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Vaccines are one of the most important means to prevent and control the epidemic of infectious diseases. Commercial vaccines not only include corresponding antigens, but also need vaccine adjuvants. Immune adjuvants play an increasingly important role in the research, development and manufacture of vaccines. Adjuvants combined with antigens can improve the stability, safety and immune efficiency of vaccines. Some substances that can enhance the immune response have been found in nature(mainly plants) and used as adjuvants in vaccines to improve the immune effect of vaccines. These plant-derived immune adjuvants often have the advantages of low toxicity, high stability, low price, etc., providing more possibilities for vaccine development. We summarized and analyzed the advantages, application research, particulate delivery systems, existing problems and future research focus of botanical adjuvant. It is hoped to provide new ideas for the research and development of immune adjuvants in the future.
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BACKGROUND: Quercetin, the key ingredient in Xiaoyao Kangai Jieyu Formula, has been previously found to relieve breast cancer-related depression (BCRD). PURPOSE: We want to explore the potential mechanisms and therapeutic targets of quercetin alleviating BCRD. METHODS: BALB/c mice were injected subcutaneously with 4T1 cells and corticosterone (CORT) to create a BCRD mice model. The primary hippocampal neurons were co-induced with 10 µg/ml lipopolysaccharide (LPS) and 200 µM CORT for 6 h to establish an in vitro model of BCRD. Quercetin was applied to explore its effect on disease symptoms, gut microbiota, and lipid metabolism of BCRD mice. Lipid metabolism-related genes were screened based on network pharmacology. Molecular docking was employed to prove whether quercetin bound to prostaglandin-endoperoxide synthase 2 (PTGS2). PTGS2 overexpression was carried out to explore the underlying mechanism of quercetin treatment on BCRD. RESULTS: Quercetin treatment not only altered the composition and abundance of gut microbiota but also alleviated abnormal lipid metabolism in BCRD mice. In particular, quercetin down-regulated BCRD and lipid metabolism-related genes screened by network pharmacology, especially PTGS2. Further, molecular docking verified the stable binding between quercetin and PTGS2. In hippocampal neurons, quercetin promoted proliferation but reduced ferroptosis-related markers (total Fe, Fe2+, MDA, and ROS) levels by targeting PTGS2. In BCRD mice, quercetin reduced the high immobility time and increased the sucrose preference rate and serotonin (5-HT), dopamine (DA), and noradrenaline (NE) levels. Meanwhile, quercetin increased CD4+/CD8+ T cells ratio and IL-2 and IFN-γ levels but reduced CA153 and IL-10 levels to alleviate BCRD development. However, PTGS2 overexpression reversed these effects of quercetin on BCRD. CONCLUSION: Quercetin inhibited neuronal ferroptosis and promoted immune responses in BCRD mice by targeting the lipid metabolism-related gene PTGS2. This provided a reference for quercetin in the treatment of BCRD.
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Ciclooxigenasa 2 , Depresión , Ferroptosis , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Neuronas , Quercetina , Animales , Quercetina/farmacología , Quercetina/análogos & derivados , Ferroptosis/efectos de los fármacos , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ciclooxigenasa 2/metabolismo , Neuronas/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Depresión/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Línea Celular Tumoral , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Breast cancer-related depression (BCRD) is strongly associated with BC and increases recurrence and mortality. This study investigated the role of kaempferol in the pathogenesis of BCRD and its underlying mechanism. METHODS: 4T1 mouse BC cells were treated with corticosterone (Cort) in vitro to develop a neuronal injury model, and a BCRD mouse model was established by injecting 4T1 cells and Cort. The effects of kaempferol on 4T1 cells and BCRD models were measured by behavioral tests, Cell Counting Kit-8 assay, wound healing assay, colony formation assay, Western blot analysis, quantitative real-time PCR, hematoxylin and eosin staining, enzyme-linked immunosorbent assay, and immunofluorescence. BCRD cells were transfected with the cyclo-oxygenase-2 (COX-2) overexpression plasmid to study the role of the COX-2/prostaglandin E2 (PGE2) axis in the anti-BCRD activity of kaempferol. The connection between kaempferol and COX-2 was analyzed by molecular docking. RESULTS: Kaempferol reduced the viability, migration, and clones of 4T1 cells and inhibited BC growth and depression-like behavior in mice. Kaempferol alleviated inflammation in BCRD, decreased interleukin 1 beta (IL-1ß) and IL-6 levels, and increased transforming growth factor beta 1 (TGF-ß1) and IL-10 levels. In addition, kaempferol elevated the levels of serotonin, dopamine, and norepinephrine and the amount of 5-Bromo-2'-deoxyuridine/neuronal nuclei-positive cells. Kaempferol downregulated COX-2 and PGE2, and kaempferol could dock with the protein structure of COX-2. Overexpression of COX-2 reduced BCRD viability, upregulated IL-1ß and IL-6 levels, and downregulated TGF-ß1 and IL-10 expression. Overexpression of COX-2 reversed the protective effects of kaempferol. CONCLUSION: Kaempferol exerted anti-BCRD effects, at least in part by inhibiting the COX-2/PGE2 pathway, which regulates neuroinflammation, neurotransmitter imbalance, and defective neurogenesis. Therefore, kaempferol may be a promising candidate active ingredient for treating BCRD.
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Dinoprostona , Neoplasias , Ratones , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Interleucina-10/genética , Interleucina-6 , Depresión , Quempferoles/farmacología , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND AND AIM: Hypertension is a major global health problem that causes target organ damage (TOD) in the heart, brain, kidney, and blood vessels. The mechanisms of hypertensive TOD are not fully understood, and its treatment is challenging. This review provides an overview of the current knowledge on the role of Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome in hypertensive TOD and the natural products and formulations that inhibit it. METHODS: We searched PubMed, Web of Science, Google Scholar, and CNKI for relevant articles using the keywords "hypertension," "target organ damage," "NLRP3 inflammasome," "natural products," and "formulations." We reviewed the effects of the NLRP3 inflammasome on hypertensive TOD in different organs and discussed the natural products and formulations that modulate it. KEY RESULTS: In hypertensive TOD, the NLRP3 inflammasome is activated by various stimuli such as oxidative stress and inflammation. Activation of NLRP3 inflammasome leads to the production of pro-inflammatory cytokines that exacerbate tissue damage and dysfunction. Natural products and formulations, including curcumin, resveratrol, triptolide, and allicin, have shown protective effects against hypertensive TOD by inhibiting the NLRP3 inflammasome. CONCLUSIONS AND IMPLICATIONS: The NLRP3 inflammasome is a promising therapeutic target in hypertensive TOD. Natural products and formulations that inhibit the NLRP3 inflammasome may provide novel drug candidates or therapies for hypertensive TOD. Further studies are needed to elucidate the molecular mechanisms and optimize the dosages of these natural products and formulations and evaluate their clinical efficacy and safety.
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Productos Biológicos , Hipertensión , Humanos , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Hipertensión/tratamiento farmacológico , Inflamación/tratamiento farmacológicoRESUMEN
This study aimed to investigate the intervention effect and mechanism of Xiaoyao Kangai Jieyu Recipe(XKJR) on hip-pocampal microglia and neuronal damage in mice with breast cancer related depression. The mouse model of breast cancer related depression was established by inoculation of 4T1 breast cancer cells in axilla and subcutaneous injection of corticosterone(30 mg·kg~(-1)). The successfully modeled mice were randomly divided into a model group, a positive drug group(capecitabine 60 mg·kg~(-1)+fluoxetine 19.5 mg·kg~(-1)), and XKJR group(19.5 mg·kg~(-1) crude drug), with 6 in each group. Another 6 normal mice were taken as a normal group. The administration groups were given corresponding drugs by gavage, while the normal and model groups were given an equal volume of distilled water, once a day for 21 consecutive days. The depressive behavior of mice was assessed by glucose consumption test, open field test and novelty-suppressed feeding test. Hematoxylin and eosin(HE) staining and tumor suppression rate were used to evaluate the changes of axillary tumors. The mRNA expressions and the relative protein expressions of interleukin-1ß(IL-1ß), interleukin-18(IL-18), cyclooxyganese-2(COX-2) and glutamyl-prolyl-tRNA synthetase(EPRs) in the hippocampus of mice were determined by quantitative real-time polymerase chain reaction(qRT-PCR) and immunohistochemistry, respectively. Immunofluorescence was performed to detect the mean fluorescence intensity of CD11b, a marker of hippocampal microglia activation. Nissler staining and transmission electron microscopy were employed to observe the morphological changes and the ultramorphological changes of hippocampal neurons, respectively. The experimental results indicated that compared with the normal group, the model group had reduced glucose consumption and lowered number of total activities in open field test(P<0.05, P<0.01), prolonged first feeding latency in no-velty-suppressed feeding test(P<0.01), and significant depression-like behavior; the contents of IL-1ß, IL-18, COX-2, and EPRs in hippocampus were increased(P<0.05, P<0.01), with hippocampal microglia activation and obvious neuronal damage. Compared with the model group, the positive drug group and the XKJR group presented an improvement in depressive behaviors, a decrease in the contents of IL-1ß, IL-18, COX-2 and EPRs in hippocampus, and an alleviation in the activation of hippocampal microglia and neuronal damage; the tumor suppression rates of positive drug and XKJR were 40.32% and 48.83%, respectively, suggesting a lower tumor growth rate than that of the model group. In summary, XKJR may improve hippocampal microglia activation and neuronal damage in mice with breast cancer related depression through activating COX signaling pathway.
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Depresión , Neoplasias , Ratones , Animales , Depresión/tratamiento farmacológico , Depresión/genética , Interleucina-18 , Ciclooxigenasa 2/genética , Hipocampo , GlucosaRESUMEN
Hypertension generally causes target organ damage (TOD) in the heart, brain, kidney, and blood vessels. This can result in atherosclerosis, plaque formation, cardiovascular and cerebrovascular events, and renal failure. Recent studies have indicated that mitochondrial dysfunction is crucial in hypertensive target organ damage. Consequently, mitochondria-targeted therapies attract increasing attention. Natural compounds are valuable resources for drug discovery and development. Many studies have demonstrated that natural compounds can ameliorate mitochondrial dysfunction in hypertensive target organ damage. This review examines the contribution of mitochondrial dysfunction to the development of target organ damage in hypertension. Moreover, it summarizes therapeutic strategies based on natural compounds that target mitochondrial dysfunction, which may be beneficial for preventing and treating hypertensive target organ damage.
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Improving hepatic glucose and lipid metabolisms is an important strategy to treat type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease (T2DM-NAFLD). Silybin (SLB) has the potential hepatoprotection, while its oral bioavailability is poor. This study aims to investigate the functional role and mechanism of liposomal SLB in modulating glucose/lipid metabolism in T2DM-NAFLD. SLB was prepared by thin film dispersion method and characterized using dynamic light scattering, scanning electron microscope, high performance liquid chromatography and zeta potential analyzer. A rat model of T2DM-NAFLD was used to determine the role of liposomal SLB in regulating glycolipid metabolism and hepatic damage. Rat primary hepatocytes were used to demonstrate the hepatoprotection mechanism of liposomal SLB. The encapsulation efficiency was more than 80%, which showed the average particle size of 119.76 nm. Also, the average Zeta potential was -4.76 mV. These liposomes were spherical. In rats with T2DM-NAFLD, liposomal SLB alleviated insulin resistance and lipid metabolism, thereby improving hepatic lipid accumulation, inflammation and fibrosis. Besides, liposomal SLB elevated AMPK phosphorylation, and decreased collagen I/III, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and the phosphorylation of Smad2/3. In hepatocyte model, compound C partially reversed the effects of liposomal SLB on cell viability, glycolipid metabolism and AMPK/TGF-ß1/Smad pathway activation. Liposomal SLB ameliorates hepatic glucose and lipid metabolisms in T2DM-NAFLD via activating AMPK/TGF-ß1/Smad pathway, providing an efficient strategy for treating T2DM-NAFLD.
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Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Ratas , Animales , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/metabolismo , Metabolismo de los Lípidos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/farmacología , Silibina/farmacología , Silibina/uso terapéutico , Silibina/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Liposomas/metabolismo , Liposomas/farmacología , Modelos Animales de Enfermedad , Hígado/metabolismo , Lípidos/farmacología , Glucolípidos/metabolismo , Glucolípidos/farmacologíaRESUMEN
Diabetic foot ulcer (DFU) is a break in the skin of the foot caused by diabetes. It is one of the most serious and debilitating complications of diabetes. The previous study suggested that dominant M1 polarization during DFU could be the leading reason behind impaired wound healing. This study concluded that macrophage M1 polarization predominates in DFU skin tissue. iNOS was increased in HG-induced M1-polarized macrophages; conversely, Arg-1 was decreased. Macrophage pellets after HG stimulation can impair endothelial cell (EC) function by inhibiting cell viability, tube formation and cell migration, indicating M1 macrophage-derived small extracellular vesicles (sEVs) -mediated HUVEC dysfunction. sEVs miR-503 was significantly upregulated in response to HG stimulation, but inhibition of miR-503 in HG-stimulated macrophages attenuated M1 macrophage-induced HUVEC dysfunction. ACO1 interacted with miR-503 and mediated the miR-503 package into sEVs. Under HG stimulation, sEVs miR-503 taken in by HUVECs targeted IGF1R in HUVECs and inhibited IGF1R expression. In HUVECs, miR-503 inhibition improved HG-caused HUVEC dysfunction, whereas IGF1R knockdown aggravated HUVEC dysfunction; IGF1R knockdown partially attenuated miR-503 inhibition effects on HUVECs. In the skin wound model in control or STZ-induced diabetic mice, miR-503-inhibited sEVs improved, whereas IGF1R knockdown further hindered wound healing. Therefore, it can be inferred from the results that the M1 macrophage-derived sEVs miR-503 targets IGF1R in HUVECs, inhibits IGF1R expression, leads to HUVEC dysfunction, and impedes wound healing in diabetic patients, while packaging miR-503 as an M1 macrophage-derived sEVs may be mediated by ACO1.
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Diabetes Mellitus Experimental , Pie Diabético , Vesículas Extracelulares , MicroARNs , Ratones , Animales , Diabetes Mellitus Experimental/complicaciones , Cicatrización de Heridas , Células Endoteliales/metabolismo , Pie Diabético/metabolismo , Macrófagos/metabolismo , MicroARNs/metabolismo , Vesículas Extracelulares/metabolismoRESUMEN
Depressive Disorder is a common mood disorder or affective disorder that is dominated by depressed mood. It is characterized by a high incidence and recurrence. The onset of depression is related to genetic, biological and psychosocial factors. However, the pathogenesis is still unclear. In recent years, there has been an increasing amount of research on the inflammatory hypothesis of depression, in which cyclo-oxygen-ase 2 (COX-2), a pro-inflammatory cytokine, is closely associated with depression. A variety of chemical drugs and natural products have been found to exert therapeutic effects by modulating COX-2 levels. This paper summarizes the relationship between COX-2 and depression in terms of neuroinflammation, intestinal flora, neurotransmitters, HPA axis, mitochondrial dysfunction and hippocampal neuronal damage, which can provide a reference for further preventive control, clinical treatment and scientific research on depression.
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Aim: To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods: Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1ß, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results: Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1ß, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion: In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.
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There has been ample research showing that insomnia is a potential trigger of depression as well as a symptom of depression. These two factors contribute to behavioural problems and are closely related to the plasticity of hippocampal synapses. Although depression and insomnia impair hippocampal synaptic plasticity, the mechanism by which this happens remains a mystery. This study aimed to investigate the pathogenesis of insomnia comorbidity in depression and the regulatory effect of venlafaxine combined with melatonin on hippocampal synaptic plasticity in chronic unpredictable mild stress (CUMS) with sleep deprivation (SD) rats. Thus, rats were subjected to 14 days of chronic mild unpredictable stress, gradually acclimated to sleep deprivation on days 12-14. Followed by 21 consecutive days of sleep deprivation, 18 h per day, with daily gavage of venlafaxine (13.5 mg/kg) + melatonin (72 mg/kg) on days 15-36. Venlafaxine + melatonin treatment improves depression-like behaviour, pentobarbital sodium experimental sleep latency, and sleep duration in CUMS +SD rats. In addition to improving depressive-like behaviors, sleep deprivation also upregulates the expression of caspase-specific cysteine protein 3 (Caspase 3) in the pineal glial cells of chronic mild rats, as well as in hippocampal microglia. Expression of ionic calcium-binding adaptor 1 (iba-1), downregulates the secretion of several synaptic plasticity-related proteins, notably cAMP response element binding protein (CREB), glial cell line-derived neurotrophic factor (GDNF), and the synaptic scaffolding protein Spinophiline (Spinophiline). Hematoxylin-eosin staining showed that the structure of the pineal gland and hippocampus was damaged, and Golgi staining showed that the dendrites and spines in the DG area of the hippocampus were destroyed, vaguely aggregated or even disappeared, and the connection network could not be established. Western blot analysis further revealed a positive correlation between low melatonin levels and reduced Spinophiline protein. Interestingly, venlafaxine + melatonin reversed these events by promoting hippocampal synaptic plasticity by regulating melatonin secretion from the pineal gland. Therefore, it exerted an antidepressant effect in sleep deprivation combined with CUMS model rats. Overall, the results of this study suggest that the pathophysiology of depressive insomnia comorbidity is mediated by impaired pineal melatonin secretion and impaired hippocampal synaptic plasticity. In addition, these responses are associated with melatonin secretion from the pineal gland.
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Melatonina , Glándula Pineal , Trastornos del Inicio y del Mantenimiento del Sueño , Animales , Depresión/metabolismo , Hipocampo/metabolismo , Melatonina/metabolismo , Melatonina/farmacología , Plasticidad Neuronal/fisiología , Ratas , Privación de Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Clorhidrato de Venlafaxina/farmacologíaRESUMEN
Background: Mitochondria play an important role in breast cancer (BRCA). We aimed to build a prognostic model based on mitochondria-related genes. Method: Univariate Cox regression analysis, random forest, and the LASSO method were performed in sequence on pretreated TCGA BRCA datasets to screen out genes from a Gene Set Enrichment Analysis, Gene Ontology: biological process gene set to build a prognosis risk score model. Survival analyses and ROC curves were performed to verify the model by using the GSE103091 dataset. The BRCA datasets were equally divided into high- and low-risk score groups. Comparisons between clinical features and immune infiltration related to different risk scores and gene mutation analysis and drug sensitivity prediction were performed for different groups. Result: Four genes, MRPL36, FEZ1, BMF, and AFG1L, were screened to construct our risk score model in which the higher the risk score, the poorer the prognosis. Univariate and multivariate analyses showed that the risk score was significantly associated with age, M stage, and N stage. The gene mutation probability in the high-risk score group was significantly higher than that in the low-risk score group. Patients with higher risk scores were more likely to die. Drug sensitivity prediction in different groups indicated that PF-562271 and AS601245 might be new inhibitors of BRCA. Conclusion: We developed a new workable risk score model based on mitochondria-related genes for BRCA prognosis and identified new targets and drugs for BRCA research.
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Neoplasias de la Mama , Neoplasias de la Mama/genética , Femenino , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Pronóstico , Curva ROCRESUMEN
Background: Breast-cancer-related depression (BCRD) is associated with an increased mortality rate among breast cancer (BC) survivors. Luteolin has many pharmacological effects, particularly in the treatment of BC. In this study, we aimed to explore the anti-BCRD activity of luteolin and its underlying functional mechanism. Methods: A BCRD mouse model was induced by injecting 4T1 cells and corticosterone (COR). Behavioral test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunofluorescence, reverse-transcription quantitative PCR (RT-qPCR), and western blotting were used to study the effect of luteolin in mice with BCRD in vivo. A COR-induced neuron injury model was established in HT-22 cells in vitro. The role of miR-124-3p in the anti-BCRD effects of luteolin was studied using a miR-124-3p inhibitor. Results: Luteolin significantly reduced the size and weight of the tumor, increased the mice entry frequency in the symmetrical sector, and reduced the duration of immobility in the tail suspension and forced swimming tests of mice affected by BCRD. Simultaneously, apoptosis of hippocampal neurons was inhibited, and the number of Nissl bodies increased with luteolin treatment. In addition, luteolin resulted in the upregulation of miR-124-3p expression in the hippocampus and downregulated the expression of tumor necrosis factor-α (TNF-α) and TNF receptor-associated factor 6 (TRAF6), as well as lowered the phosphorylation levels of nuclear factor-kappa B (NF-κB) and IkappaB (IκB). Luteolin also inhibited pyroptosis of hippocampal neurons in mice affected by BCRD, as revealed by the low protein levels of NOD-like receptor protein 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), interleukin (IL)-1ß, and IL-18. However, the miR-124-3p inhibitor significantly reversed the therapeutic effect of luteolin on COR-induced HT-22 cells. Conclusion: Our study demonstrated that the anti-BCRD function of luteolin was mediated by regulating the miR-124-3p/TNF-α/TRAF6-related pathway and inhibiting neuronal cell pyroptosis and subsequent inflammation. Therefore, luteolin may be a potential drug candidate in the treatments of BCRD.
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Background: Breast cancer-related depression (BCRD) seriously inhibits the life quality of patients with breast cancer. The Xiaoyao Kangai Jieyu Formula is known to inhibit the progression of depression. However, the detailed function of the Xiaoyao Kangai Jieyu Formula in BCRD remains unclear. Methods: Network pharmacology was constructed to assess the downstream target of the Xiaoyao Kangai Jieyu Formula in BCRD. In addition, the tail suspension test, sucrose preference test, and forced swimming test were used to test the symptom of depression in mice. Fluoro-Jade B staining was performed to observe the structure of neurons. RT-qPCR and western blot were applied to evaluate mRNA and protein levels. Besides, ELISA was performed to test the inflammatory responses and the immune response-related cytokines. Results: Quercetin was identified as the key component of the Xiaoyao Kangai Jieyu Formula. Quercetin significantly inhibited BCRD-induced neuron pyroptosis via downregulation of PYD and card domain containing (ASC), NLR family pyrin domain containing 3 (NLRP3), and caspase-1, and quercetin could reverse BCRD-caused inhibition of neuron viability. Quercetin significantly attenuated the symptom of BCRD in mice, and it could reverse the contents of 5-hydroxytryptamine (5-HT), dopamine (DA), and neutrophil elastase (NE) in mice. Moreover, quercetin could promote the immune responses in xenograft mice via upregulation of interleukin- (IL-) 2, interferon-γ (IFN-γ), and IL-10. Conclusion: Quercetin, the active ingredient of the Xiaoyao Kangai Jieyu Formula, effectively mitigated the progression of BCRD by inhibiting pyroptosis, promoting immune response, and improving serum metabolism.
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Neoplasias de la Mama , Quercetina , Animales , Neoplasias de la Mama/tratamiento farmacológico , Depresión/tratamiento farmacológico , Femenino , Humanos , Inmunidad , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis , Quercetina/uso terapéuticoRESUMEN
Photodynamic therapy (PDT) provides apparent survival benefits for unresectable cholangiocarcinoma patients. the insufficient sensitivity of cancer cell to PDT treatment limits the clinical application. In this study, according to the GEO datasets, WNT7B expression was decreased by PDT treatment in cholangiocarcinoma samples. In cholangiocarcinoma cells, PDT treatment inhibited Wnt signaling, suppressed cell viability, and enhanced cell apoptosis. Within cholangiocarcinoma cells, PDT treatment induced p53 and miR-34a-5p expression. Under PDT treatment, p53 knockdown downregulated miR-34a-5p expression, whereas the inhibition effect of p53 knockdown on miR-34a-5p could be partially attenuated by agomir-34a-5p. p53 knockdown enhanced cell viability and suppressed cell apoptosis, whereas miR-34a-5p overexpression exerted opposite effects; miR-34a-5p overexpression partially attenuated p53 knockdown effects on PDT-treated cholangiocarcinoma cells. miR-34a-5p directly targeted WNT7B and inhibited WNT7B expression. Under PDT treatment, WNT7B knockdown inhibited the Wnt signaling and cell viability, and promoted cell apoptosis, while miR-34a-5p suppression showed the opposite trends; WNT7B knockdown partially attenuated miR-34a-5p inhibition effects on PDT-treated cholangiocarcinoma cells. In conclusion, PDT treatment induces p53-induced miR-34a transactivation to inhibit cholangiocarcinoma cell proliferation; the miR-34a-5p/WNT7B axis and Wnt signaling are involved.
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Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , MicroARNs/metabolismo , Fotoquimioterapia/efectos adversos , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Wnt/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Vía de Señalización Wnt/genéticaRESUMEN
@#Objective To investigate the efficacy and mechanism of action of Compound Chaijin Jieyu Tablets (复方柴金解郁片, CCJJYT) in rats with insomnia complicated with depression. Methods Seventy-two Sprague-Dawley rats were randomly assigned into eight groups: the control, chronic unpredictable mild stress (CUMS), sleep deprivation (SD), CUMS + SD, positive drug (venlafaxine hydrochloride + diazepam), CCJJYT high-dose (CCJJYT˗2×), medium-dose (CCJJYT˗1×), and low-dose (CCJJYT˗0.5×) groups, with nine rats in each group. Depression-like behavior was evaluated by body weight, food intake, and behavioral tests such as the sucrose preference test (SPT), open field test (OFT), forced swimming test (FST), and pentobarbital-induced sleep test (PST). Hematoxylin-eosin (HE) staining and Golgi-Cox staining were used to observe changes in pathological tissue and synaptic morphology, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to detect the contents of orexin-A and acetylcholine. The expression levels of orexin receptor 1 (OXR1), melatonin receptor 1 (MT1A), melatonin receptor 2 (MT1B), acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) were detected by immunohistochemistry and Western blot. Results In the present study, rats in the model group showed significant behavioral changes as well as a reduction in hippocampal dendritic branch length and synaptic number, along with increasing the content of orexin A and acetylcholine (P< 0.05), and altered expression levels of OX1R, MT1A, MT1B, ChAT, and AChE in the hippocampus and prefrontal cortex after modeling (P < 0.05). CCJJYT can improve depressive insomnia behavior and synaptic plasticity of rats (P < 0.05), which is similar to that of the positive drug group. It can also decrease the content of orexin A and acetylcholine, and reduce the expression levels of OXR1 and ChAT in hippocampus and prefrontal cortex (P < 0.05), and increase the expression levels of MT1A, MT1B, and AChE proteins (P < 0.05). Conclusion CCJJYT has good antidepressant and insomnia effects, probably through the regu-lation of orexin-A, melatonin, and acetylcholine content in hippocampus and prefrontal cortex of rats, improving synaptic plasticity and thus exerting antidepressant and insomnia effects.
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Diabetes-related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes-related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes-related depression might be associated with the mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-glutamate receptor2 (GluR2)-Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive-like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu-GluR2-Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy-induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy-mediated hippocampal neuron apoptosis, triggered by aberrant Glu-GluR2-Parkin pathway, is responsible for depressive-like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.
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Apoptosis , Depresión/metabolismo , Diabetes Mellitus Experimental/complicaciones , Hipocampo/metabolismo , Mitofagia , Neurotransmisores/metabolismo , Animales , Células Cultivadas , Depresión/etiología , Diabetes Mellitus Experimental/psicología , Hipocampo/citología , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/agonistas , Receptores AMPA/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Clinical studies have shown that diabetes can present with underlying depression, and a combination of the two can lead to emotional, memory and cognitive disorders, closely associated with hippocampal neuroinflammation. However, the mechanism underlying the development of hippocampal neuroinflammation under the above condition remains elusive. The aims of this study were to explore the pathogenesis of diabetes combined with depression, and the effect of dexamethasone (Dex), a glucocorticoid receptor (GR) agonist, on hippocampal neuroinflammation in diabetic rats with chronic unpredictable mild stress (CUMS). Therefore, rats were intragastrically fed on a high-fat diet (10% cholesterol 10 ml/kg) for 14 days and thereafter injected with 38 mg/kg of streptozotocin on the 15th day to induce diabetes. Dex treatment of the diabetic and CUMS rats ameliorated the depression-associated behavior in the respective rats. Apart from enhanced depressive behavior, diabetes-depressed condition also up-regulated the expression of hippocampus microglia chemokine â receptor (CX3CR1) and secretion of several pro-inflammatory factors, in particular, interleukin 1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor - α (TNF-α). Hematoxylin-eosin staining revealed inflammatory damages in the hippocampus. Western blot analysis further revealed repression of GR proteins converse to the nuclear factor kappa-B (NF-κB) proteins, which were up-regulated. Intriguingly, Dex reversed the above events by inhibiting inflammatory reactions in the hippocampus. Consequently, played an antidepressant effect in diabetic and CUMS model rats. Overall, findings of this research suggest that the physiopathology of diabetes with stress cormobity are mediated by inflammatory reactions in the hippocampus. In particular, the responses are associated with regulation of GR/NF-κB signaling pathway.
Asunto(s)
Depresión/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hipocampo/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , FN-kappa B/metabolismo , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/metabolismo , Animales , Antidepresivos/farmacología , Conducta Animal , Glucemia/metabolismo , Enfermedad Crónica , Citocinas/metabolismo , Depresión/fisiopatología , Depresión/prevención & control , Depresión/psicología , Dexametasona/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Glucocorticoides/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Inflamación/fisiopatología , Inflamación/prevención & control , Inflamación/psicología , Lípidos/sangre , Prueba del Laberinto Acuático de Morris , Prueba de Campo Abierto , Ratas Sprague-Dawley , Receptores de Glucocorticoides/agonistas , Transducción de Señal , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression, and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetes-related depression. However, the underlying mechanism remains unclear. We hypothesized that diabetes-related depression might be associated with the glutamate (Glu)/metabotropic glutamate receptor2/3 (mGluR2/3)/phosphoinositide 3-kinase (PI3K) pathway, activated by glucocorticoid receptors in the hippocampal neurovascular unit. To test this hypothesis, rat hippocampal neurovascular unit models, containing hippocampal neurons, astrocytes, and brain microvascular endothelial cells, were treated with 150 mM glucose and 200 µM corticosterone, to induce diabetes-related depression. Our results showed that under conditions of diabetes complicated by depression, hippocampal neurovascular units were damaged, leading to decreased barrier function; elevated Glu levels; upregulated glucocorticoid receptor, vesicular glutamate transporter 3 (VGLUT-3), and metabotropic glutamate receptor 2/3 (mGluR2/3) expression; downregulated excitatory amino acid transporter 1 (EAAT-1) expression; and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase (ERK)/glial cell-derived neurotrophic factor (GDNF)/PI3K signaling pathway. Moreover, the viability of neurons was dramatically reduced in the model of diabetes-related depression, and neuronal apoptosis, and caspase-3 and caspase-9 expression levels, were increased. Our results suggest that the Glu/mGluR2/3/PI3K pathway, induced by glucocorticoid receptor activation in the hippocampal neurovascular unit, may be associated with diabetes-related depression. This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine, China (approval No. HN-ZYFY-2019-11-12) on November 12, 2019.
RESUMEN
BACKGROUND: Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). METHODS: The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. RESULTS: The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood-brain barrier function. CONCLUSION: In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.