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ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei Bai-Hu-Decoction (JWBHD), a prescription formulated with seven traditional Chinese medicinal material has demonstrated clinical efficacy in mitigating brain injury among heat stroke (HS) patients. AIM OF THE STUDY: This study aimed to evaluate the therapeutic efficacy of JWBHD on rat model of HS and to explore its therapeutic mechanisms by integrating network pharmacology and pharmacodynamic methodologies, which major components were analyzed by using UPLC-MS/MS. MATERIALS AND METHODS: The network pharmacology analysis was firstly conducted to predict the potential active ingredients and therapeutic targets of JWBHD. The anti-HS effectiveness of JWBHD was then evaluated on rats experienced HS. Rat brain tissues were harvested for a comprehensive array of experiments, including Western blot, PCR, H&E staining, Nissl staining, ELISA, transmission electron microscope, flow cytometry and immunofluorescence to validate the protective effects of JWBHD against HS-induced brain damage. Furthermore, the inhibitory effects of JWBHD on TLR4/NF-κB signal and mitophagy of glial were further verified on HS-challenged F98 cell line. Finally, the chemical compositions of the water extract of JWBHD were analyzed by using UPLC-MS/MS. RESULTS: Network pharmacology has identified fifty core targets and numerous HS-related signaling pathways as potential therapeutic targets of JWBHD. Analysis of protein-protein interaction (PPI) and GO suggests that JWBHD may suppress HS-induced inflammatory signals. In experiments conducted on HS-rats, JWBHD significantly reduced the core temperature, restored blood pressure and alleviated neurological defect. Furthermore, JWBHD downregulated the counts of white blood cells and monocytes, decreased the levels of inflammatory cytokines such as IL-1ß, IL-6 and TNF-α in peripheral blood, and suppressed the expression of TLR4 and NF-κB in the cerebral cortex of HS-rats. Besides, JWBHD inhibited the apoptosis of cortical cells and mitigated the damage to the cerebral cortex in HS group. Conversely, overactive mitophagy was observed in the cerebral cortex of HS-rats. However, JWBHD restored the mitochondrial membrane potential and downregulated expressions of mitophagic proteins including Pink1, Parkin, LC3B and Tom20. JWBHD reduced the co-localization of Pink1 and GFAP, a specific marker of astrocytes in the cerebral cortex of HS-rats. In addition, the inhibitory effect of JWBHD on TLR4/NF-κB signaling and overactive mitophagy were further confirmed in F98 cells. Finally, UPLC-MS/MS analysis showed that the main components of JWBHD include isoliquiritigenin, liquiritin, dipotassium glycyrrhizinate, ginsenoside Rb1, ginsenoside Re, etc. CONCLUSIONS: JWBHD protected rats from HS and prevented HS-induced damage in the cerebral cortex by suppressing TLR4/NF-κB signaling and mitophagy of glial.
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Medicamentos Herbarios Chinos , Golpe de Calor , Mitofagia , FN-kappa B , Neuroglía , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Mitofagia/efectos de los fármacos , FN-kappa B/metabolismo , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Transducción de Señal/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas , Golpe de Calor/tratamiento farmacológico , Golpe de Calor/complicaciones , Fármacos Neuroprotectores/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/prevención & control , Farmacología en Red , Modelos Animales de EnfermedadRESUMEN
Reactive oxygen species (ROS) have been recognized as prevalent contributors to the development of inner retinal injuries including optic neuropathies such as glaucoma, non-arteritic anterior ischemic optic neuropathy, traumatic optic neuropathy, and Leber hereditary optic neuropathy, among others. This underscores the pivotal significance of oxidative stress in the damage inflicted upon retinal tissue. To combat ROS-related challenges, this study focuses on creating an injectable and tissue-adhesive hydrogel with tailored antioxidant properties for retinal applications. GelCA, a gelatin-modified hydrogel with photo-crosslinkable and injectable properties, is developed. To enhance its antioxidant capabilities, curcumin-loaded polydopamine nanoparticles (Cur@PDA NPs) are incorporated into the GelCA matrix, resulting in a multifunctional nanocomposite hydrogel referred to as Cur@PDA@GelCA. This hydrogel exhibits excellent biocompatibility in both in vitro and in vivo assessments, along with enhanced tissue adhesion facilitated by NPs in an in vivo model. Importantly, Cur@PDA@GelCA demonstrates the potential to mitigate oxidative stress when administered via intravitreal injection in retinal injury models such as the optic nerve crush model. These findings underscore its promise in advancing retinal tissue engineering and providing an innovative strategy for acute neuroprotection in the context of inner retinal injuries.
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Antioxidantes , Adhesivos Tisulares , Nanogeles , Especies Reactivas de Oxígeno , Retina , HidrogelesRESUMEN
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, characterized by abdominal pain, bloating, and changes in bowel habits. Huoxiang Drink (HD), derived from traditional Chinese medicine, has been reported to effectively treat digestive disorders caused by external cold and internal dampness. However, the pharmaceutical targets and mechanisms for HD against IBS remain unclear. Data mining, bioinformatics analysis, and network pharmacology were employed to explore the potential pharmacological mechanisms of HD against IBS. In this study, we screened 50 core targets to investigate the pharmacological mechanisms of HD against IBS. Enrichment analysis revealed that HD may participate in various signaling pathways, especially the inflammation-related tumor necrosis factor, signaling pathway and hypoxia-inducible factor signaling pathway. Molecular docking results confirmed that MOL000098 (Quercetin), MOL000006 (Luteolin), MOL005828 (Nobiletin), MOL005916 (Irisolidone), and MOL004328 (Naringenin), as key active ingredients in HD, bound to core targets (tumor protein P53, tumor necrosis factor, matrix metalloproteinases 9, and vascular endothelial growth factor-A) for topical treatment of IBS. This study suggested that HD offered a potential therapeutic strategy against IBS. Our findings may facilitate the efficient screening of active ingredients in HD and provide a theoretical basis for further validating the clinical therapeutic effects of HD on treating IBS.
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Medicamentos Herbarios Chinos , Síndrome del Colon Irritable , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Farmacología en Red , Factor A de Crecimiento Endotelial Vascular , Simulación del Acoplamiento Molecular , Minería de Datos , Factores de Necrosis Tumoral , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional ChinaRESUMEN
Background: There was still no effective treatment for traumatic brain injury (TBI). Recently, many preclinical studies had shown promising efficacy of extracellular vesicles (EVs) from various cell sources. Our aim was to compare which cell-derived EVs were most effective in treating TBI through a network meta-analysis. Methods: We searched four databases and screened various cell-derived EVs for use in preclinical studies of TBI treatment. A systematic review and network meta-analysis were conducted for two outcome indicators, modified Neurological Severity Score (mNSS) and Morris Water Maze (MWM), and they were ranked by the surface under the cumulative ranking curves (SUCRA). Bias risk assessment was performed with SYRCLE. R software (version 4.1.3, Boston, MA, USA) was used for data analysis. Results: A total of 20 studies were included in this study, involving 383 animals. Astrocyte-derived extracellular vesicles (AEVs) ranked first in response to mNSS at day 1 (SUCRA: 0.26%), day 3 (SUCRA: 16.32%), and day 7 (SUCRA: 9.64%) post-TBI. Extracellular vesicles derived from mesenchymal stem cells (MSCEVs) were most effective in mNSS assessment on day 14 (SUCRA: 21.94%) and day 28 (SUCRA: 6.26%), as well as MWM's escape latency (SUCRA: 6.16%) and time spent in the target quadrant (SUCRA: 86.52%). The result of mNSS analysis on day 21 showed that neural stem cell-derived extracellular vesicles (NSCEVs) had the best curative effect (SUCRA: 6.76%). Conclusion: AEVs may be the best choice to improve early mNSS recovery after TBI. The efficacy of MSCEVs may be the best in the late mNSS and MWM after TBI. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023377350.
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ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI), which is a Chinese clinical prescription consists of Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Honghua in Chinese)(Plant names have been checked with http://www.theplantlist.org on March 1st, 2022), has been mainly used in the clinical therapy of cardiovascular diseases, including hypertension in China for many years. AIM OF THE STUDY: Cardiovascular diseases (CVDs) are the major causes of death all around the world. Due to the various stimulation, a series of vasoconstrictor substances are secreted to regulate the vasoconstriction function and then change blood pressure. The representative substances leading to abnormal vasoconstriction include renin-angiotensin system, endothelin, vasopressin and adrenaline, which act on the corresponding receptors on vascular smooth muscle to constrict blood vessels. Finally, blood pressure increases, followed by a series of cardiovascular diseases, including hypertension. However, little is known about Danhong injection's specific vasodilating mechanisms and active substances. The aims of the study were to determine the vasodilating substances of Danhong injection and explain its molecular mechanism of vasodilation. MATERIALS AND METHODS: The effects of DHI and its active components on vascular tension were measured by myograph system in the aortic or mesenteric rings of mice. Based on this, the pharmacodynamic substances were analyzed and effective molecules were found. Combined with multiple types of vascular myograph experiments and network pharmacological analysis, the molecular pathway was preliminarily determined. With molecular biology experiments, it was verified that the relevant mechanisms were closely related to calcium-mediated vasoconstriction in smooth muscle cells. RESULTS: DHI could relax endothelium-removed aortic rings pre-constricted with PE and 3 possible active vasodilator substances, including salvianolic acid A, salvianolic acid B and danshensu, were screened out by network pharmacology and vascular myograph experiments, among which the effects of salvianolic acid A were dominant. Meanwhile, salvianolic acid A could dilate mesenteric artery in a pressure-dependent manner. Interestingly, salvianolic acid A could still relax the vascular rings under the stimulation of KCl and Bayk8644, two agonists of L-type calcium channel. By contrast, inhibitors of Kir, Kv, Katp and BKCa channels did not block the effect of salvianolic acid A on vasodilation. Salvianolic acid A alleviated Ca2+ transient, referring to changes of intracellular calcium, induced by PE, Bayk8644 and high K+ in the VSMCs. Salvianolic acid A could partially restore the vasodilation function of vascular smooth muscle damaged by AngII and ET-1 induced hypertension situation. CONCLUSIONS: Our results indicate that salvianolic acid A is the major vasodilator substance in DHI and the vasorelaxation pharmacology mechanism involved in inhibiting the L-type calcium channel signaling in smooth muscle cell. Hence, there are potential therapeutic effects of taking salvianolic acid A preparation which may be beneficial to protect cardiovascular system and reduce blood pressure.
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Enfermedades Cardiovasculares , Hipertensión , Salvia miltiorrhiza , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico , Animales , Arterias , Ácidos Cafeicos , Calcio/metabolismo , Canales de Calcio Tipo L , Medicamentos Herbarios Chinos , Lactatos , Ratones , Salvia miltiorrhiza/química , Vasodilatación , Vasodilatadores/farmacologíaRESUMEN
Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.
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The human six-transmembrane epithelial antigen of the prostate (STEAP) proteins, which include STEAP1-4 and atypical STEAP1B, contain six transmembrane domains and are located in the cell membrane. STEAPs are considered archaeal metal oxidoreductases, based on their heme groups and F420H2:NADP+ oxidoreductase (FNO)-like structures, and play an important role in cell metal metabolism. Interestingly, STEAPs not only participate in biological processes, such as molecular transport, cell cycling, immune response, and intracellular and extracellular activities, but also are closely related to the occurrence and development of several diseases, especially malignant tumors. Up to now, the expression patterns of STEAPs have been found to be diverse in different types of tumors, with controversial participation in different aspects of malignancy, such as cell proliferation, migration, invasion, apoptosis, and therapeutic resistance. It is clinically important to explore the potential roles of STEAPs as new immunotherapeutic targets for the treatment of different malignant tumors. Therefore, this review focuses on the molecular mechanism and function of STEAPs in the occurrence and development of different cancers in order to understand the role of STEAPs in cancer and provide a new theoretical basis for the treatment of diverse cancers.
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A low NM23-H1 expression in head and neck squamous cell carcinoma (HNSCC) was found to be associated with poor clinical outcome. Therefore, we investigated the role of NM23-H1 in the susceptibility of HNSCC cells to irradiation and its clinical significance. An in vitro study was also conducted to validate the results. Furthermore, we used immunohistochemistry to analyze NM23-H1 expression found in specimens of 50 HNSCC patients with cervical metastases receiving postoperative radiotherapy. Low tumor NM23-H1 expression was associated with locoregional recurrence of HNSCC (p=0.040; Hazard ratio=5.62) and poor clinical outcome (p=0.001; Hazard ratio=4.90). To confirm the effect of NM23-H1 on radiation-induced cytotoxicity, we generated several stable clones derived from a human HNSCC cell line (SAS) using knockdown and overexpression of NM23-H1. Knockdown of NM23-H1 decreased the radio-sensitivity of SAS cells, possibly associated with a decrease in the radiation-induced G2/M-phase accumulation and upregulation of cyclin B1. On the contrary, overexpression of NM23-H1 can reverse the aforementioned adverse results. Consequently, we suggest that NM23-H1 expression may be considered as a potential therapeutic treatment option for HNSCC patients.
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BACKGROUND: Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. METHODS: Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3's effect on angiogenesis. RESULTS: Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. CONCLUSIONS: This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.