ABSTRACT
BACKGROUND: Icaritin has a wide range of pharmacological activities, including significant an-titumor activity. However, the mechanism of action of icaritin in endometrial cancer (UCEC) remains unknown. FOX proteins are a highly conserved transcription factor superfamily that play important roles in epithelial cell differentiation, tumor metastasis, angiogenesis, and cell cycle regulation. FOXC1 is an important member of the FOX protein family. FOXC1 is aberrantly expressed in endometrial cancer and may play a role in the migration and invasion of endometrial cancer; however, its mechanism of action has not yet been reported. O-GlcNAc glycosylation is a common post-translational modification. In endometrial cancer, high levels of O-GlcNAcylation promote cell proliferation, migration, and invasion. Cancer development is often accompanied by O-GlcNAc modification of proteins; however, O-GlcNAc modification of the transcription factor FOXC1 has not been reported to date. PURPOSE: To investigate the inhibitory effects of icaritin on RL95-2 and Ishikawa endometrial cancer cells in vitro and in vivo and to elucidate the possible molecular mechanisms. METHODS/STUDY DESIGN: CCK8, colony formation, migration, and invasion assays were used to determine the inhibitory effects of icaritin on endometrial cancer cells in vitro. Cell cycle regulation was assayed by flow cytometry. Protein levels were measured based on western blotting. The level of FOXC1 expression in endometrial cancer tissues was determined by immunohistochemistry. To assess whether icaritin also has activity in vivo, its effect on tumor xenografts was evaluated. RESULTS: Immunohistochemical analysis of clinical samples revealed that FOXC1 expression was significantly higher in endometrial cancer tissues than in normal tissues. Downregulation of FOXC1 inhibited the proliferative, colony formation, migration, and invasive abilities of RL95-2 and Ishikawa endometrial cancer cells. Icaritin inhibited the proliferation, colony formation, migration, and invasion of endometrial cancer cells and blocked the cell cycle in S phase. Icaritin affected O-GlcNAc modification of FOXC1 and thus the stability of FOXC1, which subsequently triggered the inhibition of endometrial cancer cell proliferation. CONCLUSION: The anti-endometrial cancer effect of icaritin is related to the inhibition of abnormal O-GlcNAc modification of FOXC1, which may provide an important theoretical foundation for the use of icaritin against endometrial cancer.
Subject(s)
Endometrial Neoplasms , Humans , Female , Endometrial Neoplasms/drug therapy , Flavonoids/pharmacology , Cell Division , Cell Proliferation , Forkhead Transcription FactorsABSTRACT
Okra (Abelmoschus esculentus (L.) Moench) is rich in various bioactive ingredients and used as a medicinal plant in traditional medicine. In the present study, to find the polysaccharide with anti-lipotoxicity effects from okra and clarify its structure, a pectin OP-1 was purified from okra, which had a backbone containing â4)-α-GalpA-(1 â residues, and 1,5-Ara linked the main chain through the O-3 of the residue â3,4)-α-GalpA-(1â, and the C-6 of residue 1, 4-α-GalpA replaced by methyl ester. In vitro experiments showed that OP-1 pretreatment alleviated oleic acid (OA)-induced lipid accumulation, ROS generation, apoptosis, transaminase leakage, and inflammatory cytokine secretion in HepG2 cells, resulting in reduced lipotoxicity. Further molecular results revealed that OP-1 increased Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and affected the expression of AMPK downstream targets, including inhibit SREBP1c and FAS, as well as activate CPT-1A. Impressively, AMPK inhibitor dorsomorphin (Compound C) blocked the effects of OP-1 against lipotoxicity. The effects of OP-1 on lipid metabolism were also diminished by dorsomorphin. Our results demonstrated that OP-1 possesses a potent function in preventing lipotoxicity via regulating AMPK-mediated lipid metabolism and provide a novel insight into the future utilization of okra polysaccharide.
Subject(s)
Abelmoschus , Pectins , Pectins/pharmacology , Abelmoschus/chemistry , AMP-Activated Protein Kinases , Polysaccharides/pharmacology , Polysaccharides/chemistry , Antioxidants/chemistrySubject(s)
Abdominal Pain , Drugs, Chinese Herbal , Female , Humans , Middle Aged , Abdominal Pain/diagnosis , Abdominal Pain/etiologyABSTRACT
Objective: To discuss whether tongue acupuncture is more effective than traditional acupuncture in the treatment of poststroke dysarthria and explore the advantage of tongue acupuncture treatment parameters. Methods: We evaluated the efficacy of tongue acupuncture compared with traditional acupuncture through a rigorous meta-analysis process. The included studies were from eight databases in English and Chinese. The Cochrane risk of bias assessment tool was used to evaluate the quality of studies. Stata15.1 software was used for meta-analysis and sensitivity analysis. Tongue acupuncture therapeutic parameters were classified and counted based on tongue acupoint location, acupuncture manipulation, and the number of manipulations. Subgroup analysis was used to compare the differences between various treatment parameters. Outcome The meta-analysis eventually included a total of 9 studies. Tongue acupuncture is superior to traditional acupuncture in clinical efficacy [OR = 3.62, 95%Cl (2.24, 5.85), P < 0.0001], FDA score [SMD = -1.99, 95%Cl (-3.77, -0.21), P=0.028], and NIHSS score [WMD = 0.86, 95%Cl (0.15, 1.57), P=0.017, I2 = 31.7%] in the treatment of poststroke dysarthria. According to the classified statistics of tongue acupuncture treatment parameters, there are three kinds of tongue acupuncture points in 9 studies: lingual surface, sublingual, and both lingual surface and sublingual acupoints. The operation methods include the oblique stabbing of the root of the tongue, twisting after stabbing, and acupoint pricking. The number of operation methods varies from 1 to 3. Conclusion: Tongue acupuncture outperforms traditional acupuncture in terms of clinical efficacy, FDA score, and NIHSS score in the treatment of poststroke dysarthria. The curative effect of sublingual acupoints is better than that of lingual surface acupoints, the combined use of multiple manipulations is better than that of a single manipulation, and acupuncture manipulation has a cumulative effect. PROSPERO registration number: CRD42021285722.
ABSTRACT
BACKGROUND: Motor aphasia after stroke is a common and intractable complication of stroke. Acupuncture and language training may be an alternative and effective approach. However, the efficacy of acupuncture and language training for motor aphasia after stroke has not been confirmed. The main objectives of this trial are to evaluate the effectiveness and safety of acupuncture and low-intensity, low-dose language training in treating ischemic motor aphasia after stroke from 15 to 90 days. METHODS: This is a multicenter randomized sham-controlled clinical trial. We will allocate 252 subjects aged between 45 and 75 years diagnosed with motor aphasia after stroke with an onset time ranging from 15 to 90 days into two groups randomly in a 1:1 ratio. Patients in the experimental group will be treated with "Xing-Nao Kai-Qiao" acupuncture therapy plus language training, and those in the control group will be treated with sham-acupoint (1 cun next to the acupoints) acupuncture therapy plus language training. All the patients will be given acupuncture and language training for 6 weeks, with a follow-up evaluation 6 weeks after the end of the treatment and 6 months after the onset time. The patients will mainly be evaluated using the Western Aphasia Battery and Chinese Functional Communication Profile, and the incidence of treatment-related adverse events at the 2nd, 4th, and 6th weeks of treatment will be recorded. The baseline characteristics of the patients will be summarized by group, the chi-squared test will be used to compare categorical variables, and repeated measures of analysis of variance or a linear mixed model will be applied to analyze the changes measured at different time points. DISCUSSION: The present study is designed to investigate the effectiveness and safety of traditional acupuncture therapy and language training in ischemic motor aphasia after stroke and explore the correlation between the treatment time and clinical effect of acupuncture. We hope our results will help doctors understand and utilize acupuncture combined with language training. TRIAL REGISTRATION: ChiCTR ChiCTR1900026740 . Registered on 20 October 2019.
Subject(s)
Acupuncture Therapy , Aphasia, Broca , Language Therapy , Stroke , Acupuncture Points , Acupuncture Therapy/adverse effects , Acupuncture Therapy/methods , Aged , Aphasia, Broca/etiology , Aphasia, Broca/therapy , Combined Modality Therapy/adverse effects , Humans , Language Therapy/methods , Middle Aged , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Stroke/complications , Treatment OutcomeABSTRACT
Professor GAO Wei-bin's clinical experience of electroacupuncture (EA) with dense wave at periotic points for neurotic tinnitus is introduced. Based on the basic theory of TCM and the perspective of neuroanatomy, EA with dense wave at new periotic points (four points at mastoid process) and Ermen (TE 21), Tinggong (SI 19) could have the effects of qi reaching affected area, and play the treatment role of "where the acupoint is, where the efficacy is".
Subject(s)
Electroacupuncture , Tinnitus , Humans , Tinnitus/therapy , Acupuncture Points , Medicine, Chinese TraditionalABSTRACT
Crassostrea sikamea (C.sikamea) is an important edible and medicinal seafood in China. In the present study, a compound named flazin was separated and identified from the ethyl acetate extract of C.sikamea (EAECs) for the first time. In addition, the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetra zolium (MTS) assay revealed that EAECs and flazin inhibited the transformation of splenic lymphocytes in vitro. Moreover, flazin (20 µg·mL-1) altered the populations of splenic lymphocyte subtypes. Real-time quantitative PCR (RT-qPCR) analysis and enzyme-linked immunosorbent assay (ELISA) showed that flazin suppressed the mRNA expression and secretion of TNF-α and IL-2, and reversed Concanavalin A (ConA)-induced mRNA up-regulation and protein secretion of TNF-α and IL-2. Western blot results showed that flazin reversed ConA-induced increases in p-ERK1/2 and p-p38 in splenocytes. In conclusion, flazin exhibits effective immunomodulatory function and may be useful for treating immune-related disorders, which indicates the application potential of C.sikamea as a functional food or immunomodulator.
Subject(s)
Crassostrea , Animals , Carbolines , Furans , Lymphocytes , Rats , Rats, Sprague-Dawley , SpleenABSTRACT
BACKGROUND: When the patients of advanced non-squamous non-small cell lung cancer (NSCLC) have achieved remission by induction therapy, it is controversial that combination with bevacizumab is used as maintenance therapy. Pemetrexed is a classic drug for maintenance therapy, is bevacizumab the superiority to pemetrexed is also unclear. This meta-analysis aims to evaluate the effectiveness and safety of advanced non-squamous NSCLC in the maintenance treatment. METHOD: From the establishment as of December 6, 2020, PubMed, Embase, and Cochrane electronic databases were searched and the American Society of Clinical Oncology, European Society of Medical Oncology, and National Comprehensive Cancer Network databases in the past 10 years. The application of combination with bevacizumab, pemetrexed was studied in clinical trials of maintenance treatment for advanced NSCLC. The extracted data include progression-free survival (PFS), overall survival (OS), and grade 3-4 adverse events (AE). RESULTS: Seven clinical trials we screened, 6 were phase III RCTs, and a cohort trial, including 3298 patients. Compared with bevacizumab and pemetrexed, PFS of combination with bevacizumab was significantly improved (hazard ratio [HR]â=â0.71, 95% confidence interval [CI]â=â0.65-0.77, Pâ<â.00001), but OS was not improved (HRâ=â0.93, 95% CIâ=â0.85-1.01, Pâ=â.10). Compared with bevacizumab and pemetrexed, no significant difference of PFS (HRâ=â0.87, 95% CIâ=â0.69-1.09, Pâ=â.21), and OS (HRâ=â0.87, 95% CIâ=â0.72-1.05, Pâ=â.15) was found. A higher incidence of grade 3-4 AE occurred in combination with bevacizumab (odds ratioâ=â1.63, 95% CIâ=â1.35-1.97, Pâ<â.00001). CONCLUSIONS: PFS was significantly improved in patients with advanced non-squamous NSCLC who use bevacizumab combination with single-agent as maintenance treatment, but it does not translate into the advantages of OS; compared with bevacizumab, no PFS and OS benefits were found. A higher incidence of grade 3-4 AE occurred in combination with bevacizumab than pemetrexed and bevacizumab.
Subject(s)
Bevacizumab/pharmacology , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Medication Therapy Management/standards , Pemetrexed/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Treatment OutcomeABSTRACT
The bulbs of several Lilium species are considered to be both functional foods and traditional medicine in northern and eastern Asia. Considering the limited information regarding the specific bioactive compounds contributing to the functional properties of these bulbs, we compared the secondary metabolites of ten Lilium bulb samples belonging to five different species, using an ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS)-based secondary metabolomics approach. In total, 245 secondary metabolites were detected; further, more metabolites were detected from purple Lilium bulbs (217 compounds) than from white bulbs (123-171 compounds). Similar metabolite profiles were detected in samples within the same species irrespective of where they were collected. By combining herbal analysis and screening differential metabolites, steroid saponins were considered the key bioactive compounds in medicinal lilies. Of the 14 saponins detected, none were accumulated in the bulbs of L. davidii var. willmottiae, also called sweet lily. The purple bulbs of L. regale accumulated more secondary metabolites, and, notably, more phenolic acid compounds and flavonoids. Overall, this study elucidates the differential metabolites in lily bulbs with varying functions and colors and provides a reference for further research on functional foods and the medicinal efficacy of Lilium species.
Subject(s)
Flavonoids/analysis , Hydroxybenzoates/analysis , Lilium/metabolism , Metabolome , Plant Extracts/metabolism , Plant Roots/metabolism , Chromatography, High Pressure Liquid , Discriminant Analysis , Lilium/chemistry , Lilium/classification , Plant Roots/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729 × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.
Subject(s)
Cytochrome P-450 CYP3A/genetics , Drugs, Chinese Herbal/pharmacology , Immunosuppressive Agents/pharmacokinetics , Tacrolimus/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , China , Dose-Response Relationship, Drug , Drug Therapy, Combination , Genotype , Hematocrit , Humans , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Monte Carlo Method , Polymorphism, Single Nucleotide , Retrospective Studies , Tacrolimus/administration & dosageABSTRACT
Baihui-penetrating-Qubin acupuncture is frequently used to treat intracerebral hemorrhage (ICH) in China. Acupuncture affects multiple microRNAs in diseases. MicroRNA-23a-3p (miR-23a-3p) has been demonstrated to be up-regulated in ICH patients. Herein, the effect of Baihui-penetrating-Qubin acupuncture on miR-23a-3p expression after ICH and the role of miR-23a-3p in ICH were discussed. A rat model of ICH was induced by infusing autologous blood into caudate nucleus. Acupuncture was performed after ICH once a day for 30 min. After 3 consecutive days of acupuncture, the neurobehavioral function, brain edema, neuronal cell death, inflammation, ferroptosis, nuclear factor E2-like 2 (NFE2L2) signaling and miR-23a-3p levels in brain tissues were analyzed. Additionally, antagomiR-23a-3p was injected into rats 3 days prior to ICH modeling to analyze the function of miR-23a-3p in neuronal cell death, inflammation, ferroptosis, and NFE2L2 signaling. Acupuncture relieved the ICH-induced neurological function deficits, increases in brain water content and Fluoro-Jade B (FJB)-positive cells and release of proinflammatory cytokines. Acupuncture also alleviated ferroptosis and decreased miR-23a-3p expression, as evidenced by the increased NFE2L2 nuclear translocation and expressions of heme oxygenase-1 and glutathione peroxidase 4 and the decreased iron and malondialdehyde contents and reactive oxygen species accumulation. Additionally, antagomiR-23a-3p inhibited the ICH-induced increases in FJB-positive cells, release of proinflammatory cytokines, ferroptosis, and promoted NFE2L2 activation. Notably, the binding site of miR-23a-3p existed in NFE2L2. Taken together, acupuncture may alleviate the neuronal cell death, inflammation, and ferroptosis after ICH by down-regulating miR-23a-3p. This study provides a potential mechanism underlying the Baihui-penetrating-Qubin acupuncture improving the early injury after ICH.
Subject(s)
Acupuncture Therapy/methods , Apoptosis , Cerebral Hemorrhage/therapy , Ferroptosis , MicroRNAs/metabolism , Neurons/metabolism , Animals , Cells, Cultured , Cerebral Hemorrhage/metabolism , Cytokines/genetics , Cytokines/metabolism , Down-Regulation , Male , MicroRNAs/genetics , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
To study the effect of scalp acupuncture (SA) on the mitophagy signaling pathway in the caudate nucleus of Sprague-Dawley rats following intracerebral hemorrhage (ICH). An ICH model was established by injecting autologous arterial blood into the caudate nucleus in 200 male Sprague-Dawley rats, which were divided into five groups: sham, ICH, 3-methyladenine group (3-MA, 30 mg/kg), SA, and SA+3-MA. Animals were analyzed at 6 and 24 h as well as at 3 and 7 days. Composite neurological scale score was significantly higher in the SA group than in the ICH group. Transmission electron microscopy showed less structural damage and more autophagic vacuoles within brain in the SA group than in the ICH group. SA group showed higher levels of Beclin1, Parkin, PINK1, NIX protein, and a lower level of Caspase-9 in brain tissue. These animals consequently showed less neural cell apoptosis. Compared with the SA group, however, the neural function score and levels of mitophagy protein in the SA+3-MA group were decreased, neural cell apoptosis was increased with more severe structural damage, which suggested that 3-MA may antagonize the protective effect of SA on brain in rats with ICH. SA may mitigate the neurologic impairment after ICH by enhancing mitophagy and reducing apoptosis.
ABSTRACT
OBJECTIVE: To compare the therapeutic effect of electro-nape-acupuncture (ENA) combined with hyperbaric oxygen therapy (HBOT) and single HBOT on refractory flat descending idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: A total of 78 patients were randomized into an ENA combined with HBOT (ENA+HBOT) group and a HBOT group, 39 cases in each one. Patients in both groups were treated with oral extract of ginkgo biloba leaves and mecobalamin tablets. On the basis of the conventional medication treatment, HBOT was adopt in the HBOT group. On the basis of the treatment in the HBOT group, electro-nape-acupuncture was applied at Fengchi (GB 20), Gongxue (Extra), Zhongzhu (TE 3), Waiguan (TE 5) and Yifeng (TE 17), Tinggong (SI 19), Tinghui (GB 2) and the vertigo-auditory area of affected side in the ENA+HBOT group. Pulse acupuncture instrument was connected at Fengchi (GB 20) and Gongxue (Extra) for 30 min (with continuous wave, 2 Hz in frequency), the needles were retained for another 30 min after electroaupuncture. The treatment was given once a day, 6 times a week for 4 weeks in both groups. Before the treatment and 2,4 weeks into the treatment, the average auditory threshold, the scores of tinnitus handicap inventory (THI) and dizziness handicap inventory (DHI) were observed, and the therapeutic effect was evaluated in both groups. RESULTS: Compared before treatment, the average auditory threshold, the scores of THI and DHI of 2,4 weeks into the treatment were decreased in both groups (P<0.000 1). Compared with the HBOT group, the average auditory threshold, the scores of THI and DHI of 4 weeks into the treatment were lower in the ENA+HBOT group (P<0.000 1). The total effective rate was 69.2% (27/39) in the ENA+HBOT group and 51.3% (20/39) in the HBOT group, there was no statistical difference (P>0.05). CONCLUSION: Electro-nape- acupuncture can improve the mean auditory threshold and the symptoms of tinnitus and dizziness in patients with refractory flat descending idiopathic sudden sensorineural hearing loss.
Subject(s)
Acupuncture Therapy , Hearing Loss, Sensorineural/therapy , Hearing Loss, Sudden/therapy , Hyperbaric Oxygenation , Dizziness/therapy , Ginkgo biloba , Humans , Plant Extracts/therapeutic use , Tinnitus/therapy , Treatment Outcome , Vitamin B 12/analogs & derivatives , Vitamin B 12/therapeutic useABSTRACT
The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIAIS178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL+ leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAIS178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL+ leukemia.
Subject(s)
Fusion Proteins, bcr-abl/antagonists & inhibitors , Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Drug Design , Drug Evaluation, Preclinical , Fusion Proteins, bcr-abl/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Piperazines/metabolism , Piperazines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15mg/kg, i.p.) at 0.5h, 2h, and 8h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Liver/drug effects , Sepsis/drug therapy , Sirtuin 1/metabolism , Stilbenes/therapeutic use , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Blueberry Plants/metabolism , Cecum/surgery , Cytokines/metabolism , Disease Models, Animal , Inflammation Mediators/metabolism , Liver/immunology , Male , Mice , Mice, Inbred C57BL , RNA, Small Interfering/genetics , Signal Transduction , Sirtuin 1/genetics , Stilbenes/metabolismABSTRACT
Polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) is an essential enzyme for the growth of Mycobacterium tuberculosis (Mtb) and some other bacteria. Mtb WecA catalyzes the transformation from UDP-GlcNAc to decaprenyl-P-P-GlcNAc, the first membrane-anchored glycophospholipid that is responsible for the biosynthesis of mycolylarabinogalactan in Mtb. Inhibition of WecA will block the entire biosynthesis of essential cell wall components of Mtb in both replicating and non-replicating states, making this enzyme a target for development of novel drugs. Here, we report a fluorescence-based method for the assay of WecA using a modified UDP-GlcNAc, UDP-Glucosamine-C6-FITC (1), a membrane fraction prepared from an M. smegmatis strain, and the E. coli B21WecA. Under the optimized conditions, UDP-Glucosamine-C6-FITC (1) can be converted to the corresponding decaprenyl-P-P-Glucosamine-C6-FITC (3) in 61.5% yield. Decaprenyl-P-P-Glucosamine-C6-FITC is readily extracted with n-butanol and can be quantified by ultraviolet-visible (UV-vis) spectrometry. Screening of the compound libraries designed for bacterial phosphotransferases resulted in the discovery of a selective WecA inhibitor, UT-01320 (12) that kills both replicating and non-replicating Mtb at low concentration. UT-01320 (12) also kills the intracellular Mtb in macrophages. We conclude that the WecA assay reported here is amenable to medium- and high-throughput screening, thus facilitating the discovery of novel WecA inhibitors.
Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Mycobacterium tuberculosis/enzymology , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Bacterial Proteins/metabolism , Drug Evaluation, Preclinical , Transferases (Other Substituted Phosphate Groups)/metabolismABSTRACT
Parthenolide, the principal sesquiterpene lactone present in medicinal plants such as feverfew, has anti-microbial, anti-inflammatory and anticancer activities. In the present study, we investigated the protective role of parthenolide against acute hepatitis in mice. Mice acute hepatitis were induced by Concanavalin A and treated by parthenolide in vivo. Results shown that parthenolide remarkably reduced the congestion and necroinflammation of the mice livers with Concanavalin A-induced acute hepatitis. Meanwhile, parthenolide treatment recover the liver function which indicated by decreased the serum alanine transaminase and alkaline phosphatase activities and promoted the expression of Ki67 in the livers of these mice. In addition, parthenolide administration suppressed the Concanavalin A-induced immune reaction, as indicated by the number of F4/80, CD49b and CD4 cells present in the liver. Furthermore, parthenolide also significantly reduced the expression of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-17A, IL-1ß and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in vitro. Moreover, parthenolide exposure decreased the phosphorylation of STAT3 and p38, and promoted the phosphorylation of p53 in RAW264.7 cells in vitro. In conclusion, parthenolide represents a drug candidate to protect the liver against Concanavalin A-induced acute hepatitis. The possible molecular mechanism involves the anti-inflammatory effects of parthenolide may by suppressing the STAT3/p38 signals and enhanced the p53 signals.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Hepatitis/drug therapy , Liver/drug effects , Macrophages/drug effects , Sesquiterpenes/therapeutic use , Tumor Suppressor Protein p53/metabolism , Acute Disease , Animals , Concanavalin A/immunology , Cytokines/metabolism , Disease Models, Animal , Humans , Immunity, Cellular/drug effects , Inflammation Mediators/metabolism , Liver/metabolism , Liver/pathology , Macrophages/immunology , Male , Mice , RAW 264.7 Cells , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Low-frequency acoustic cues have been shown to enhance speech perception by cochlear-implant users, particularly when target speech occurs in a competing background. The present study examined the extent to which a continuous representation of low-frequency harmonicity cues contributes to bimodal benefit in simulated bimodal listeners. Experiment 1 examined the benefit of restoring a continuous temporal envelope to the low-frequency ear while the vocoder ear received a temporally interrupted stimulus. Experiment 2 examined the effect of providing continuous harmonicity cues in the low-frequency ear as compared to restoring a continuous temporal envelope in the vocoder ear. Findings indicate that bimodal benefit for temporally interrupted speech increases when continuity is restored to either or both ears. The primary benefit appears to stem from the continuous temporal envelope in the low-frequency region providing additional phonetic cues related to manner and F1 frequency; a secondary contribution is provided by low-frequency harmonicity cues when a continuous representation of the temporal envelope is present in the low-frequency, or both ears. The continuous temporal envelope and harmonicity cues of low-frequency speech are thought to support bimodal benefit by facilitating identification of word and syllable boundaries, and by restoring partial phonetic cues that occur during gaps in the temporally interrupted stimulus.
Subject(s)
Cochlear Implantation , Cues , Periodicity , Persons With Hearing Impairments/rehabilitation , Speech Acoustics , Speech Perception , Acoustic Stimulation , Acoustics , Adolescent , Adult , Audiometry, Speech , Cochlear Implantation/instrumentation , Cochlear Implants , Electric Stimulation , Humans , Noise/adverse effects , Perceptual Masking , Persons With Hearing Impairments/psychology , Phonetics , Sound Spectrography , Speech Intelligibility , Time Factors , Young AdultABSTRACT
Low-frequency acoustic cues have shown to improve speech perception in cochlear-implant listeners. However, the mechanisms underlying this benefit are still not well understood. This study investigated the extent to which low-frequency cues can facilitate listeners' use of linguistic knowledge in simulated electric-acoustic stimulation (EAS). Experiment 1 examined differences in the magnitude of EAS benefit at the phoneme, word, and sentence levels. Speech materials were processed via noise-channel vocoding and lowpass (LP) filtering. The amount of spectral degradation in the vocoder speech was varied by applying different numbers of vocoder channels. Normal-hearing listeners were tested on vocoder-alone, LP-alone, and vocoder + LP conditions. Experiment 2 further examined factors that underlie the context effect on EAS benefit at the sentence level by limiting the low-frequency cues to temporal envelope and periodicity (AM + FM). Results showed that EAS benefit was greater for higher-context than for lower-context speech materials even when the LP ear received only low-frequency AM + FM cues. Possible explanations for the greater EAS benefit observed with higher-context materials may lie in the interplay between perceptual and expectation-driven processes for EAS speech recognition, and/or the band-importance functions for different types of speech materials.
Subject(s)
Acoustic Stimulation/methods , Acoustics , Cues , Recognition, Psychology , Speech Perception , Adolescent , Adult , Audiometry, Speech , Computer Simulation , Humans , Periodicity , Phonetics , Sound Spectrography , Speech Acoustics , Time Factors , Voice Quality , Young AdultABSTRACT
L-Carnitine supplementation has been used to reduce obesity caused by high-fat diet, which is beneficial for lowering blood and hepatic lipid levels, and for ameliorating fatty liver. However, whether l-carnitine may affect irregular feeding-induced obesity and lipid metabolism disorder is still largely unknown. In the present study, we developed a time-delayed pattern of eating, and investigated the effects of l-carnitine on the irregular eating induced adiposity in mice. After an experimental period of 8 weeks with l-carnitine supplementation, l-carnitine significantly inhibited body weight increase and epididymal fat weight gain induced by the time-delayed feeding. In addition, l-carnitine administration decreased levels of serum alanine aminotransferase (GPT), glutamic oxalacetic transaminase (GOT) and triglyceride (TG), which were significantly elevated by the irregular feeding. Moreover, mice supplemented with l-carnitine did not display glucose intolerance-associated hallmarks, which were found in the irregular feeding-induced obesity. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis indicated that l-carnitine counteracted the negative alterations of lipid metabolic gene expression (fatty acid synthase, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, cholesterol 7α-hydroxylase, carnitine/acylcarnitine translocase) in the liver and fat of mice caused by the irregular feeding. Therefore, our results suggest that the time-delayed pattern of eating can induce adiposity and lipid metabolic disorders, while l-carnitine supplementation might prevent these negative symptoms.