ABSTRACT
BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.
Subject(s)
Actins , Meiosis , Oocytes , cdc42 GTP-Binding Protein , Animals , Oocytes/metabolism , Mice , Female , Actins/metabolism , Actins/genetics , cdc42 GTP-Binding Protein/metabolism , cdc42 GTP-Binding Protein/genetics , Phosphorylation , Spindle Apparatus/metabolismABSTRACT
The conventional transmission and reflection operating mode switching metasurface depends on phase change materials, which are often difficult to integrate with metasurface devices and work in real time. Here, we propose an integration of a transmission-reflection metasurface that can dynamically control beam direction and functions in both transmission and reflection modes by varying the frequency of the incident wave. Remarkably, the transmission and reflection modes of terahertz beam manipulation can be obtained by illuminating only the transmission side of the metasurface. The full-wave simulation results are in good agreement with the theoretically calculated results, which verifies the terahertz wave manipulation capability of the proposed structure. This metasurface provides a design method for full-space terahertz beam regulation devices.
ABSTRACT
The retinoid-related orphan receptor α (RORα) is one subfamily of nuclear hormone receptors (NRs). This review summarizes the understanding and potential effects of RORα in the cardiovascular system and then analyzes current advances, limitations and challenges, and further strategy for RORα-related drugs in cardiovascular diseases. Besides regulating circadian rhythm, RORα also influences a wide range of physiological and pathological processes in the cardiovascular system, including atherosclerosis, hypoxia or ischemia, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, hypertension, and myocardial hypertrophy. In terms of mechanism, RORα was involved in the regulation of inflammation, apoptosis, autophagy, oxidative stress, endoplasmic reticulum (ER) stress, and mitochondrial function. Besides natural ligands for RORα, several synthetic RORα agonists or antagonists have been developed. This review mainly summarizes protective roles and possible mechanisms of RORα against cardiovascular diseases. However, there are also several limitations and challenges of current research on RORα, especially the difficulties on the transformability from the bench to the bedside. By the aid of multidisciplinary research, breakthrough progress on RORα-related drugs to combat cardiovascular disorder may appear.
Subject(s)
Cardiovascular Diseases , Diabetic Cardiomyopathies , Humans , Cardiomegaly , Nuclear Receptor Subfamily 1, Group F, Member 1 , Receptors, Cytoplasmic and Nuclear , RetinoidsABSTRACT
A Rh(III)-catalyzed direct cyanation of 2H-indazoles with N-cyano-N-phenyl-p-toluenesulfonamide has been realized via a chelation-assisted strategy. The methodology enables regioselective access to various ortho-cyanated phenylindazoles in good yields with a broad substrate scope and good functional group compatibility. The obtained cyanated indazoles could further be converted into other value-added chemicals. Importantly, the current protocol is featured with several characteristics, including a novel cyanating agent, good regioselectivity, and operational convenience.
ABSTRACT
BACKGROUND/AIMS: Systemic iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including AS (Atherosclerosis). The hepcidin-ferroportin axis plays the key role in regulation of iron homeostasis and modulation of this signaling could be a potential therapeutic strategy in the treatment of these diseases. TMP (Tetramethylpyrazine) has been reported to have therapeutical effect on AS. Here, we aimed to investigate the effect of iron overload under hyperlipidemia condition on the endothelial injury, inflammation and oxidative stress by employing FPN1 Tek-cre mouse model with or without TMP intervention. METHODS: Subjects for this study were 80 FPN1 Tek-cre mice and 40 C57BL/6 mice and we randomly divided them into six groups: Group N: C57BL/6 mice with normal diet, Group M: C57BL/6 mice with high-fat diet, Group FN: FPN1 Tek-cre mice with normal diet, Group FNT: FPN1 Tek-cre mice with normal diet and TMP injection, Group FM: FPN1 Tek-cre mice with high-fat diet, Group FMT: FPN1 Tek-cre mice with high-fat diet and TMP injection. After seven days of treatment, blood samples were obtained to detect the levels of blood lipids, Hepcidin, NO, ET-1, ROS, MDA, SOD, IL-1, IL-6 and TNF-α respectively. The liver and aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE). RESULTS: Hyperlipidemia could cause iron overload in the aorta and increased serum hepcidin level, particularly in FPN1 Tek-cre mice, and can be reversed by TMP intervention. Knockout of Fpn1 induced increase of serum hepcidin, exacerbated endothelial dysfunction, oxidative stress and inflammatory response, particularly under hyperlipidemia condition. TMP intervention attenuated these processes. CONCLUSIONS: Our study signifies the potential application of certain natural compounds to ameliorating iron disorders induced by hyperlipidemia and protecting on endothelial function through modulation of hepcidin-ferroportin signaling.
Subject(s)
Antioxidants/therapeutic use , Cation Transport Proteins/metabolism , Endothelial Cells/drug effects , Hyperlipidemias/complications , Iron Overload/drug therapy , Iron Overload/etiology , Pyrazines/therapeutic use , Animals , Aorta/drug effects , Aorta/metabolism , Aorta/pathology , Drugs, Chinese Herbal/therapeutic use , Endothelial Cells/metabolism , Female , Hepcidins/blood , Hepcidins/metabolism , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Iron Overload/metabolism , Iron Overload/pathology , Male , Mice, Inbred C57BL , Oxidative Stress/drug effectsABSTRACT
Angiogenesis plays a crucial role in the growth, invasion and metastasis of breast cancer. Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are the key regulators of tumor angiogenesis. VEGFR-2, known as the kinase insert domain receptor (KDR), is a key receptor involved in malignant angiogenesis. We previously showed that knocking down KDR with short interference RNA (KDR-siRNA) markedly decreased KDR expression and suppressed tumor growth in a xenograft model. However, the mechanisms underlying the anti-cancer effects of KDR-siRNA are not clearly understood. This study aimed to elucidate the molecular mechanisms that induce apoptosis in human breast cancer MCF-7 cells after transfection with KDR-siRNA. We studied the effects of KDR-siRNA on proliferation, apoptosis, antiapoptotic and pro-apoptotic proteins, mitochondrial membrane permeability, cytochrome c release and caspase-3 activity. The results indicated that KDR-siRNA treatment significantly inhibited the proliferation and induced the apoptosis of MCF-7 cells, reduced the levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xl, and increased the level of the pro-apoptotic protein Bax, resulting in a decreased Bcl-2/Bax ratio. KDR-siRNA also enhanced the mitochondrial membrane permeability, induced cytochrome c release from the mitochondria, upregulated apoptotic protease-activating factor-1 (Apaf-1), cleaved caspase-3, and increased caspase-3 activity in MCF-7 cells. Furthermore, KDR-siRNA-induced apoptosis in MCF-7 cells was blocked by the caspase inhibitor Z-VAD-FMK, suggesting a role of caspase activation in the induction of apoptosis. These results indicate that the Bcl-2 family proteins and caspase-related mitochondrial pathways are primarily involved in KDR-siRNAinduced apoptosis in MCF-7 cells and that KDR might be a potential therapeutic target for human breast cancer treatments.
Subject(s)
Apoptosis , Mitochondria/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Breast Neoplasms , Cell Proliferation , Down-Regulation , Female , Gene Expression , Humans , MCF-7 Cells , Mitochondrial Membranes/metabolism , Permeability , RNA, Small Interfering/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Microtubule-severing enzymes (MTSEs) play important roles in mitosis and meiosis of the primitive organisms. However, no studies have assessed their roles in mammalian meiosis of females, whose abnormality accounts for over 80% of the cases of gamete-originated human reproductive disease. In the current study, we reported that katanin-like 2 (KL2) was the only MTSE concentrating at chromosomes. Furthermore, the knockdown of KL2 significantly reduced chromosome-based increase in the microtubule (MT) polymer, increased aberrant kinetochore-MT (K-MT) attachment, delayed meiosis, and severely affected normal fertility. Importantly, we demonstrated that the inhibition of aurora B, a key kinase for correcting aberrant K-MT attachment, eliminated KL2 from chromosomes completely. KL2 also interacted with phosphorylated eukaryotic elongation factor-2 kinase; they competed for chromosome binding. We also observed that the phosphorylated KL2 was localized at spindle poles, and that KL2 phosphorylation was regulated by extracellular signal-regulated kinase 1/2. In summary, our study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.
ABSTRACT
Seizures may influence epileptogenesis, but it is not yet clearly established whether subthreshold stimulations that are not sufficient to induce visible behavioral seizures change epileptic susceptibility, and the possible underlying mechanisms have not been completely understood. We assessed the susceptibility to epilepsy after subthreshold dose of pilocarpine, as well as glial fibrillary acidic protein (GFAP) expression using immunohistochemistry. An increase in the susceptibility to pentylenetetrazole (PTZ)-induced seizures was observed in rats previously subjected to subthreshold dose of pilocarpine. The immunoreactivity of GFAP was also increased, indicating that astrocytes became reactive in some brain subfields. The increased epileptic susceptibility was significantly reduced by L-alpha-aminoadipic acid (L-AAA), an inhibitor of astrocytic function. Our results suggest that subthreshold stimulation may increase the susceptibility to subsequent development of epilepsy, and reactive astrocytes might be an important contributor to this process. Adequate inhibition of astrocytic function may be a potential preventive approach against epileptogenesis.
Subject(s)
Astrocytes/drug effects , Disease Susceptibility/chemically induced , Epilepsy/chemically induced , Epilepsy/pathology , Muscarinic Agonists/toxicity , Pilocarpine/toxicity , 2-Aminoadipic Acid/therapeutic use , Analysis of Variance , Animals , Brain/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Interactions , Epilepsy/drug therapy , Excitatory Amino Acid Antagonists/therapeutic use , Glial Fibrillary Acidic Protein/metabolism , Male , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
The present study investigated the effects of Forsythoside B on an experimental model of sepsis induced by caecal ligation and puncture (CLP) in rats and elucidated the potential mechanism in cultured RAW 264.7 cells. Results showed that Forsythoside B concentration-dependently down-regulated the levels of TNF-α, IL-6 and high-mobility group-box 1 protein (HMGB1) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, inhibited the IκB kinase (IKK) pathway and modulated nuclear factor (NF)- κB. Intravenous injection (i.v.) of Forsythoside B alone or plus Imipenem reduced serum levels of TNF-α, IL-6, HMGB1, triggering receptor expressed on myeloid cells (TREM-1) and endotoxin, while the serum level of IL-10 was up-regulated and myeloperoxidase (MPO) in lung, liver and small intestine was reduced. Meanwhile, i.v. of Forsythoside B alone or plus Imipenem reduced CLP-induced lethality in rats. These data indicated that the antisepsis effect of Forsythoside B is mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. Its antisepsis mechanism may be that Forsythoside B binds to LPS and reduces the biological activity of serum LPS, and inhibits NF-κB activition. Our studies enhance the case for the use of Forsythoside B in sepsis. Forsythoside B itself has promise as a therapy for the treatment of sepsis in humans.
Subject(s)
Caffeic Acids/pharmacology , Glucosides/pharmacology , Inflammation Mediators/metabolism , Sepsis/drug therapy , Animals , Cell Line , HMGB1 Protein/metabolism , I-kappa B Kinase/metabolism , Imipenem/pharmacology , Interleukin-10/blood , Interleukin-6/metabolism , Intestine, Small/drug effects , Lipopolysaccharides/pharmacology , Liver/drug effects , Lung/drug effects , Male , Mice , NF-kappa B/metabolism , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Immunologic/metabolism , Triggering Receptor Expressed on Myeloid Cells-1 , Tumor Necrosis Factor-alpha/metabolismABSTRACT
This study is to investigate protective effect of safflor yellow B (SYB) against vascular endothelial cells (VECs) injury induced by angiotensin-II (Ang-II). VECs were cultured and divided into six groups: control group, Ang-II group, Ang-II + SYB (1 micromolL(-1)) group, Ang-II + SYB (10 micromolL(-1)) group, Ang-II + SYB (100 micromolL(-1)) group and Ang- II + verapamil (10 micromolL(-1)) group. Except control group, all of VECs in other groups were treated with Ang- II at the final concentration of 0.1 micromolL(-1). Mitochondria membrane potential (MMP) and free calcium concentration ([Ca2+]i) were measured by laser scanning confocal microscopy, and mitochondria complex IV activity was detected by BCA method. The levels of reactive oxygen species (ROS) in VECs were analyzed by fluorescence detector and apoptosis of VECs was observed by flow cytometer. Caspase 3 was determined by Western blotting method. Comparing with control group, Ang-II was able to increase [Ca2+]i and ROS level, decrease MMP level, inhibit complex IV activity and enhance caspase 3 activity in VECs, as a result, enhance apoptosis of VECs. But SYB could significantly reduce the result induced by Ang- II relying on different dosages (P < 0.05 or P < 0.01). SYB was able to eliminate the effect of Ang-II on VECs via regulating [Ca2+]i, mitochondrial structure and function and inhibiting apoptosis.
Subject(s)
Apoptosis/drug effects , Carthamus tinctorius/chemistry , Chalcone/analogs & derivatives , Drugs, Chinese Herbal/pharmacology , Endothelial Cells/cytology , Angiotensin II/adverse effects , Antioxidants/isolation & purification , Antioxidants/pharmacology , Calcium/metabolism , Caspase 3/metabolism , Cells, Cultured , Chalcone/isolation & purification , Chalcone/pharmacology , Drugs, Chinese Herbal/isolation & purification , Electron Transport Complex IV/metabolism , Endothelial Cells/metabolism , Humans , Membrane Potential, Mitochondrial/drug effects , Mitochondrial Proton-Translocating ATPases/metabolism , Plants, Medicinal/chemistry , Reactive Oxygen Species/metabolism , Vasoconstrictor Agents/adverse effectsABSTRACT
OBJECTIVE: To investigate the effects of the transient receptor potential V6 (TRPV6) gene silencing on the proliferation and apoptosis of trophoblasts HTR-8/SVneo cells. METHODS: siRNA sequences targeting the TRPV6 gene were constructed and then transfected into HTR-8/SVneo cells mediated by liposome. The cells were divided three groups, including blank control (add the reagent of transfenction), negative control groups (transfecting nonspecific siRNA) and experimental groups (transfecting TRPV6-siRNA). Those cells in every group were collected at 24, 48, 72 hours after transfecting. The expression levels of TRPV6 mRNA were detected by reverse transcription (RT) PCR at different times after transfecting. The effects of siRNA on the proliferation and apoptosis of the cells were assayed by methyl thiagolyl tetragolium (MTT) and flow cytometry at different times after transfecting. RESULTS: siRNA TRPV6 transfection could inhibit the expression of TRPV6 mRNA in the HTR-8/SVneo cells. The expression was decreased with the extension of time, by 0.72 ± 0.02, 0.54 ± 0.02 and 0.29 ± 0.01 after 12, 48 and 72 hours of siRNA transfection as compared with the blank control and the negative control groups (P < 0.01). The rates of proliferation inhibition were (19.29 ± 1.23)%, (32.12 ± 1.35)% and (46.51 ± 1.42)% at 24, 48 and 72 hours respectively when compared with the blank control (2.12 ± 0.03)%, (2.42 ± 0.02)%, (3.13 ± 0.04)% and the negative control groups (2.37 ± 0.01)%, (2.61 ± 0.05)%, (2.93 ± 0.03)% (P < 0.01). The apoptosis rates of HTR-8/SVneo cells was 16.21% at 48 hours after transfected with siRNA TRPV6, which were significantly higher than 3.27% in the blank control and 5.34% in the negative control groups (P < 0.05). CONCLUSION: Silenceing of TRPV6 genen could inhibit the proliferation and increase the apoptosis of extravillous trophoblas of human placenta.
Subject(s)
Apoptosis , Calcium Channels/genetics , Cell Proliferation , RNA, Small Interfering/genetics , TRPV Cation Channels/genetics , Trophoblasts/cytology , Calcium Channels/metabolism , Cell Line , Female , Gene Expression Regulation , Gene Silencing , Humans , Pregnancy , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , TRPV Cation Channels/metabolism , Time Factors , Transfection , Trophoblasts/metabolismABSTRACT
In the title coordination polymer, [Co(C(9)H(6)O(4))(C(12)H(10)N(4))](n), the Co(II) atom is four-coordinated by two O atoms from two different 5-methyl-isophthalate bivalent anions and two N atoms from two different 1,4-bis-(1H-imidazol-4-yl)benzene ligands, forming a four-coordinated tetra-hedral coordination geometry. Each 5-methyl-isophthalate ligand acts as a µ(2)-bridge, linking two Co(II) atoms and forming chains which are further linked by 1,4-bis-(1H-imidazol-4-yl)benzene ligands into a two-dimensional network parallel to ([Formula: see text]01). These planes are, in turn, linked by two inter-molecular N-Hâ¯O inter-actions, forming a three-dimensional structure. Weak C-Hâ¯O hydrogen bonds are also present in the structure.
ABSTRACT
This study was conducted to investigate the efficacy of cornin, an iridoid glycoside, in an experimental cerebral ischemia induced by middle cerebral artery occlusion (MCAO) and reperfusion (I/R), and to elucidate the potential mechanism. Adult male Sprague-Dawley rats were subjected to MCAO for 1 h, then reperfusion for 23 h. Behavioral tests were used to evaluate the damage to central nervous system. The cerebral infarct volume and histopathological damage were assessed to evaluate the brain pathophysiological changes. Spectrophotometric assay methods were used to determine the activities of superoxide dismutase (SOD) and glutathione-peroxidase (GPx). Contents of malondialdehyde (MDA), the generation of reactive oxygen species (ROS) as well as respiratory control ratio and respiratory enzymes of the brain mitochondria were also determined. The results showed that cornin significantly decreased neurological deficit scores, and reduced cerebral infarct volume and degenerative neurons. Meanwhile, cornin significantly increased the brain ATP content, improved mitochondrial energy metabolism, inhibited the elevation of MDA content and ROS generation, and attenuated the decrease of SOD and GPx activities in brain mitochondria. These findings indicate that cornin has protective potential against cerebral ischemia injury and its protective effects may be due to amelioration of cerebral mitochondrial function and its antioxidant property.
Subject(s)
Infarction, Middle Cerebral Artery/drug therapy , Iridoids/therapeutic use , Phytotherapy , Verbena , Animals , Brain/metabolism , Brain/pathology , Calcium/metabolism , Cell Respiration/drug effects , Electron Transport/drug effects , Glutathione Peroxidase/metabolism , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/pathology , Iridoid Glycosides , Male , Malondialdehyde/metabolism , Membrane Fluidity/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Neuroprotective Agents/therapeutic use , Phospholipids/metabolism , Plant Extracts/therapeutic use , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Reperfusion Injury/drug therapy , Superoxide Dismutase/metabolism , Water/metabolismABSTRACT
The mononuclear title complex, [Cu(C(17)H(14)N(2)O(3))(C(5)H(5)N)], was synthesized by the reaction of CuCl(2)·2H(2)O with N-(4-oxo-4-phenyl-butan-2-yl-idene)benzohydrazide (H(2)L). The central Cu(II) atom exhibits a distorted square-planar coordination geometry, defined by two O atoms, one N atom from the ligand and one pyridine N atom with Cu-N distances of 1.874â (4) and 1.963â (4)â Å, while the Cu-O distances are 1.857â (3) and 1.890â (3)â Å. An intra-molecular O-Hâ¯N inter-action occurs.
ABSTRACT
In the title compound, [Mn(CHO(2))(2)(C(12)H(10)N(4))(2)](n), the Mn(II) atom and the benzene ring of the ligand lie on an inversion centers. The Mn(II) atom has an octa-hedral coordination environment composed of four N atoms from two different symmetry-related N-heterocyclic ligands forming the basal plane, and two O atoms from symmetry-related formate anions occupying the apical positions. The title compound forms a two-dimensional (4,4) net parallel to (100) with all the Mn(II) atoms lying on a plane. The crystal structure is consolidated by inter-molecular N-Hâ¯O hydrogen bonds..
ABSTRACT
BACKGROUND: This study will investigate the effects of Spore Powder of Ganoderma Lucidum (SPGL) on CaSR and apoptosis-related proteins (ARP) in hippocampus tissue of epilepsy following dementia. METHODS: This study will retrieve all potential studies from both electronic databases (Cochrane Library, EMBASE, MEDLINE, CINAHL, AMED, and CNKI) and other literature sources to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. We will search all literature sources from the inception to the present. All eligible case-control studies will be included in this study. Two authors will independently carry out literature selection, data collection, and study quality evaluation. Any divergence will be resolved by another author through discussion. RevMan 5.3 software will be employed for data analysis. RESULTS: This study will summarize existing evidence to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. CONCLUSIONS: The findings of this study may provide helpful evidence of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. SYSTEMATIC REVIEW REGISTRATION: INPLASY202070041.
Subject(s)
Dementia/drug therapy , Drugs, Chinese Herbal/therapeutic use , Epilepsy/drug therapy , Hippocampus/drug effects , Reishi , Animals , Dementia/complications , Drugs, Chinese Herbal/pharmacology , Epilepsy/etiology , Hippocampus/metabolism , Receptors, Calcium-Sensing/metabolism , Systematic Reviews as TopicABSTRACT
BACKGROUND: Intense pulsed light (IPL), as a therapeutic approach for rosacea, had advantage in removing erythema and telangiectasia and was gradually accepted by rosacea patients, but there have been few studies on economic evaluation of this therapy. PURPOSE: This study aimed to detect willingness-to-pay (WTP) of IPL treatment for rosacea and to conduct a benefit-cost analysis (BCA) among the Chinese population, so as to provide an economic reference for doctors to make treatment decisions. MATERIALS AND METHODS: An observational, cross-sectional study assessed respondent's demographic characteristics and willingness-to-pay (WTP) of IPL and rosacea patients' clinical data and Dermatology Life Quality Index (DLQI). WTP was obtained by contingent valuation (CV) method. In brief, contrast figures of three cases treated with IPL (Case1, Case2, and Case3 represented the increasing severity of rosacea) were showed and WTP was inquired. The costs were obtained according the market and compared with WTP (benefits) to get a benefit-cost ratio (BCR). Predictors of cost-effective WTP were identified using the multivariable logistic regression model. RESULTS: A total of 303 rosacea patients and 202 controls were included in the study. The average cost of a single IPL treatment for rosacea was USD 208.04 in Changsha, China. The mean WTP for Case 1, Case 2, and Case 3 was USD 201.57, 214.64, and 221.74, respectively. WTP was statistically lower for Case 1 than that for Case 2 or Case 3 (P<0.05). The BCRs were 0.85, 1.03, and 1.06 for Case 1, Case 2, and Case 3, respectively. WTP is significantly associated with household monthly income, previous treatment cost, and DLQI after adjustments for demographic characteristics (P<0.05). CONCLUSION: IPL is an acceptable treatment for rosacea with moderate to severe erythema. For patients with relatively high income or severely impaired quality of life, IPL is an economically feasible therapy and deserves to be recommended.
ABSTRACT
Ligand-dependent or independent oligomerization of receptor protein tyrosine kinase (RPTK) is often an essential step for receptor activation and intracellular signaling. The novel oncogene with kinase-domain (NOK) is a unique RPTK that almost completely lacks an ectodomain, expresses intracellularly and activates constitutively. However, it is unknown whether NOK can form oligomer or what function oligomerization would have. In this study, two NOK deletion mutants were generated by either removing the ectodomain (NOKDeltaECD) or including the endodomain (NOK-ICD). Co-immunoprecipitation demonstrated that the transmembrane (TM) domain of NOK was essential for its intermolecular interaction. The results further showed that NOK aggregated more closely as lower order oligomers (the dimer- and trimer-sized) than either deletion mutant did since NOK could be cross-linked by both Sulfo-EGS and formaldehyde, whereas either deletion mutant was only sensitive to Sulfo-EGS. Removing the NOK TM domain (NOK-ICD) not only markedly promoted higher order oligomerization, but also altered the subcellular localization of NOK and dramatically elevated the NOK-mediated constitutive activation of extracellular signal-regulated kinase (ERK). Moreover, NOK-ICD but not NOK or NOKDeltaECD was co-localized with the upstream signaling molecule RAS on cell membrane. Thus, TM-mediated intermolecular contacting may be mainly responsible for the constitutive activation of NOK and contribute to the autoinhibitory effect on RAS/MAPK signaling.
Subject(s)
Cell Membrane/enzymology , MAP Kinase Signaling System , Mitogen-Activated Protein Kinases/metabolism , Protein Multimerization , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , ras Proteins/metabolism , Animals , COS Cells , Chlorocebus aethiops , Humans , Mutant Proteins/metabolism , Protein Structure, Quaternary , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Transport , Structure-Activity Relationship , Subcellular Fractions/metabolismABSTRACT
In the title compound, C(20)H(16)N(4)O(2), the benzene rings of the 2-hydroxy-phenyl and 4-methoxy-lphenyl groups form dihedral angles of 64.02â (8) and 77.39â (7)°, respectively, with the mean plane of the triazole ring. The dihedral angle between the triazole ring mean plane and the pyridyl ring is 9.61â (8)°. In the crystal, inter-molecular N-Hâ¯O hydrogen bonds link the mol-ecules into zigzag chains propagating in [010].
ABSTRACT
The title mol-ecule, C(14)H(11)ClN(2)O(2), adopts a trans configuration with respect to the C=N double bond. An intra-molecular N-Hâ¯O hydrogen bond contributes to mol-ecular conformation and the two benzene rings form a dihedral angle of 17.9â (8)°. In the crystal structure, inter-molecular O-Hâ¯O hydrogen bonds link the mol-ecules into chains running along [10].