects. Melittin is an anti-tumor Traditional Chinese Medicine with low side effects. The purpose of this study was to explore the anti-osteosarcoma effect of melittin and its possible molecular mechanisms. METHODS: The effects of melittin on cell growth were detected by CCK-8, clonal formation, and flow cytometry. The related molecules were also investigated by Real-time PCR and Western blot. A xenograft model in nude mice was established to observe the effects of melittin on tumor growth and the related molecular expression was detected by immunohistochemistry. RESULTS: Melittin can inhibit the proliferation of osteosarcoma 143B cells, reduce colony formation, and induce apoptosis while significantly up-regulating the expression of Bax and Caspase-3 and down-regulating the expression of Bcl-2 proteins. Moreover, treatment with melittin significantly reduced the mRNA and protein levels of ß-catenin and Wnt/ß- catenin related genes (LRP5, c-Myc, and Survivin) in osteosarcoma 143B cells in vitro. The xenograft model found that melittin significantly inhibited tumor growth and decreased the protein expression levels of ß-catenin and Wnt/ß- catenin related genes in vivo. CONCLUSION: These findings show that melittin could inhibit the growth of osteosarcoma 143B cells, which may be related to the inhibition of Wnt/ß-catenin signaling pathway activity and induce apoptosis by up-regulating the ratio of Bax/Bcl-2 in osteosarcoma 143B cells. Therefore, melittin is a promising anti-tumor drug for the treatment of osteosarcoma.


Assuntos
Antineoplásicos , Neoplasias Ósseas , Osteossarcoma , Adolescente , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias Ósseas/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Criança , Humanos , Meliteno/farmacologia , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro , Sincalida/farmacologia , Sincalida/uso terapêutico , Survivina/metabolismo , Via de Sinalização Wnt , Proteína X Associada a bcl-2 , beta Catenina/metabolismo
14.
J Ethnopharmacol ; 295: 115309, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35597410

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Piperine (PIP), a main active component isolated from Piper nigrum L., exerts neuroprotective effects in a rat model of ischemic stroke (IS). However, studies on the effects of PIP on neuroprotection and autophagy after IS are limited. AIM OF THE STUDY: This study aimed to prove the protective effects of PIP against brain IS and elucidate its underlying mechanisms. MATERIALS AND METHODS: Specific pathogen-free male Sprague-Dawley rats were selected to establish a permanent middle cerebral artery occlusion model. The experiment was randomly divided into six groups: sham group, model group, PIP intervention group (10, 20, and 30 mg/kg group), and nimodipine group (Nimo group, 12 mg/kg). Neurological function score, postural reflex score, body swing score, balance beam test, and grip strength test were used to detect behavioral changes of rats. The area of cerebral infarction was detected by TTC staining, and the number and morphological changes of neurons were observed by Nissl and HE staining. In addition, the ultrastructure of hippocampal dentate gyrus neurons was observed using a transmission electron microscope. Western blot was used to detect the expression of PI3K/AKT/mTOR signaling pathway proteins and autophagy-related proteins, namely, Beclin1 and LC3, in the hippocampus and cortex. Cell experiments established an in vitro model of oxygen-glucose deprivation (OGD) with the HT22 cell line to verify the mechanism. The experiment was divided into five groups: control group, OGD group, OGD + PIP 20 µg/mL group, OGD + PIP 30 µg/mL group, and OGD + PIP 40 µg/mL group. CCK-8 was used to measure cell activity, and Western blot was used to measure the expression of PI3K/AKT/mTOR signaling pathway proteins and autophagy-related proteins (Beclin1 and LC3). RESULTS: Compared with the model group, the neurological function scores, body swing scores, and postural reflex scores of rats in the 10, 20, and 30 mg/kg PIP intervention groups and Nimo groups decreased, whereas the balance beam score and grip test scores increased (all p < 0.05). After 10, 20, and 30 mg/kg PIP and Nimo intervention, the cerebral infarction area of pMCAO rats was reduced (p < 0.01), and Nissl and HE staining results showed that the number of neurons survived in the 30 mg/kg PIP and Nimo intervention groups increased. Cell morphology and structure were significantly improved (p < 0.05). Most of the hippocampal dentate gyrus neurons and their organelles gradually returned to normal in the 30 mg/kg PIP and Nimo intervention groups, with less neuronal damage. The expression levels of p-mTOR, p-AKT, and p-PI3K in the hippocampus and cortex of the 30 mg/kg PIP and Nimo intervention groups decreased, whereas the expression level of PI3K increased (all p < 0.05). In addition, the expression level of autophagy-related proteins, namely, Beclin1 and LC3-II, in the 30 mg/kg PIP and Nimo intervention groups decreased (all p < 0.05). Results of CCK-8 showed that after 1 h of OGD, the 30 and 40 µg/mL PIP intervention groups had higher cell viability than the OGD group (p < 0.01). Western blot results showed that compared with the OGD group, the expression level of p-mTOR, p-AKT, and p-PI3K in the 30 and 40 µg/mL PIP intervention groups decreased, and the expression level of PI3K increased (all p < 0.05). Moreover, the expression level of autophagy-related proteins, namely, Beclin1 and LC3-II, in the 30 and 40 µg/mL PIP intervention groups decreased (all p < 0.05). CONCLUSIONS: This study shows that PIP is a potential compound with neuroprotective effects. PIP can inhibit the PI3K/AKT/mTOR pathway and autophagy. Its inhibition of autophagy is possibly related to modulating the PI3K/AKT/mTOR pathway. These findings provide new insights into the use of PIP for the treatment of IS and its underlying mechanism.


Assuntos
Lesões Encefálicas , AVC Isquêmico , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Alcaloides , Animais , Autofagia , Proteína Beclina-1 , Benzodioxóis , Infarto Cerebral , Glucose/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oxigênio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Piperidinas , Alcamidas Poli-Insaturadas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Sincalida , Acidente Vascular Cerebral/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo
15.
Fitoterapia ; 157: 104981, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34182052

RESUMO

Osteoporosis is a disease, which causes huge economic and social burden. Using natural compound to treat such disease is beneficial for the fewer side effects and effectiveness. D-(-)-salicin (DSA) is a component extracted from the bark of Populus and Salix species. In our research, we discovered that DSA suppressed RANKL-induced differentiation of osteoclast in vitro in a dose-dependent manner. It was also found that the mineral resorbing activity by osteoclasts was depressed via DSA. For the mechanism, we confirmed the inhibitory effect, by which DSA suppressed osteoclast formation and function, was through the inhibition of ROS signaling, MAPK and NF-κB cascades. DSA also suppressed the expression and activity of NFATc1. Therefore, by inhibiting the ROS production, MAPK and NF-κB signal cascade, DSA inhibited the osteoclast differentiation and function in vitro.


Assuntos
Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Osteoclastos/efeitos dos fármacos , Populus/química , Transdução de Sinais/efeitos dos fármacos , Actinas , Animais , Western Blotting , Diferenciação Celular , Inibidores de Ciclo-Oxigenase/farmacologia , Fêmur/citologia , Expressão Gênica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Osteoclastos/citologia , Osteoclastos/fisiologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sincalida , Tíbia/citologia
16.
Fitoterapia ; 157: 105108, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34954263

RESUMO

This research aimed to investigate the estrogen-like effects of Leonurine hydrochloride (Leo). First, we developed a total synthesis of Leo from 3,4,5-trimethoxy-benzoic acid and the structure was confirmed through 1H NMR and mass spectrometry (MS). Then the estrogenic activity of Leo in vitro and in vivo was studied. The proliferation and proliferation inhibitory effects of Leo on MCF-7 cells and MDA-MB-231 cells indicate that Leo exerts estrogen-like effects through estrogen receptor α (ERα) and estrogen receptor ß((ERß) in vitro. Uterotrophic assay in juvenile mice showed that Leo has an estrogen-like effect in vivo, as it can promote the development of the uterus of juvenile mice, increase its uterine coefficient and the size of the uterine cavity, as well as the increased number of uterine glands and the thickened uterine wall. For further research, cyclophosphamide (CTX) was used to establish a mouse model of ovarian function decline. Through this model, we found that Leo can restore the estrous cycle of mice, increase the number of primordial and primary follicles in the ovaries of mice, and regulate the disordered hypothalamic-pituitary-ovarian (HPOA) axis of mice. Finally, the pharmacokinetics of Leo was studied and oral bioavailability of Leo was calculated to be 2.21%. Leo was synthesized and the estrogen-like effect in vitro and in vivo was confirmed as well as its pharmacokinetics.


Assuntos
Ácido Gálico , Menopausa , Animais , Feminino , Humanos , Masculino , Camundongos , Ratos , Disponibilidade Biológica , Western Blotting , Peso Corporal/efeitos dos fármacos , Estro/efeitos dos fármacos , Ácido Gálico/análogos & derivados , Ácido Gálico/síntese química , Ácido Gálico/metabolismo , Ácido Gálico/farmacocinética , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Hidroxibenzoatos/síntese química , Menopausa/efeitos dos fármacos , Camundongos Endogâmicos ICR , Ovário/patologia , Distribuição Aleatória , Sincalida/análise , Útero/patologia , Vagina/citologia
17.
J Pharm Pharm Sci ; 24: 475-483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34516949

RESUMO

PURPOSE: Organic anion transporting polypeptide (OATP) 1B3 transports many clinically important drugs, including statins, from blood into the liver. It exclusively expresses in human liver under normal physiological conditions. There is no rodent ortholog of human OATP1B3. Tissue targeting of therapeutic molecules mediated by transporters, including liver-targeting via liver-specific OATPs, is an emerging area in drug development. Sandwich-cultured primary hepatocytes (SCH) are a well characterized in vitro model for assessment of hepatic drug uptake and biliary excretion. The current study was designed to develop a novel rat SCH model expressing human OATP1B3 to study the hepatic disposition of OATP1B3 substrates. METHODS: Primary rat hepatocytes transduced with adenoviral vectors expressing FLAG-tagged OATP1B3 (Ad-OATP1B3), a control vector Ad-LacZ, or that were non-transduced were cultured in a sandwich configuration. FLAG immunoblot and immunofluorescence-staining determined expression and localization of OATP1B3. Uptake of [3H]-cholecystokinin octapeptide (CCK-8), a specific OATP1B3 substrate, was determined. Taurocholate (TC) is a substrate routinely used in SCH to assess biliary excretion via bile canaliculi (BC) and is also a substrate of OATP1B3. [3H]-TC accumulation in cells+BC, cells, biliary excretion index (BEI) and in vitro Clbiliary were determined using B-CLEAR® technology. RESULTS: OATP1B3 protein was extensively expressed and primarily localized on the plasma membrane in day 4 Ad-OATP1B3-transduced rat SCH. [3H]-CCK-8 accumulation in cells+BC was significantly greater (~5-13 folds, p<0.001) in day 4 SCH with vs. without Ad-OATP1B3-transduction. Expressing OATP1B3 in rat SCH significantly increased [3H]-TC accumulation in cells+BC and cells, without affecting BEI and in vitro Clbiliary. CONCLUSIONS: Rat SCH expressing human OATP1B3-is a novel in vitro model allowing simultaneous assessment of hepatic uptake, hepatocellular accumulation and biliary excretion process of a human OATP1B3 substrate. This model could be a potential tool for screening for liver-targeting compounds mediated by OATP1B3.


Assuntos
Técnicas de Cultura de Células , Hepatócitos/metabolismo , Fígado/metabolismo , Modelos Biológicos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adenoviridae/genética , Animais , Avaliação Pré-Clínica de Medicamentos , Vetores Genéticos , Masculino , Ratos Wistar , Sincalida/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
18.
Acta Histochem ; 122(6): 151576, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32778238

RESUMO

BACKGROUND: In recent years, microRNAs (miRNAs) are reported to act as molecular biomarkers for cancer diagnosis, treatment, and prognosis (including liver cancer) and to be involved in the development and progression of cancer and other physiological and pathological changes. However, the role of miR-34a-5p in liver cancer is still largely unknown. METHODS: In our study, the expression of miR-34a-5p in liver cancer tissues and HCC cell lines was detected by qRT-PCR. The CCK-8, scratch wound-healing motility and Transwell assays were used to evaluate the effect on cell proliferation, migration and invasion. The expression of YY1, E-cadherin, N-cadherin and vimentin was analysed by western blotting. The dual luciferase assay was performed to confirm whether YY1 is a target of miR-34a-5p. The combination of YY1 and MYCT1 was detected by chromatin immunoprecipitation (ChIP) assay. RESULTS: The results showed that miR-34a-5p was downregulated in liver cancer tissues and HCC cell lines. Overexpression of miR-34a-5p inhibited the proliferation, migration and invasion of liver cancer cells. YY1 was a direct target of miR-34a-5p, and the expression of YY1 could reverse the influence of miR-34a-5p on the proliferation, migration and invasion of liver cancer cells. YY1 inhibited MYCT1 expression by directly binding to its promoter region, and knockdown of MYCT1 reversed the influence of miR-34a-5p on the proliferation, migration and invasion of liver cancer cells. CONCLUSION: Our results suggest that miR-34a-5p could inhibit the invasion and metastasis of hepatoma cells by targeting YY1-mediated MYCT1 transcriptional repression.


Assuntos
Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fator de Transcrição YY1/metabolismo , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sincalida/metabolismo , Cicatrização/genética , Cicatrização/fisiologia , Fator de Transcrição YY1/genética
19.
Am J Chin Med ; 48(4): 793-811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32420752

RESUMO

Acupuncture reduces pain by activating specific areas called acupoints on the patient's body. When these acupoints are fully activated, sensations of soreness, numbness, fullness, or heaviness called De qi or Te qi are felt by clinicians and patients. There are two kinds of acupuncture, manual acupuncture and electroacupuncture (EA). Compared with non-acupoints, acupoints are easily activated on the basis of their special composition of blood vessels, mast cells, and nerve fibers that mediate the acupuncture signals. In the spinal cord, EA can inhibit glial cell activation by down-regulating the chemokine CX3CL1 and increasing the anti-inflammatory cytokine interleukin-10. This inhibits P38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways, which are associated with microglial activation of the C-Jun N-terminal kinase signaling pathway and subsequent astrocyte activation. The inactivation of spinal microglia and astrocytes mediates the immediate and long-term analgesic effects of EA, respectively. A variety of pain-related substances released by glial cells such as the proinflammatory cytokines tumor necrosis factor [Formula: see text], interleukin-1[Formula: see text], interleukin-6, and prostaglandins such as prostaglandins E2 can also be reduced. The descending pain modulation system in the brain, including the anterior cingulated cortex, the periaqueductal gray, and the rostral ventromedial medulla, plays an important role in EA analgesia. Multiple transmitters and modulators, including endogenous opioids, cholecystokinin octapeptide, 5-hydroxytryptamine, glutamate, noradrenalin, dopamine, [Formula: see text]-aminobutyric acid, acetylcholine, and orexin A, are involved in acupuncture analgesia. Finally, the "Acupuncture [Formula: see text]" strategy is introduced to help clinicians achieve better analgesic effects, and a newly reported acupuncture method called acupoint catgut embedding, which injects sutures made of absorbable materials at acupoints to achieve long-term effects, is discussed.


Assuntos
Analgesia por Acupuntura , Eletroacupuntura , Neurotransmissores/fisiologia , Analgesia por Acupuntura/métodos , Pontos de Acupuntura , Hormônio Adrenocorticotrópico/fisiologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Quimiocina CX3CL1/metabolismo , Citocinas/metabolismo , Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Hemodinâmica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Neuroglia/fisiologia , Norepinefrina/fisiologia , Peptídeos Opioides/fisiologia , Serotonina/fisiologia , Sincalida/fisiologia , Medula Espinal/citologia , Ácido gama-Aminobutírico/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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