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1.
Plant Biotechnol J ; 22(2): 363-378, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37794842

RESUMO

Brassinosteroids (BRs) play a crucial role in shaping the architecture of rice (Oryza sativa) plants. However, the regulatory mechanism of BR signalling in rice immunity remains largely unexplored. Here we identify a rice mutant dla, which exhibits decreased leaf angles and is insensitive to 24-epiBL (a highly active synthetic BR), resembling the BR-deficient phenotype. The dla mutation caused by a T-DNA insertion in the OsDLA gene leads to downregulation of the causative gene. The OsDLA knockout plants display reduced leaf angles and less sensitivity to 24-epiBL. In addition, both dla mutant and OsDLA knockout plants are more susceptible to rice blast compared to the wild type. OsDLA is a GRAS transcription factor and interacts with the BR signalling core negative regulator, GSK2. GSK2 phosphorylates OsDLA for degradation via the 26S proteasome. The GSK2 RNAi line exhibits enhanced rice blast resistance, while the overexpression lines thereof show susceptibility to rice blast. Furthermore, we show that OsDLA interacts with and stabilizes the WRKY transcription factor OsWRKY53, which has been demonstrated to positively regulate BR signalling and blast resistance. OsWRKY53 directly binds the promoter of PBZ1 and activates its expression, and this activation can be enhanced by OsDLA. Together, our findings unravel a novel mechanism whereby the GSK2-OsDLA-OsWRKY53 module coordinates blast resistance and plant architecture via BR signalling in rice.


Assuntos
Brassinosteroides , Oryza , Brassinosteroides/metabolismo , Proteínas de Plantas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transdução de Sinais/genética , Regiões Promotoras Genéticas , Oryza/genética , Oryza/metabolismo , Regulação da Expressão Gênica de Plantas/genética
2.
Plant Physiol ; 192(2): 1621-1637, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-36943290

RESUMO

Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is one of the most devastating diseases in rice (Oryza sativa L.). Plant annexins are calcium- and lipid-binding proteins that have multiple functions; however, the biological roles of annexins in plant disease resistance remain unknown. Here, we report a rice annexin gene, OsANN1 (Rice annexin 1), that was induced by M. oryzae infection and negatively regulated blast disease resistance in rice. By yeast 2-hybrid screening, we found that OsANN1 interacted with a cytochrome P450 monooxygenase, HAN1 ("HAN" termed "chilling" in Chinese), which has been reported to catalyze the conversion of biologically active jasmonoyl-L-isoleucine (JA-Ile) to the inactive form 12-hydroxy-JA-Ile. Pathogen inoculation assays revealed that HAN1 was also a negative regulator in rice blast resistance. Genetic evidence showed that OsANN1 acts upstream of HAN1. OsANN1 stabilizes HAN1 in planta, resulting in the inactivation of the endogenous biologically active JA-Ile. Taken together, our study unravels a mechanism where an OsANN1-HAN1 module impairs blast disease resistance via inactivating biologically active JA-Ile and JA signaling in rice.


Assuntos
Magnaporthe , Oryza , Resistência à Doença/genética , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ciclopentanos/metabolismo , Anexinas/metabolismo , Oryza/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Magnaporthe/fisiologia
3.
Exp Cell Res ; 422(1): 113432, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36442518

RESUMO

Cerebral ischemia-reperfusion injury (CIRI) is a brain injury that usually occurs during thrombolytic therapy for acute ischemic stroke and impacts human health. Oxidative stress is one of the major causative factors of CIRI. DhHP-3 is a novel peroxidase-mimicking enzyme that exhibits robust reactive oxygen species (ROS) scavenging ability in vitro. Here, we established in vitro and in vivo models of cerebral ischemia-reperfusion to mechanistically investigate whether DhHP-3 can alleviate CIRI. DhHP-3 could reduce ROS, down-regulate apoptotic proteins, suppress p53 phosphorylation, attenuate the DNA damage response (DDR), and inhibit apoptosis in SH-SY5Y cells subjected to oxygen-glucose deprivation/re-oxygenation (OGD/R) and in the brain of Sprague Dawley rats subjected to transient middle cerebral artery occlusion. In conclusion, DhHP-3 has bioactivity of CIRI inhibition through suppression of the ROS-induced apoptosis.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Neuroblastoma , Traumatismo por Reperfusão , Ratos , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/genética , Isquemia Encefálica/metabolismo , Estresse Oxidativo , Apoptose , Peptídeos/metabolismo
4.
Environ Res ; 257: 119293, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38838749

RESUMO

Recently, photocatalysis combined peroxydisulfate activation under visible light (PC-PDS/Vis) was developed as a promising technology for removing antibiotics in water. Herein, Mn doped FeOOH (Mn-FeOOH) nanoclusters were grown in-situ on the surface of graphitic carbon nitride nanosheets (CNNS) using a wet chemical method, which served as a visible-light-driven photocatalyst for peroxydisulfate (PDS) activation. Photovoltaic property characterizations revealed that Mn-FeOOH/CNNS owned superior light capture ability and carrier separation efficiency. According to DFT calculations, the synergistic effect between Mn and Fe species was proved to enhance the adsorption and activation of PDS. 99.7% of tetracycline (TC) was rapidly removed in 50 min in the PC-PDS/Vis system. In addition, Mn-FeOOH/CNNS exhibited high recycling stability with low iron leaching, attributed to the interaction between Mn-FeOOH clusters and carbon species. Quenching experiments and electron spin resonance (ESR) tests unveiled that •O2- played a significant role in TC removal, while •OH and SO4•- acted as additional roles contributing to the overall process. These findings given a new strategy for antibiotics degradation by photocatalysis, offering deeper insights for the advancement of sustainable and cutting-edge wastewater treatment technologies.

5.
Int Wound J ; 21(5): e14888, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38686514

RESUMO

Allografts derived from live-birth tissue obtained with donor consent have emerged as an important treatment option for wound and soft tissue repairs. Placental membrane derived from the amniotic sac consists of the amnion and chorion, the latter of which contains the trophoblast layer. For ease of cleaning and processing, these layers are often separated with or without re-lamination and the trophoblast layer is typically discarded, both of which can negatively affect the abundance of native biological factors and make the grafts difficult to handle. Thus, a full-thickness placental membrane that includes a fully-intact decellularized trophoblast layer was developed for homologous clinical use as a protective barrier and scaffold in soft tissue repairs. Here, we demonstrate that this full-thickness placental membrane is effectively decellularized while retaining native extracellular matrix (ECM) scaffold and biological factors, including the full trophoblast layer. Following processing, it is porous, biocompatible, supports cell proliferation in vitro, and retains its biomechanical strength and the ability to pass through a cannula without visible evidence of movement or damage. Finally, it was accepted as a natural scaffold in vivo with evidence of host-cell infiltration, angiogenesis, tissue remodelling, and structural layer retention for up to 10 weeks in a murine subcutaneous implant model.


Assuntos
Placenta , Humanos , Feminino , Gravidez , Animais , Camundongos , Alicerces Teciduais , Liofilização/métodos , Matriz Extracelular Descelularizada , Cicatrização/fisiologia
6.
Mol Biol Evol ; 39(4)2022 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-35277964

RESUMO

Sinocyclocheilus represents a rare, freshwater teleost genus endemic to China that comprises the river-dwelling surface fish and the cave-dwelling cavefish. Using a combinatorial approach of quantitative lipidomics and mass-spectrometry imaging (MSI), we demonstrated that neural compartmentalization of lipid distribution and lipid metabolism is associated with the evolution of troglomorphic traits in Sinocyclocheilus. Attenuated docosahexaenoic acid (DHA) biosynthesis via the Δ4 desaturase pathway led to reductions in DHA-phospholipids in cavefish cerebellum. Instead, cavefish accumulates arachidonic acid-phospholipids that may disfavor retinotectal arbor growth. Importantly, MSI of sulfatides coupled with immunostaining of myelin basic protein and transmission electron microscopy images of hindbrain axons revealed demyelination in cavefish raphe serotonergic neurons. Demyelination in cavefish parallels the loss of neuroplasticity governing social behavior such as aggressive dominance. Outside the brain, quantitative lipidomics and qRT-PCR revealed systemic reductions in membrane esterified DHAs in the liver, attributed to suppression of genes along the Sprecher pathway (elovl2, elovl5, and acox1). Development of fatty livers was observed in cavefish; likely mediated by an impeded mobilization of storage lipids, as evident in the diminished expressions of pnpla2, lipea, lipeb, dagla, and mgll; and suppressed ß-oxidation of fatty acyls via both mitochondria and peroxisomes as reflected in the reduced expressions of cpt1ab, hadhaa, cpt2, decr1, and acox1. These neurological and systemic metabolic adaptations serve to reduce energy expenditure, forming the basis of recessive evolution that eliminates nonessential morphological and behavioral traits and giving cavefish a selective advantage to thrive in caves where proper resource allocation becomes a major determinant of survival.


Assuntos
Characidae , Cyprinidae , Doenças Desmielinizantes , Animais , Evolução Biológica , Cavernas , Characidae/genética , Lipidômica , Redes e Vias Metabólicas , Fosfolipídeos
7.
Heart Surg Forum ; 26(6): E687-E693, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38178360

RESUMO

OBJECTIVE: Peak blood lactate at 24 h after extracorporeal membrane oxygenation (ECMO) can predict 30-day mortality in infants after complex cardiac surgery. METHODS: Twenty-eight infants with ECMO after complex congenital heart disease surgery were selected from March 2019 to March 2022 in our hospital. The infants were divided into survival group (n = 11) and non-survival group (n = 17) according to 30-day survival after discharge from hospital. The risk factors at 30-day mortality after discharge were analyzed by Cox regression analysis. RESULTS: When compared to the non-survival group, there were significant differences in peak blood lactate at 24 h after ECMO, liver dysfunction and multiple organ dysfunction syndrome (MODS) in the survival group (p < 0.05). Cox regression analysis showed that peak blood lactate at 24 h after ECMO (HR = 1.074, 95% CI: 1.005-1.149, p = 0.036) and MODS (HR = 4.120, 95% CI: 1.373-12.362, p = 0.012) were related risk factors affecting the prognosis of infants. The best cutoff value for the peak blood lactate at 24 h after ECMO was 10.2 mmol/L. The area under the curve (AUC) for predicting the 30-day survival rate of the ECMO assisted infants after discharge from hospital was 0.770 (95% CI: 0.592-0.948, p = 0.018), with a sensitivity of 94.1% and specificity of 54.5%. CONCLUSION: The peak blood lactate at 24 h after ECMO can predict the 30-day mortality after discharge of infants treated with ECMO after complex cardiac surgery. The best cut-off value for peak blood lactate at 24 h after ECMO was 10.2 mmol/L.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Oxigenação por Membrana Extracorpórea , Lactente , Humanos , Estudos Retrospectivos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Prognóstico , Lactatos
8.
Zhonghua Nan Ke Xue ; 29(3): 233-238, 2023 Mar.
Artigo em Zh | MEDLINE | ID: mdl-38597704

RESUMO

OBJECTIVE: To observe the clinical effect of combined application of Compound Amino Acid Capsule (8-11) (CAAC8-11) and L-carnitine (LC) in the treatment of idiopathic asthenospermia (IAS), and to explore its possible therapeutic mechanism. METHODS: Based on the principle of double-blind and control, we selected 120 cases of IAS meeting the diagnostic criteria of asthenospermia in the WHO Manual for the Examination and Processing of Human Semen (5th Ed) and randomly divided them into three groups of an equal number: CAAC8-11 + LC, LC control and blank control, the former given CAAC8-11 in addition to LC oral liquid, and the latter two given LC oral liquid and life intervention, respectively, all for 12 weeks. We collected semen samples from all the patients before and after treatment, and examined perm motility, the contents of neutral α- glucosidase (NAG) and reactive oxygen species (ROS), sperm DNA fragmentation index (DFI), and the expression of the Nrf2 protein. RESULTS: Compared with the baseline, the total sperm motility was significantly improved in the IAS patients after treated with CAAC8-11 + LC (ï¼»27.50 ± 0.77ï¼½% vs ï¼»32.50 ± 0.74ï¼½%, P < 0.05) or LC only (ï¼»27.60 ± 0.66ï¼½% vs ï¼»30.90 ± 0.70ï¼½%, P < 0.05), dramatically higher in the CAAC8-11 + LC than in the LC and blank control groups (P < 0.01). The content of NAG in the epididymis was remarkably increased after treatment in the CAAC8-11 + LC than in the LC and blank control groups (ï¼»23.90 ± 0.56ï¼½ vs ï¼»21.20 ± 0.49ï¼½ and ï¼»16.80 ± 0.42ï¼½ mU, P < 0.05), so was the expression of Nrf2 (P < 0.05), while the ROS level was markedly decreased in the former than in the latter two groups (ï¼»81.60 ± 2.50ï¼½ vs ï¼»88.50 ± 2.50ï¼½ and ï¼»88.70 ± 2.40ï¼½ µg/ml, P < 0.05). CONCLUSION: CAAC8-11 + LC has a good clinical effect on asthenospermia, with no adverse reactions, which may be attributed to its ability to regulate the high expression of Nrf2, decrease the production of ROS and reduce the damage of oxidative stress to sperm motility.


Assuntos
Astenozoospermia , Carnitina , Humanos , Masculino , Carnitina/uso terapêutico , Carnitina/farmacologia , Aminoácidos/uso terapêutico , Contagem de Espermatozoides , Sêmen , Fator 2 Relacionado a NF-E2 , Espécies Reativas de Oxigênio , Motilidade dos Espermatozoides , Espermatozoides , Astenozoospermia/tratamento farmacológico , alfa-Glucosidases
9.
Plant Cell ; 31(1): 172-188, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30610168

RESUMO

To defend against pathogens, plants have developed complex immune systems, including plasma membrane receptors that recognize pathogen-associated molecular patterns, such as chitin from fungal cell walls, and mount a defense response. Here, we identify a chitinase, MoChia1 (Magnaporthe oryzae chitinase 1), secreted by M. oryzae, a fungal pathogen of rice (Oryza sativa). MoChia1 can trigger plant defense responses, and expression of MoChia1 under an inducible promoter in rice enhances its resistance to M. oryzae MoChia1 is a functional chitinase required for M. oryzae growth and development; knocking out MoChia1 significantly reduced the virulence of the fungus, and we found that MoChia1 binds chitin to suppress the chitin-triggered plant immune response. However, the rice tetratricopeptide repeat protein OsTPR1 interacts with MoChia1 in the rice apoplast. OsTPR1 competitively binds MoChia1, thereby allowing the accumulation of free chitin and re-establishing the immune response. Overexpressing OsTPR1 in rice plants resulted in elevated levels of reactive oxygen species during M. oryzae infection. Our data demonstrate that rice plants not only recognize MoChia1, but also use OsTPR to counteract the function of this fungal chitinase and regain immunity.


Assuntos
Magnaporthe/patogenicidade , Oryza/metabolismo , Quitinases/genética , Quitinases/metabolismo , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno , Imunidade Vegetal/genética , Imunidade Vegetal/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
10.
Heart Surg Forum ; 25(5): E750-E752, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36317901

RESUMO

Internal jugular vein placement is frequently utilized in clinical practice for rapid infusion, intraoperative monitoring, peritoneal dialysis, and access for interventions. Additionally, the process may lead to complications like hematoma, infection, misdirection of the artery, pneumothorax, and arteriovenous fistula. In the case described in this report, all vascular ruptures effectively were repaired because when internal jugular vein placement was adopted, a dialysis catheter would go through the right internal jugular vein into the subclavian artery, then the ascending aorta via the cephalic trunk, and finally the ectopic catheter would be surgically removed. The patient was released from the hospital on the seventh postoperative day after maintaining stable vital signs throughout the procedure.


Assuntos
Fístula Arteriovenosa , Cateterismo Venoso Central , Humanos , Veias Jugulares/cirurgia , Cateterismo Venoso Central/efeitos adversos , Cateterismo Venoso Central/métodos , Fístula Arteriovenosa/etiologia , Veias Braquiocefálicas , Aorta
11.
Entropy (Basel) ; 24(3)2022 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-35327930

RESUMO

This paper proposes an H∞ observer based on descriptor systems to estimate the state of charge (SOC). The battery's open-current voltage is chosen as a generalized state variable, thereby avoiding the artificial derivative calculation of the algebraic equation for the SOC. Furthermore, the observer's dynamic performance is saved. To decrease the impacts of the uncertain noise and parameter perturbations, nonlinear H∞ theory is implemented to design the observer. The sufficient conditions for the H∞ observer to guarantee the disturbance suppression performance index are given and proved by the Lyapunov stability theory. This paper systematically gives the design steps of battery SOC H∞ observers. The simulation results highlight the accuracy, transient performance, and robustness of the presented method.

12.
Int J Mol Sci ; 22(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34830111

RESUMO

Although some breast cancer patients die due to tumor metastasis rather than from the primary tumor, the molecular mechanism of metastasis remains unclear. Therefore, it is necessary to inhibit breast cancer metastasis during cancer treatment. In this case, after designing and synthesizing CTI-2, we found that CTI-2 treatment significantly reduced breast cancer cell metastasis in vivo and in vitro. Notably, with the treatment of CTI-2 in breast cancer cells, the expression level of E-cadherin increased, while the expression level of N-cadherin and vimentin decreased. In addition, after CTI-2 treatment, those outflow levels for p-ERK, p-p38, and p-JNK diminished, while no significant changes in the expression levels of ERK, JNK, or p38 were observed. Our conclusion suggested that CTI-2 inhibits the epithelial-mesenchymal transition (EMT) of breast carcinoma cells by inhibiting the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, thereby inhibiting the metastasis of breast tumor cells. Therefore, we believe that CTI-2 is another candidate for breast tumor medication.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Neoplasias da Mama/metabolismo , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924155

RESUMO

Ferulic acid (FA) is a naturally-occurring well-known potent antioxidant and free radical scavenger. FA supplementation is an effective strategy to delay aging, but the underlying mechanism remains unknown. In the present study, we examined the effects of FA on lifespan extension and its mechanism of FA in Caenorhabditis elegans (C. elegans). Results suggested that FA increased the lifespan of C. elegans, rather than altering the growth of E. coli OP50. Meanwhile, FA promoted the healthspan of C. elegans by improving locomotion and reducing fat accumulation and polyQ aggregation. FA increased the resistance to heat and oxidative stress through reducing ROS. The upregulating of the expression of the hlh-30, skn-1, and hsf-1 were involved in the FA-mediated lifespan extension. Furthermore, FA treatment had no impact on the lifespan of daf-2, hlh-30, skn-1, and hsf-1 mutants, confirming that insulin/IGF-1 signaling pathway and multiple longevity mechanisms were associated with the longevity mechanism of FA. We further found that mitochondrial signaling pathway was modulation involved in FA-mediated lifespan extension. With the results from RNA-seq results and mutants lifespan assay. These findings contribute to our knowledge of the lifespan extension and underlying mechanism of action of FA in C. elegans.


Assuntos
Ácidos Cumáricos/administração & dosagem , Suplementos Nutricionais , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Longevidade , Transdução de Sinais , Estresse Fisiológico , Animais , Autofagia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
Entropy (Basel) ; 23(9)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34573806

RESUMO

The coupling between variables in the multi-input multi-output (MIMO) systems brings difficulties to the design of the controller. Aiming at this problem, this paper combines the particle swarm optimization (PSO) with the coefficient diagram method (CDM) and proposes a robust controller design strategy for the MIMO systems. The decoupling problem is transformed into a compensator parameter optimization problem, and PSO optimizes the compensator parameters to reduce the coupling effect in the MIMO systems. For the MIMO system with measurement noise, the effectiveness of CDM in processing measurement noise is analyzed. This paper gives the control design steps of the MIMO systems. Finally, simulation experiments of four typical MIMO systems demonstrate the effectiveness of the proposed method.

15.
J Anat ; 237(5): 933-940, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32515838

RESUMO

The peripheral nervous system lacks lymphatic vessels and is protected by the blood-nerve barrier, which prevents lymphocytes and antibodies from entering the neural parenchyma. Peripheral nerve injury results in degeneration of the distal nerve and myelin degeneration causes macrophage aggregation, T lymphocyte infiltration, major histocompatibility complex class II antigen expression, and immunoglobulin G deposition in the nerve membrane, which together result in nerve edema and therefore affect nerve regeneration. In the present paper, we show myelin expression was absent from the sciatic nerve at 7 days after injury, and the expression levels of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and Prospero Homeobox 1 (Prox1) were significantly increased in the sciatic nerve at 7 days after injury. The lymphatic vessels were distributed around the myelin sheath and co-localized with lymphatic endothelial cells. Prox1 induces the formation of new lymphatic vessels, which play important roles in the elimination of tissue edema as well as in morphological and functional restoration of the damaged nerve. This study provides evidence of the involvement of new lymphatic vessels in nerve repair after sciatic nerve injury.


Assuntos
Proteínas de Homeodomínio/metabolismo , Linfangiogênese , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/metabolismo , Nervo Isquiático/lesões , Proteínas Supressoras de Tumor/metabolismo , Animais , Modelos Animais de Doenças , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Compressão Nervosa , Traumatismos dos Nervos Periféricos/patologia , Distribuição Aleatória , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
16.
Bioorg Med Chem Lett ; 30(4): 126907, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31902710

RESUMO

Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.


Assuntos
Anticorpos Monoclonais/imunologia , Portadores de Fármacos/química , Receptor alfa de Estrogênio/imunologia , Anticorpos Monoclonais/química , Antineoplásicos/química , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Receptor alfa de Estrogênio/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Células MCF-7 , Proteólise/efeitos dos fármacos , Receptor ErbB-2/metabolismo
17.
Neuropathology ; 40(3): 215-223, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31960509

RESUMO

We investigated the distribution and formation of new lymphatic vessels in gliomas. Specimens from seven glioma cases were analyzed by immunohistochemical staining for CD34, lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1), prospero-related homeobox 1 (Prox1), nestin, and hypoxia-inducible factor 1α (HIF-1α). Three types of vessels were observed in glioma specimens: LYVE-1+ lymphatic vessels, CD34+ blood vessels, and LYVE-1+ /CD34+ blood vessels. Prox1+ /LYVE-1+ cells were distributed in some lymphatic vessels as well as among vascular endothelial cells and glioma cells. Nestin+ cells were scattered throughout the gliomas, and some lymphatic cells also expressed nestin. HIF-1α+ Prox1+ cells were widely distributed within the glioma specimens. The present immunohistochemical analysis revealed upregulation of Prox1 and HIF-1α in some glioma tissues as well as the differentiation of nestin+ tumor stem cells into LYVE-1+ lymphatic vessels.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Vasos Linfáticos/patologia , Adolescente , Adulto , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
J Obstet Gynaecol Res ; 46(8): 1355-1363, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32500644

RESUMO

AIM: To evaluate the relationship between physiological and psychological stress on pregnancy outcome in women undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment. METHODS: Women undergoing the first IVF cycle were enrolled to complete the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). Their blood samples were collected on the 3rd day of the menstrual cycle to measure 5-hydroxytryptamine, renin, norepinephrine, angiotensin II and cortisol. Salivary amylase was obtained on the embryo transfer day. RESULTS: Compared with normal women who came to the hospital for regular physical examination, the incidence of anxiety and depression was higher in women seeking for IVF treatment. After psychological intervention, the condition got improved and the incidence of anxiety and depression was 6.25% and 7.81% separately in these women. There were no significant differences between the anxiety scores in women with and without pregnancy. The depression scores did show some statistically differences, with higher scores in the nonpregnancy group. The level of 5-hydroxytryptamine, renin, norepinephrine and cortisol were not significantly different between the two groups, while angiotensin II and salivary amylase seemed to be negatively correlated with pregnancy outcome. Simultaneously, a positive correlation was found between angiotensin II and anxiety and depression scores. CONCLUSION: Depression during IVF has a negative impact on pregnancy outcome. The measurement of angiotensin II and salivary amylase might be reference index for the psychological status of patients during IVF-ET.


Assuntos
Fertilização in vitro , Resultado da Gravidez , Ansiedade/epidemiologia , Transferência Embrionária , Feminino , Humanos , Gravidez , Resultado da Gravidez/epidemiologia , Estudos Prospectivos , Estresse Psicológico/epidemiologia
19.
J Integr Plant Biol ; 62(10): 1552-1573, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32129570

RESUMO

Crosstalk between plant hormone signaling pathways is vital for controlling the immune response during pathogen invasion. Salicylic acid (SA) and jasmonic acid (JA) often play important but antagonistic roles in the immune responses of higher plants. Here, we identify a basic helix-loop-helix transcription activator, OsbHLH6, which confers disease resistance in rice by regulating SA and JA signaling via nucleo-cytosolic trafficking in rice (Oryza sativa). OsbHLH6 expression was upregulated during Magnaporthe oryzae infection. Transgenic rice plants overexpressing OsbHLH6 display increased JA responsive gene expression and enhanced disease susceptibility to the pathogen. Nucleus-localized OsbHLH6 activates JA signaling and suppresses SA signaling; however, the SA regulator OsNPR1 (Nonexpressor of PR genes 1) sequesters OsbHLH6 in the cytosol to alleviate its effect. Our data suggest that OsbHLH6 controls disease resistance by dynamically regulating SA and JA signaling.


Assuntos
Citosol/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Oryza/genética , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Fatores de Transcrição/genética
20.
J Mol Evol ; 87(7-8): 199-208, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31332479

RESUMO

Cave animals possess remarkable phenotypes associated with existence in their dark environments. The Chinese cavefish Sinocyclocheilus tileihornes shows substantial eye degeneration, a trait shared by most cave species. The extent to which independent evolution of troglomorphic traits uses convergent molecular genetic mechanisms is as yet unknown. We performed transcriptome-wide gene expression profiling in S. tileihornes eyes and compared results with those from the closely related surface species S. angustiporus and an independently derived congeneric cavefish, S. anophthalmus. In total, 52.85 million 100 bp long paired-end clean reads were generated for S. tileihornes, and we identified differentially expressed genes between the three possible pairs of species. Functional analysis of genes differentially expressed between S. tileihornes and S. angustiporus revealed that phototransduction (KEGG id: dre04744) was the most significantly enriched pathway, indicating the obvious differences in response to captured photons between the cavefish S. tileihornes and the surface species S. angustiporus. Analysis of key genes regulating eye development showed complete absence of otx5b (orthodenticle homolog 5) expression in S. tileihornes eyes, probably related to degradation of rods, but normal expression of crx (cone-rod homeobox). The enriched pathways and Otx5 are involved in phototransduction, photoreceptor formation, and regulation of photoreceptor-related gene expression. Unlike the S. tileihornes reported here, S. anophthalmus has reduced crx and otx5 expression. These results show that different species of cavefish within the same genus that independently evolved troglodyte characteristics can have different genetic mechanisms of eye degeneration.


Assuntos
Adaptação Biológica/genética , Cyprinidae/genética , Fatores de Transcrição Otx/genética , Animais , Evolução Biológica , Cavernas , Cyprinidae/metabolismo , Evolução Molecular , Olho/metabolismo , Regulação da Expressão Gênica , Fenômenos Fisiológicos Oculares , Fatores de Transcrição Otx/biossíntese , Fatores de Transcrição Otx/metabolismo , Fenótipo , Células Fotorreceptoras de Vertebrados/metabolismo , Transcriptoma
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