ABSTRACT
Liver injury and progressive liver failure are severe life-threatening complications in sepsis, further worsening the disease and leading to death. Macrophages and their mediated inflammatory cytokine storm are critical regulators in the occurrence and progression of liver injury in sepsis, for which effective treatments are still lacking. l-Ascorbic acid 6-palmitate (L-AP), a food additive, can inhibit neuroinflammation by modulating the phenotype of the microglia, but its pharmacological action in septic liver damage has not been fully explored. We aimed to investigate L-AP's antisepticemia action and the possible pharmacological mechanisms in attenuating septic liver damage by modulating macrophage function. We observed that L-AP treatment significantly increased survival in cecal ligation and puncture-induced WT mice and attenuated hepatic inflammatory injury, including the histopathology of the liver tissues, hepatocyte apoptosis, and the liver enzyme levels in plasma, which were comparable to NLRP3-deficiency in septic mice. L-AP supplementation significantly attenuated the excessive inflammatory response in hepatic tissues of septic mice in vivo and in cultured macrophages challenged by both LPS and ATP in vitro, by reducing the levels of NLRP3, pro-IL-1ß, and pro-IL-18 mRNA expression, as well as the levels of proteins for p-I-κB-α, p-NF-κB-p65, NLRP3, cleaved-caspase-1, IL-1ß, and IL-18. Additionally, it impaired the inflammasome ASC spot activation and reduced the inflammatory factor contents, including IL-1ß and IL-18 in plasma/cultured superannuants. It also prevented the infiltration/migration of macrophages and their M1-like inflammatory polarization while improving their M2-like polarization. Overall, our findings revealed that L-AP protected against sepsis by reducing macrophage activation and inflammatory cytokine production by suppressing their activation in NF-κB and NLRP3 inflammasome signal pathways in septic liver.
Subject(s)
Inflammasomes , Sepsis , Mice , Animals , Inflammasomes/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Caspase 1/genetics , Caspase 1/metabolism , Interleukin-18 , Macrophage Activation , Signal Transduction , Liver/metabolism , Ascorbic Acid , Sepsis/complications , Sepsis/drug therapy , Lipopolysaccharides/pharmacologyABSTRACT
Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.
Subject(s)
Angiotensin II , Hypertension , Mice , Male , Animals , Angiotensin II/metabolism , Fibronectins/metabolism , AMP-Activated Protein Kinases/metabolism , Vascular Remodeling , Calcium/metabolism , Muscle, Smooth, Vascular/metabolism , Endoplasmic Reticulum StressABSTRACT
In this work, shrimp shell-derived magnetic NiFe2O4/N, O co-doped porous carbon nanozyme with superior oxidase (OXD)-like activity was prepared and used for colorimetric/photothermal/smartphone dual-signal triple-mode detection of antioxidants in fruits and beverages. The magnetic NiFe2O4/N, O co-doped porous carbon (MNPC) material was triumphantly fabricated using a combined in-situ surface chelation and pyrolysis method. The resultant MNPC composite exhibits a superior OXD-like activity, which can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) for yielding colorimetric/temperature dual-signal (CTDS) in absence of H2O2. This CTDS output sensor was successfully used for the determination of ascorbic acid and tannic acid. The proposed CTDS sensor with good specificity and high sensitivity can satisfy different on-site analysis requirements. Interestingly, the MNPC as a sustainable filler was further used for improving packaging properties of polyvinyl alcohol film. In short, this work offers a large-scale and cheap method to fabricate magnetic carbon-based nanozyme for monitoring antioxidants and ameliorating packaging properties.
Subject(s)
Aluminum Oxide , Antioxidants , Hydrogen Peroxide , Magnesium Oxide , Polyphenols , Porosity , Carbon , ColorimetryABSTRACT
This study aims to investigate the mechanism of acacetin in protecting rats from cerebral ischemia-reperfusion injury via the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. Wistar rats were randomized into sham, model, low-and high-dose acacetin, and nimodipine groups, with 10 rats in each group. The rat model of middle cerebral artery occlusion(MCAO) was established with the improved suture method in other groups except the sham group. The neurological deficit score and cerebral infarction volume of each group were evaluated 24 h after modeling. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1ß(IL-1ß), IL-6, tumor necrosis factor-α(TNF-α), malondialdehyde(MDA), supe-roxide dismutase(SOD), and glutathione(GSH). Western blot was employed to determine the expression levels of B-cell lymphonoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and TLR4/NLRP3 signaling pathway-related proteins(TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß) in the rat brain tissue. Hematoxylin-eosin(HE) staining was employed to reveal the histopathological changes in the ischemic area. Compared with the sham group, the modeling of MCAO increased the neurological deficit score and cerebral infarction volume, elevated the IL-1ß, IL-6, TNF-α, and MDA levels and lowered the SOD and GSH levels in the brain tissue(P<0.05). Compared with the MCAO model group, low-and high-dose acacetin and nimodipine decreased the neurological deficit score and cerebral infarction volume, lowered the IL-1ß, IL-6, TNF-α, and MDA levels and elevated the SOD and GSH levels in the brain tissue(P<0.05). Compared with the sham group, the model group showed up-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß and down-regulated protein level of Bcl-2 in the brain tissue(P<0.05). Compared with the MCAO model group, the acacetin and nimodipine groups showed down-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1ß, and cleaved IL-1ß and up-regulated protein level of Bcl-2 in the brain tissue(P<0.05). In conclusion, acacetin regulates the TLR4/NLRP3 signaling pathway to inhibit neuroinflammatory response and oxidative stress, thus exerting the protective effect on cerebral ischemia-reperfusion injury in rats.
Subject(s)
NF-kappa B , Reperfusion Injury , Rats , Animals , NF-kappa B/genetics , NF-kappa B/metabolism , bcl-2-Associated X Protein , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Tumor Necrosis Factor-alpha/metabolism , Rats, Sprague-Dawley , Caspase 1/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Nimodipine/pharmacology , Interleukin-6 , Rats, Wistar , Signal Transduction , Infarction, Middle Cerebral Artery , Reperfusion Injury/drug therapy , Reperfusion Injury/genetics , Reperfusion Injury/prevention & control , Superoxide Dismutase/metabolismABSTRACT
The increase of circulating galactose-deficient IgA1 (Gd-IgA1) is caused by excessive activation of IgA-positive secretory cells in the process of mucosal immune responses, which is a critical link in the pathogenesis of IgA nephropathy (IgAN). Peyer's patch, the prominent place where B lymphocytes are transformed into IgA-secreting plasma cells, is the primary source of IgA. In addition, the lower expression of core 1ß-1,3-galactosyltransferase (C1GalT1) and its molecular chaperone, C1GalT1-specific molecular chaperone (Cosmc), is related to abnormal glycosylation of IgA1 in IgAN patients. Our clinical experience shows that Dioscoreae Nipponicae Rhizoma's (DNR) herbal medicine can relieve proteinuria and hematuria and improve renal function in IgAN patients. Dioscin (DIO) is one of the main active ingredients of DNR, which has various pharmacological activities. This study explores DIO's possible mechanism in treating IgAN.The IgAN model mouse was established by mucosal immune induction. The mice were divided into the control, model, and DIO gavage groups. The glomerular IgA deposition in mice, renal pathological changes, and B cell markers CD20 and CXCR5 expression in Peyer's patch were detected by immunofluorescence and immunohistochemistry. After lipopolysaccharide (LPS) stimulation, DIO's effects on DAKIKI cells proliferation, IgA and Gd-IgA1 secretion, C1GalT1, and Cosmc expression were studied by cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA) test, quantitative real-time polymerase chain reaction (QRT-PCR), and western blotting (WB). In in vivo studies, IgA deposition accompanied by glomerular mesangial hyperplasia and increased expression of CD20 and CXCR5 in Peyer's patch in the IgAN model mouse was alleviated by DIO. In vitro studies showed 0.25 µg/mL to 1.0 µg/mL DIO inhibited LPS-induced DAKIKI cell proliferation, IgA and Gd-IgA1 secretion, and up-regulated the mRNA and protein expression of C1GalT1 and Cosmc. This study demonstrates that DIO may reduce Gd-IgA1 production by inhibiting excessive activation of IgA-secreting cells and up-regulating C1GALT1/Cosmc expression.
Subject(s)
Glomerulonephritis, IGA , Humans , Animals , Mice , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/genetics , Lipopolysaccharides/pharmacology , Immunoglobulin A/metabolism , Molecular Chaperones/metabolism , Galactose/metabolismABSTRACT
Biomineralization inspired the development of simultaneous biological transformations and chemical precipitation for simultaneous nitrogen removal and phosphorus recovery from wastewater, which could compensate for the incapacity of phosphorus management in the new biological route of anaerobic ammonium oxidation (anammox). In this study, we strengthened anammox-mediated biomineralization by long-term feeding of concentrated N, P, and Ca substrates, and a self-assembled matrix of anammox bacteria and hydroxyapatite (HAP) was fabricated in a granular shape, defined as HAP-anammox granules. HAP was identified as the dominant mineral using elemental analysis, X-ray diffraction, and Raman spectroscopy. The intensive precipitation of HAP resulted in a higher inorganic fraction and substantially improved settleability of anammox biomass, which facilitated HAP precipitation by acting as nucleation and metabolically elevated pH. By using X-ray microcomputed tomography, we visually represented the hybrid texture of interwoven HAP pellets and biomass, the core-shell layered architecture of different-sized HAP-anammox granules, and their homogeneously regulated thickness of the outer biofilm (from 118 to 635 µm). This unique architecture endows HAP-anammox granules with outstanding settleability, active biofilm, and tightly bonded biofilm with the carrier, which may explain the excellent performance of these HAP-anammox granules under various challenging operational conditions in previous studies.
Subject(s)
Ammonium Compounds , Sewage , Sewage/chemistry , Anaerobic Ammonia Oxidation , Durapatite , X-Ray Microtomography , Bioreactors/microbiology , Phosphorus , Nitrogen , Biofilms , Oxidation-Reduction , DenitrificationABSTRACT
Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.
Subject(s)
Berberine , Myocardial Infarction , Mice , Animals , Berberine/pharmacology , beta Catenin/metabolism , Myocardium , Myocardial Infarction/drug therapy , Myocytes, Cardiac , Macrophages/metabolismABSTRACT
OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of Iba-1, complement C1q and CD68 in hippocampus of SAMP8 mice, so as to explore its mechanisms underlying improvement of Alzheimer's disease (AD). METHODS: Twenty-four male SAMP8 mice were randomly and equally divided into model and EA groups, and 12 SAMR1 mice were used as the control group. EA (2 Hz, 1.5-2.0 mA) was applied to "Baihui" (GV20), "Dazhui"(GV14) and "Shen-shu"(BL23) for 20 min once daily in the EA group, each course of treatment was 8 days, with an interval of 2 days between two courses, and the mice were treated for 3 courses. Morris water maze test was performed to assess the learning-memory ability of mice. The positive expression levels of Iba-1 and CD68 proteins in the hippocampus CA1 region were detected by immunohistochemistry. The mRNA and protein expression levels of Iba-1,C1q and CD68 in the hippocampus were detected by real-time PCR and Western blot, separately. RESULTS: Compared with the control group, the average escape latency of Morris water maze test was prolonged in the model group (P<0.01), duration of swimming in the original platform quadrant and the number of original platform crossing were significantly shorter and decreased respectively (P<0.01). Compared with the model group, the average escape latency in the EA group was shortened (P<0.05, P<0.01), the duration of swimming in the original platform quadrant and the number of original platform crossing were significantly prolonged and increased (P<0.01). The immunoactivity of Iba-1 and CD68 in hippocampal CA1 region, and mRNA and protein expression levels of hippocampal Iba-1,C1q and CD68 were significantly up-regulated in the model group in contrast to the control group (P<0.01, P<0.05), and obviously down-regulated except the mRNA expression level of hippocampal Iba-1 in the EA group relevant to the model group (P<0.01, P<0.05). CONCLUSION: EA can improve the learning and memory ability of SAMP8 mice, which may be associated with its effect in inhibiting of complement C1q-dependent microglial phagocytosis in the hippocampus.
Subject(s)
Electroacupuncture , Animals , Complement C1q/genetics , Complement C1q/metabolism , Hippocampus/metabolism , Male , Memory , Mice , Microglia/metabolism , Phagocytosis , RNA, Messenger/metabolismABSTRACT
RATIONALE: Salvianolic acid B (Sal B), the Q-marker in Salvia miltiorrhiza, was proved to present an obvious anti-diabetes effect when treated as a food intake. Until now, the metabolism feature, tissue distribution and anti-diabetes mechanism of Sal B have not been fully elucidated. METHODS: The metabolites of Sal B in rats were profiled using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-diabetes mechanism of Sal B was predicted by network pharmacology. RESULTS: A total of 31 metabolites were characterized in rats after ingestion of Sal B at a dosage of 40 mg/kg, including 1 in plasma, 19 in urine, 31 in feces, 0 in heart, 0 in liver, 0 in spleen, 1 in lung, 1 in kidney and 0 in brain. Among them, 18 metabolites were reported for the first time. Phase I reactions of hydrolysis, hydrogenation, dehydroxylation, hydroxylation, decarboxylation and isomerization, and phase II reactions of methylation were found in Sal B. Notably, decarboxylation and dehydroxylation were revealed in Sal B for the first time. The pharmacology network results showed that Sal B and its metabolites could regulate ALB, PLG, ACE, CASP3, MMP9, MMP2, MTOR, etc. The above targets were involved in insulin signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, etc. CONCLUSIONS: The metabolism feature of Sal B in vivo was systematically revealed, and its anti-diabetes mechanism for further pharmacological validations was predicted based on metabolite profiling and network pharmacology for the first time.
Subject(s)
Benzofurans/pharmacokinetics , Diabetes Mellitus/drug therapy , Drugs, Chinese Herbal/pharmacokinetics , Hypoglycemic Agents/pharmacokinetics , Animals , Benzofurans/administration & dosage , Benzofurans/chemistry , Caspases/genetics , Caspases/metabolism , Chromatography, High Pressure Liquid , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/chemistry , Feces/chemistry , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Isomerism , Kidney/chemistry , Kidney/metabolism , Liver/chemistry , Liver/metabolism , Lung/chemistry , Lung/metabolism , Male , Mass Spectrometry , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Network Pharmacology , Rats , Salvia miltiorrhiza/chemistryABSTRACT
RATIONALE: Characterizing the functional mechanism of quality control marker (Q-marker) was of great importance in revealing the primary pharmacological mechanism of herbs or the other complex system, and drug-related metabolites always contribute to the pharmacological functions. Cortex Phellodendri was used as a core herb in the treatment of diabetes mellitus (DM). As a Q-marker of Cortex Phellodendri, the role of phellodendrine in DM was still unclear. Thus, the characterization of phellodendrine-related metabolites in vivo and the subsequent induced functional mechanism exerted great importance in elucidating the anti-DM mechanism of Cortex Phellodendri. METHODS: An ultra-high-performance liquid chromatography-coupled time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method was developed to profile metabolites of phellodendrine in rats. The potential pharmacological mechanism against DM was predicted by network pharmacology. RESULTS: A total of 19 phellodendrine-related metabolites were screened out in rats for the first time. Among them, M4, M5, M9, and M12 were regarded as the primary metabolites. Meanwhile, phase I metabolic reactions of hydroxylation, demethylation, and isomerization and phase II reactions of glucuronidation and sulfation occurred to phellodendrine; glucuronidation and hydroxylation were the two main metabolic reactions. Moreover, the potential targets of phellodendrine and three main metabolites (M4, M5, and M12) were predicted by a network pharmacological method, and they mainly shared 52 targets, including PDE5A, CHRNA3, SIGMAR1, F3, ESR1, DRD1, DRD2, DRD3, and DRD4. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that calcium signaling pathway, cGMP-PKG signaling pathway, and cAMP signaling pathway were regarded as the core mechanism of phellodendrine to treat DM. CONCLUSION: The metabolic feature of phellodendrine in vivo was revealed for the first time, and its anti-DM mechanism information for further pharmacological validations was also supplied. It also gave a direction to further elucidation of pharmacological mechanism of Cortex Phellodendri in treating DM.
Subject(s)
Chromatography, High Pressure Liquid/methods , Diabetes Mellitus/drug therapy , Drugs, Chinese Herbal/pharmacokinetics , Mass Spectrometry/methods , Quinolizines/pharmacokinetics , Animals , Diabetes Mellitus/metabolism , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/metabolism , Humans , Male , Network Pharmacology , Quinolizines/administration & dosage , Quinolizines/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
River ecosystems are the most important resource of surface freshwater, but they have frequently been contaminated by excessive nutrient input of nitrogen (N) and phosphorus (P) in particular. An efficient and economic river water treatment technology that possesses the capacity of simultaneous N and P removal is urgently required. In this study, a solar-driven, self-sustainable electrolytic treatment was conducted in situ to intensify N and P removal from eutrophic river water. Solar panel was applied to provide the electrolysis setups with energy (voltage 10 ± 0.5 V), and the current density was controlled to be 0.06 ± 0.02 mA cm-2. Results indicated that the average removal efficiencies of total N (TN) and total P (TP) under electrolysis conditions reached 72.4 ± 11.7 and 13.8 ± 5.3 mg m-2 d-1, which were 3.7- and 4.7-fold higher compared to untreated conditions. Enhanced TN removal mainly reflected the abatement of nitrate N (NO3--N) (80.6 ± 4.1%). The formation of ferric ions through the electro-dissolution of the sacrificial iron anode improved TP removal by coprecipitation with SPS. Combined high-throughput sequencing and statistical analyses revealed that electrolysis significantly reshaped the microbial communities in both the sediment-water interface and suspended sediment (SPS), and hydrogenotrophic denitrifiers (e.g., Hydrogenophaga) were highly enriched under electrolysis conditions. These findings indicated that in situ electrolysis is a feasible and effective technology for intensified nutrient removal from river water.
Subject(s)
Microbiota , Waste Disposal, Fluid , Electrolysis , Fresh Water , Nitrogen , Nutrients , Phosphorus , Rivers , WaterABSTRACT
Lonicerae japonicae flos.(LJF) was widely used as a drug to treat upper respiratory tract infection or a tea to clear heat in Asian countries for thousands of years. Despite of its curative effects confirmed by modern pharmacological methods, its functional materials and mechanism against influenza were still unclear and needed further investigation. In this study, an integrated strategy based on in vivo substances profiling and network pharmacology was proposed and applied to screen out the potential anti-influenza substances and mechanism of LJF. An UHPLC/Q-TOF MS method was utilized to profile the chemical components in LJF and their metabolites in rats. The targets of absorbed prototypes were predicted by Swiss Target Prediction, and they were further analyzed by String and Kyoto Encyclopedia of Genes and Genomes (KEGG). As a result, a total of 126 chemical components mainly featuring three chemical structure types were characterized, including 70 iridoid glycosides, 17 caffeoylquinic acids, 24 flavonoids, and 15 other types compounds. Among them, ten N-contained iridoid glycosides were characterized as potential novel compounds. Moreover, 141 xenobiotics (74 prototypes and 67 metabolites) were clearly screened out in rat plasma and urine after ingestion of LJF. Phase II reactions (sulfation, glucuronidation, methylation) and phase I reactions (dehydroxylation, hydrogenation, hydrolysis, N-heterocyclization) were the main metabolic reactions of LJF in rats. Further, a total of 338 targets were predicted and TNF, PTGS2 and EGFR were the three main targets involved in the pathology of influenza. In addition to normal NF-κB pathway, T cell signal pathway and mTOR signal pathway were the other patterns for LJF to achieve its anti-flu effects. Our work provided the meaningful data for further pharmacological validation of LJF against influenza, and a new strategy was also proposed for minimizing the process to reveal the mechanism and functional basis of TCMs.
Subject(s)
Drugs, Chinese Herbal , Influenza, Human , Lonicera , Animals , Chromatography, High Pressure Liquid , Dissection , Drugs, Chinese Herbal/pharmacology , RatsABSTRACT
Traditional Chinese medicine was widely used in China since its definite effects and therapy. The components of TCM were absorbed into the circle system as the format of prototypes or metabolites, which contributed to the therapy or side effects. Declaring the functional changes in this process was of great importance to the clinical applications. In this work, an integrated strategy based on metabolites' profiling and network pharmacology was proposed for exploring the pharmacological changes of compounds in vivo. Arctiin, the main component in Fructus Arctii with various kinds of bioactivities, was used as an example. An ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry and metabolynx™software was applied to characterize the metabolites of arctiin in rats at a dosage of 100 mg/kg; network pharmacology was applied to characterize the functional changes. As a result, fifty-three metabolites (32 in plasma, 40 in urine, 19 in bile, 20 in feces, 1 in brain, 12 in liver and 4 in lungs) were screened out and characterized, and 3 of them were unambitiously identified by comparison with standard substances. Among them, 38 metabolites were reported for the first time. It was found the major metabolic pathways of arctiin in rats were demethylation, lactone-opening and phase II conjugations with sulfate and glucuronide.It also confirmed that M14, M15, M18, M23, M22, M43 and M45 were the major circulating forms of arctiin in rats following oral administration. In addition to the above metabolic reactions, phase I reactions of hydrolysis, demethylation, dehydroxylation were also observed, and dehydrogenation were first revealed metabolic patterns of arctiin in rats. Meanwhile, in addition to the main targets of arctiin (MTOR, EGFR and MAPK14), its metabolites targeted additional 392 targets with additional functions of anti-hepatitis B or viral carcinogenesis (SRC, CAPS3, PIK3CA, CDK4, ESR1, MMP9 and ERBB2). The above results provided very important information for understanding the metabolism and functional changes of arctiinin vivo, and supporting data for further pharmacological evaluation. Our work also provided a newsight for elucidation of functional changes of TCMs in vivo.
Subject(s)
Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal , Furans , Glucosides , Mass Spectrometry/methods , Animals , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/metabolism , Drugs, Chinese Herbal/pharmacokinetics , Furans/administration & dosage , Furans/metabolism , Furans/pharmacokinetics , Glucosides/administration & dosage , Glucosides/metabolism , Glucosides/pharmacokinetics , Male , Metabolic Networks and Pathways , Protein Interaction Maps , Rats , Rats, Sprague-Dawley , Tissue DistributionABSTRACT
This study employed the International Osteoporosis Foundation's One-Minute Osteoporosis Risk Test to examine factors related to the osteoporosis risk of institutional caregivers. In this cross-sectional study, a self-developed structured questionnaire comprising the One-Minute Osteoporosis Risk Test was used to obtain data on the caregivers' demographic data, health habits, working style, and osteoporosis risk. Seven disability welfare institutions were selected as research sites, and 465 copies of questionnaires were distributed to the institutions' employees, with 455 valid responses collected for a valid return rate of 98%. SPSS for Windows (Version 20.0) was used to analyze questionnaire data; descriptive-statistical frequency, a χ2 test, and logistic regression were used to determine the correlation between demographic data, health habits, working style, and osteoporosis risk. The results revealed that primary risk factors include < 30 min of daily exercise (38%), lack of dairy product or calcium tablet intake (28%), and < 10 min of daily outdoor activity or not taking vitamin D supplements (29.9%). In total, 395 (86.8%) of the respondents scored less than 5 in the osteoporosis risk test; the remaining 60 (13.2%) scored 5 or higher, revealing a high risk of early osteoporosis. An independent variable analysis revealed that the risk factors of early osteoporosis include age, education level, having undergone bone density tests, prior disease diagnosis, long-term medication use, physical fitness, dietary habits, and average time of exposure to sunlight. In the multivariate analysis, poor physical fitness (odds ratio [OR] = 2.18, 95% confidence interval [CI]: 1.12-4.27, p = 0.023) and average daily time of exposure to sunlight (OR = 0.24, 95% CI: 0.59-2.59, p < 0.001) were significantly correlated with osteoporosis risk. In other words, respondents with poor physical fitness were 2.18 times as likely to have osteoporosis as those with good physical fitness, and those exposed to sunlight for 30 min or longer every day were 0.24 times as likely to have osteoporosis as those exposed to sunlight for less than 30 min every day. Accordingly, institutions must encourage employees to spend more time in the sun every day and improve their physical fitness through exercise.
Subject(s)
Bone Density , Caregivers/psychology , Exercise , Health Promotion/methods , Osteoporosis/prevention & control , Cross-Sectional Studies , Humans , Risk Factors , Sunlight , Surveys and QuestionnairesABSTRACT
Non-suspended microalgae cultivation technology coupled with wastewater purification has received more scientific attention in recent decades. Since the non-suspended microalgae cultivation is quite different from the suspended ones, the following issues are compared in this study such as advantages and disadvantages, pollutant removal mechanisms and regulations, influential factors, and microalgae biomass accumulation. The analysis aims to support the further application of this technology. The median removal rates of COD, TN, TP, NH4+-N and NO3--N were 91.6%, 78.2%, 87.5%, 93.2% and 81.7%, respectively, by non-suspended microalgae under the TN & TP load rates up to 150 mg·L-1·d-1. The main pathway for TN & TP removal is microalgae cell absorbance. Light intensity, pollutant composition and microalgae metabolic types are the major factors that influence pollutant removal and the lipid content of microalgae. Meanwhile the mechanism concerning how macro-outer conditions influence the micro-environment and further growth of non-suspended microalgae requires more investigation.
Subject(s)
Microalgae , Biomass , Lipids , Nitrogen , Phosphorus , WastewaterABSTRACT
Synaptic loss and dysfunction is associated with cognitive impairment in Alzheimer's disease (AD). Recent evidence indicates that the AMP-activated protein kinase (AMPK)/eukaryotic elongation factor-2 kinase (eEF2K)/eukaryotic elongation factor-2 (eEF2) pathway was implicated in synaptic plasticity in AD. Therapeutic strategies for AD treatment are currently limited. Here, we investigate the effects of electroacupuncture (EA) on synaptic function and the AMPK/eEF2K/eEF2 signaling pathway in male senescence-accelerated mouse-prone 8 (SAMP8) mice. Male 7-month-old SAMP8 and SAMR1 mice (senescence-accelerated mouse resistant 1) were randomly divided into 3 groups: SAMR1 control group (Rc), SAMP8 control group (Pc), and SAMP8 electroacupuncture group (Pe). The Pe group was treated with EA for 30 days. Transmission electron microscopy (TEM) was used to observe the structure of synapse. The protein and mRNA expression of synaptophysin (SYN) and postsynaptic density 95 (PSD95) was examined by immunohistochemistry, western blot, and real-time RT-PCR. The activity of AMPK and eEF2K was studied by western blot. Our results showed that EA ameliorated synaptic loss, increased the expression of SYN and PSD95, and inhibited AMPK activation and eEF2K activity. Collectively, these findings suggested that the mechanisms of EA improving synaptic function in AD may be associated with the inhibition of the AMPK/eEF2K/eEF2 signaling pathway.
ABSTRACT
BACKGROUND Ginkgo biloba extract (EGb761), a standard extract of the Chinese traditional medicine Ginkgo biloba, plays an anti-tumor role in various cancers. However, whether EGb761 is involved in the invasion and metastasis of gastric cancer remains unclear. MATERIAL AND METHODS In the current study, cell viability assay, Western blotting, wound-healing assay, Transwell invasion assay, and orthotopic transplantation model were performed to explore the effects of EGb761 on gastric cancer. RESULTS In vitro, the results showed that EGb761 suppressed the proliferation of gastric cancer cells in a dose-dependent manner. Furthermore, the migration and invasiveness were weakened and the protein levels of p-ERK1/2, NF-kappaB P65, NF-kappaB p-P65, and MMP2 were decreased by EGb761 or U0126 (an inhibitor of ERK signaling pathway) exposure in gastric cancer cells. Moreover, the combined treatment with EGb761 and U0126 significantly inhibited ERK, NF-kappaB signaling pathway, and the expression of MMP2 than those of single drug. In vivo, EGb761 inhibited the tumor growth and hepatic metastasis of gastric cancer in the mouse model. Results of immunohistochemistry indicated that the expression of ERK1/2, NF-kappaB P65 and MMP2 were decreased by EGb761 in the tumor tissues. CONCLUSIONS EGb761 plays a vital role in the suppression of metastasis and ERK/NF-kappaB signaling pathway in gastric cancer.
Subject(s)
Extracellular Signal-Regulated MAP Kinases/metabolism , NF-kappa B/metabolism , Plant Extracts/therapeutic use , Signal Transduction , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Animals , Butadienes/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Ginkgo biloba , Humans , MAP Kinase Signaling System/drug effects , Matrix Metalloproteinase 2/metabolism , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Nitriles/pharmacology , Phosphorylation/drug effects , Signal Transduction/drug effectsABSTRACT
Constructed wetland (CW) for wastewater treatment has attracted increasing attention. In this review, the system configuration optimization, purification effect and general mechanisms of nitrogen removal in CW are systematically summarized and discussed. Ammonia oxidation is a crucial and primary process for total nitrogen (TN) removal in domestic or livestock wastewater treatment. Aeration, waterdrop influent and tidal operation are three main methods to strengthen the oxygen supplement and nitrification process in CW. Aeration significantly increases the ammonia removal rate (almost 100%), followed by the removal of chemical oxygen demand (COD) and TN. Solid carbon source, iron and anode material can be filled as electron donor for the denitrification process. The co-adjustment of oxygen and carbon/electron donor can form different conditions for different nitrogen removal pathways (e.g. the simultaneous nitrification-denitrification, the partial nitrification-denitrification and the anammox process), and achieve the optimal removal of nitrogen.
Subject(s)
Wastewater , Wetlands , Denitrification , Nitrification , NitrogenABSTRACT
Based on the requirements for advanced treatment and resource recovery of nitrogen and phosphorus pollutants in wastewater, the coupled anammox and hydroxyapatite crystallization (anammox-HAP) process was studied with an aim of achieving high efficiency and low energy consumption during simultaneous nitrogen and phosphorus removal. In the long-term experiments and batch tests, the effects of substrate conditions (nitrogen and phosphorus load, calcium concentration, etc.) on the nitrogen removal and phosphorus recovery efficiencies were investigated. The granular structure and crystal properties were analyzed together with microscopic characterization methods, and the formation mechanism of coupled anammox-HAP granules was verified. Based on these experiments, a theoretical model and technical method for realizing the coupled process were established, and a reference for practical engineering application was provided.
Subject(s)
Nitrogen , Phosphorus , Bioreactors , Crystallization , Denitrification , Durapatite , Oxidation-ReductionABSTRACT
BACKGROUND: Hirudin, an extract from Hirudo spp., is an anticoagulant used to treat a variety of renal diseases, including diabetic nephropathy (DN). Currently, hirudin has to be used at high dosages to treat DN because it poorly targets the kidneys, although at high dosages it can have severe side effects. Developing a targeted drug delivery system for hirudin, then, could boost its positive therapeutic effects while lowering the risk of side effects. Liposomes have been demonstrated to have significant renal targeting potential, but here we show that a hirudin-loaded liposome is an effective delivery method for patients with DN. METHOD: In this study, we prepared a hirudin/liposome complex and tested its efficacy by injecting it into a rat model. We then compared the renal accumulation of hirudin between complex-injected rat models and rat models that received injections of hirudin alone. We also investigated the mechanisms behind the complex's effects. RESULT: The hirudin/liposome complex increased the accumulation of hirudin in kidney tissues and relieved the renal injury in DN rat models. Moreover, the hirudin/liposome complex down-regulated the expression of TGF-ß1 and VEGF in the kidneys. CONCLUSION: We demonstrated that a hirudin/liposome complex can have a significant positive effect on DN. The mechanism may be that the complex inhibits the expression of VEGF and TGF-ß1.