8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase-hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood-brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19.

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

Abstract Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies.

Clinical Research Progress of the Non-Peptide Oral Somatostatin Receptor Ligand Paltusotine / 罕见病研究

The research and development of somatostatin analogues is a hot area in endocrinology and metabolism. The first generation octreotide, lanreotide and the second generation pareotide have been approved to be effective for the treatment of neuroendocrine tumors such as acromegaly. However, paltusotine, a somatostatin receptor ligand, is a novel non-peptide small molecule drug which can be administered orally and inhibits excessive secretion of growth hormone and insulin-like growth factor 1. This review summarizes the research progress of the pharmacokinetics, pharmacodynamics, clinical efficacy, telerability, and safety of paltusotine.

Molecular docking and Antibacterial activities of Cobalt (II) complexes derived from precursors of Hydrazones

The Schiff base ligands in their deprotonated forms have been utilized to synthesize thermodynamically and kinetically stabilized Cobalt(II) complexes. In the complexes, cobalt ion present is in distorted octahedral arrangement and is coordinated by four tridentate ligands in complexes. The synthesized Schiff base ligands coordinate with Cobalt (II) ion through four azomethine nitrogen atoms and two sulfur atoms developing a 6- membered chelate ring. Synthesized Cobalt(II) complexes via hexadentate ligands have been characterized thoroughly through various spectroscopic techniques like FT-IR, UV-Vis, 1HNMR, TGA, TEM, SEM, Particle size, Elemental analysis (C, H, N, Co, S) and conductivity measurements. All Cobalt(II) complexes have been evaluated for in vitro antimicrobial activity against isolated bacterial strains of E. coli (MTCC-1687), E. faecalis (MTCC-439), S. aureus (MTCC-737) and MR S. aureus (Indigenous). All Cobalt complexes show mild to moderate antibacterial activity. The MIC ranged from 50 µg/ mL to 3.125 µg/ mL. All Cobalt(II) complexes displayed in-vitro antibacterial activity against both gram-positive and gram-negative bacterial strains. It may be proved that the antibacterial activity of the complexes is related to the cell wall structure of the tested bacteria. In-vitro toxicity tests explained the Cobalt complexes were less cytotoxic than the Vancomycin drug on A431 cancer cell lines and the results explain that synthesized Cobalt complexes can act as potent antimicrobial agents and can be considered as a good drug candidate for medicinal chemistry researchers.

Anti pathogenic studies of new mixed ligand metal chelates

Drug discovery aimed at the methodical extermination of life-threatening bacterial infection, especially considering the emergence of multi-drug resistance of pathogenic bacteria has remained a challenge for medicinal inorganic chemistry. In this article, the mixed ligand complexes of Cu (II), Co (II), and Ni (II) containing heterocyclic ligands were synthesized and characterized by IR, LC-MS, UV, and TG-DTA. Complexes are screened for Anti-microbial activity against human pathogenic bacteria.

Value of octreotide suppression test in predicting the efficacy of long-acting somatostatin receptor ligands in pituitary GH adenomas / 中华内分泌代谢杂志

Objective:To explore the value of octreotide suppression test(OST) in predicting the efficacy of somatostatin receptor ligands(SRLs) in the treatment of active acromegaly.Methods:The clinical data of 76 patients with active acromegaly from 2011 to 2020 was retrospectively analyzed. OST was carried out as follows: After an overnight fasting and baseline sampling of growth hormone(GH), 100 μg octreotide was subcutaneously injected, and sampling for GH was obtained every 2 hours for 8 hours. All patients were treated with SRLs for at least 3 months. A good GH response is defined as a post-treatment random GH<1 μg/L or >80% fall compared with the baseline GH. A good insulin-like growth factor Ⅰ(IGF-Ⅰ) response is defined as IGF-Ⅰ<1.3 upper limit of normal(ULN) or >50% reduction compared with the baseline. If both GH and IGF-Ⅰ fulfill the criteria of a good response, it is defined as a good GH and IGF-Ⅰ response.Results:The baseline level of GH during OST was 15.00(6.38, 34.20) μg/L, the median time to reach the nadir GH was(3.65±1.65) hours, and the nadir GH level was 1.47(0.50, 4.19) μg/L. The median GH suppression rate was 89.12%(72.71%, 95.09%). When the cutoff value of GH suppression rate in predicting a good GH response was 89.32%, the area under the curve(AUC) was 0.74, with a sensitivity of 81.80% and specificity of 66.00%. When the cutoff value of GH suppression rate in predicting a good IGF-Ⅰ response was 93.14%, the AUC was 0.64, with a sensitivity of 50.00% and specificity of 75.60%. When the GH suppression rate was 90.71%, the AUC was 0.78, with the sensitivity of 83.30% and specificity of 70.00% in predicting a good GH and IGF-Ⅰ response. Compared with GH/IGF-Ⅰ non-responders, GH/IGF-Ⅰ responders displayed lower nadir GH during OST, higher GH suppression rate and IGF-Ⅰ reduction rate, and lower ratio of IGF-1 to ULN( P<0.05). Conclusion:GH suppression rate during the OST is a valuable predictor to evaluate the efficacy of SRLs in patients with acromegaly, with the highest sensitivity and specificity when the cutoff value is 90.71%.

Complexos imínicos de cobre com atividade antiparasitária frente à doença de chagas / Imine copper complexes with antiparasitic activity against Chagas disease

Neste trabalho foram sintetizados e caracterizados três complexos de cobre com ligantes imínicos, com o objetivo de avaliar sua atividade tripanocida. Esses complexos foram caracterizados por diversas técnicas espectroscópicas, como UV-Vis, Infravermelho e EPR, além de análise elementar e espectrometria de massa. Juntamente com outros complexos similares previamente sintetizados pelo nosso grupo, tiveram suas atividades avaliadas frente à forma tripomastigota do parasita T. cruzi, responsável pela fase aguda da doença de Chagas, por ensaios de viabilidade celular, com determinação do valor de seus IC50, concentração em que observamos a morte de 50% da cultura celular, pela metodologia denominada MTT. Todos os complexos mostraram-se eficientes frente a tripomastigotas, apresentando valores de IC50 abaixo de 10 µM, com quatro deles obtendo índice de seletividade maior que 10, fator importante para definir agentes promissores antichagásicos. Complexos selecionados também tiveram sua atividade verificada frente à forma amastigota do parasita, responsável pela fase crônica da doença, utilizando método de imageamento por microscópio de fluorescência e contagem celular. Estudos de inibição da cruzaína, uma cisteíno-protease importante para o metabolismo do parasita foram conduzidos em colaboração com o laboratório do Prof. Wagner Alves de Souza Júdice, da Universidade de Mogi das Cruzes. Quatro dos compostos testados apresentaram atividade inibitória frente a cruzaína, sendo dois de cobre, um de zinco e um ligante livre. Os estudos também permitiram diferenciar os mecanismos de inibição dos compostos, com os complexos de cobre apresentando um mecanismo de inibição clássico e o composto de zinco e o ligante livre apresentando o mecanismo de inibição competitiva parabólica com cooperatividade

In this work, three copper complexes with iminic ligands were synthesized and characterized, with the objective of evaluating their trypanocidal activity. These complexes were characterized by several spectroscopic techniques, such as UV-Vis, Infrared and EPR, in addition to elementary analysis and mass spectrometry. Together with other similar complexes previously synthesized by our group, their activities were evaluated against the trypomastigote form of the parasite T. cruzi, responsible for the acute phase of Chagas disease, by cell viability tests, with determination of the value of their IC50, concentration in that we observed the death of 50% of the cell culture, by the methodology called MTT, all presenting IC50 values below 10 µM, with four of them obtaining a selectivity index greater than 10, important factor for defining promising antichagasic agents. Selected complexes also had their activity verified against the amastigote form of the parasite, responsible for the chronic phase of the disease, using a fluorescence microscope and cell counting imaging method. Inhibition studies of cruzain, a cysteine protease important for the metabolism of the parasite, were conducted in collaboration with the laboratory of Professor Wagner Alves de Souza Júdice at the University of Mogi das Cruzes. Four of the tested compounds showed inhibitory activity against cruzain, two of copper, one of zinc and a free ligand. The studies also allowed to differentiate the mechanisms of inhibition of the compounds, with the copper complexes presenting a classic inhibition mechanism and the zinc compound and the free ligand presenting the competitive parabolic inhibition mechanism with cooperativity

Chimeric Antigen Receptor T Cell Therapy: A Novel Modality for Immune Modulation / 전남의대학술지

Cancer remains a leading cause of death, despite multimodal treatment approaches. Even in patients with a healthy immune response, cancer cells can escape the immune system during tumorigenesis. Cancer cells incapacitate the normal cell-mediated immune system by expressing immune modulation ligands such as programmed death (PD) ligand 1, the B7 molecule, or secreting activators of immune modulators. Chimeric antigen receptor (CAR) T cells were originally designed to target cancer cells. Engineered approaches allow CAR T cells, which possess a simplified yet specific receptor, to be easily activated in limited situations. CAR T cell treatment is a derivative of the antigen-antibody reaction and can be applied to various diseases. In this review, the current successes of CAR T cells in cancer treatment and the therapeutic potential of CAR T cells are discussed.

Proteínas homólogas de unión a reticulocitos de Plasmodium falciparum involucradas en el proceso de invasión al eritrocito: revisión de la literatura / Plasmodium falciparum reticulocyte-binding homologous proteins involved in the process of erythrocyte invasion: literature review / Proteínas de ligação a reticulócitos de Plasmodium falciparum homólogas envolvidas no pro-cesso de invasão de eritrócitos: revisão da literatura

Introducción: la malaria es uno de los mayores retos de la salud pública mundial. Es causada principalmente por los parásitos Plasmodium falciparum y Plasmodium vivax. Durante el proceso de invasión, se encuentran involucra-das las proteínas homólogas de unión a reticulocitos de P.falciparumPfRH1, PfRH2a, PfRH2b, PfRH4 y PfRH5, que tras su unión a receptores específicos de membrana permiten la invasión del merozoíto al eritrocito. Objetivo: compilar y resumir las características moleculares y estructurales de las interacciones entre las proteínas pertenecientes a la familia de proteínas homólogas de unión a reticulocitos de P.falciparum y los receptores expre-sados en la célula del hospedero. Método: revisión descriptiva sobre las proteínas homólogas de unión a reticulocitos de P. falciparum involucradas en el proceso de invasión al eritrocito. Esta revisiónincluye literatura publicada hasta el año 2020 en bases de datos electrónicas especializadas en investigación biomédica. Se encontraron 105 documentos, de los cuales se se-leccionaron 70 y se excluyeron 11, por no presentar los criterios de inclusión, analizando un total de 59 referencias. Conclusión: la invasión del merozoíto es mediada por interacciones específicas de los ligandos de las familias EBL y PfRH. La unión de las proteínas PfRH1 y PfRH2b a sus receptores en el eritrocito da lugar a la liberación de la proteína EBL-175 que, junto con PfRH4, median la formación de una unión estrecha entre el parásito y los glóbulos rojos. Ello permite la unión de la proteína PfRH5 a la basigina y la entrada del parásito a la célula del hospedero

Introduction: Malaria is one of the world's greatest public health challenges, caused mainly by Plas-modium falciparum and Plasmodium vivax. During the invasion process, the P. falciparum reticulo-cyte-binding homologous proteins PfRH1, PfRH2a, PfRH2b, PfRH4 and PfRH5 are involved, which after binding to specific membrane receptors allow the invasion of the merozoite into the erythrocyte. Objective: To compile and summarize the molecular and structural characteristics of the interactions between proteins belonging to the P. falciparum family of reticulocyte-binding homologous proteins and the receptors expressed in the host cell. Method: Descriptive review of the P. falciparum reticulocyte-binding homologous proteins involved in the process of erythrocyte invasion. This review includes literature published until 2020 in electronic databases specialized in biomedical research. We found 105 papers, of which 70 were selected and 11 were excluded for not presenting the inclusion criteria, analyzing a total of 59 references. Conclusion: The invasion of merozoite is mediated by specific interactions of the ligands of the LBS and PfRH families. The binding of the PfRH1 and PfRH2b proteins to their receptors in the erythrocyte results in the release of the EBL-175 protein, which together with PfRH4 mediates the formation of a close bond between the parasite and the red blood cells, thus allowing the binding of the PfRH5 protein to basigin and the entry of the parasite into the host cell.

Introdução: a malária é um dos maiores desafios globais de saúde pública. É causada principalmente pelos parasitas Plasmodium falciparum e Plasmodium vivax. Durante o processo de invasão, proteínas homólogas de ligação a reticulócitos de P. falciparum PfRH1, PfRH2a, PfRH2b, PfRH4 e PfRH5 estão envolvidas, que após a ligação a receptores de membrana específicos permitem a invasão do mero-zoíta ao andritro. Objetivo: compilar e resumir as características moleculares e estruturais das interações entre as pro-teínas pertencentes à família das proteínas reticulocitárias homólogas de P. falciparum e os receptores expressos na célula hospedeira. Método: revisão descritiva das proteínas ho-mólogas de ligação a reticulócitos de P. falciparum envol-vidas no processo de invasão eritrocitária. Esta revisão inclui literatura publicada até 2020 em bases de dados eletrônicas especializadas em pesquisa biomédica. Foram encontrados 105 documentos, dos quais 70 foram selecionados e 11 excluídos por não apresentarem os critérios de inclusão, anali-sando um total de 59 referências. Conclusão: a invasão de merozoítos é mediada por interações específicas dos ligantes das famílias EBL e PfRH. A ligação das proteínas PfRH1 e PfRH2b aos seus receptores no eritrócito resulta na libe-ração da prote-ína EBL-175 que, junto com PfRH4, a mediação da formação de uma junção compacta entre o parasita e as hemácias. Isso permite a ligação da proteína PfRH5 à basigina e a entrada do parasita na célula hospedeira.

Current Research Status of Aptamer-mediated Liposome Targeted Delivery of Antitumor Drugs / 中国实验方剂学杂志

Tumor has become the second most serious disease that threatens human health and life. Treating with chemical drugs (referred to as chemotherapy) is the most basic treatment, but most chemotherapeutic drugs cause damage to normal tissues. It is a difficult problem in the field of biomedical research that how to deliver anti-tumor drugs more efficiently, increase the concentration of drugs in tumor tissues, enhance the anti-tumor effect, and decrease the drug distribution in normal tissues to weaken the damage to normal tissues. In order to achieve the goals of accurate delivery of anti-tumor drugs and synergism and attenuation, the researchers used systematic evolution of ligands by exponential enrichment technology (SELEX technology) to screen aptamers that can specifically target tumor markers or tumor cells, and designed the novel liposome targeting drug delivery system with aptamers as targeting molecules (ligands). This paper briefly introduced nucleic acid aptamer technology and common tumor markers, and reviewed the research advances on the antitumor effect of aptamer-liposome drug delivery system. It will provide references for the selection of appropriate tumor markers as targets and the application of aptamer technology in the research and development of high-efficiency and low-toxicity liposome targeting agents of anti-tumor traditional Chinese medicine. Meanwhile, it is of great significance for promoting the application of aptamer technology in targeted drug delivery systems.

Acromegaly in the elderly patient

ABSTRACT Acromegaly is an insidious disease, usually resulting from growth hormone hypersecretion by a pituitary adenoma. It is most often diagnosed during the 3rd to 4th decade of life. However, recent studies have shown an increase in the incidence and prevalence of acromegaly in the elderly, probably due to increasing life expectancy. As in the younger population with acromegaly, there is a delay in diagnosis, aggravated by the similarities of the aging process with some of the characteristics of the disease. As can be expected elderly patients with acromegaly have a higher prevalence of comorbidities than younger ones. The diagnostic criteria are the same as for younger patients. Surgical treatment of the pituitary adenoma is the primary therapy of choice unless contraindicated. Somatostatin receptor ligands are generally effective as both primary and postoperative treatment. The prognosis correlates inversely with the patient's age, disease duration and last GH level. Arch Endocrinol Metab. 2019;63(6):638-45

Effect of 3 neuroprotective measures on expressions of Fas/FasL in brain tissue of neonatal rats with hypoxicischemic brain damage / 中国中西医结合急救杂志

Objective To observe the effects of 3 neuroprotective measures on the expressions of apoptosis-related factors and their ligands (Fas and FasL) in brain tissue of neonatal rats with hypoxic ischemic brain injury. Methods One hundred and twenty Wistar rats 7 days old were selected as experimental subjects, the rats were divided into four groups: neural stem cell, erythropoietin (EPO), ω-3 unsaturated fatty acid treatment groups and hypoxic ischemic brain damage model group according to random number table method, with 30 rats in each group. Neural stem cell group, EPO group and ω-3 unsaturated fatty acid group were respectively injected with neural stem cells, EPO and ω-3 unsaturated fatty acid, each 5 mL via tail vein after modeling; the hypoxic ischemic brain damage model group was given equal volume of normal saline. At 6, 12, 24, 48 and 72 hours after administration of drug, 6 rats were sacrificed in each group, brain tissue was taken, the mRNA expression levels of Fas/FasL, protein expression levels of Toll-like receptor 4 (TLR4), nuclear transcription factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), interleukin (IL-1β, IL-6) and cell apoptotic rate in hippocampus tissue were measured. Results ① mRNA expressions: the mRNA expressions of Fas and FasL of the 3 experimental groups were significantly lower than those of the hypoxic ischemic brain damage model group, the degrees of descent after administration for 24 hours were the most significant, neural stem cell treatment group < EPO treatment group < ω-3 unsaturated fatty acid treatment group < hypoxic ischemic brain damage model group [Fas mRNA expression (2-ΔΔCt): 140.5±2.9, 156.4±2.5, 165.2±2.7 vs. 173.7±2.8, FasL mRNA expression (2-ΔΔCt): 143.1±4.3, 154.6±1.5, 160.7±1.4 vs. 174.7±2.8], the differences were statistically significant (all P < 0.05). ② Protein expressions: the protein expressions of TLR4, NF-κB, TNF-α, IL-1β, IL-6 of the 3 experimental groups were significantly lower than those of the hypoxic ischemic brain damage model group (TLR4/GAPDH: 0.7±0.2, 0.6±0.1, 0.2±0.1 vs. 1.4±0.1; NF-κB/GAPDH: 6.7±0.4, 5.3±0.1, 1.1±0.2 vs. 11.2±0.3; TNF-α/GAPDH: 14.3±1.4, 11.2±1.2, 3.2±2.1 vs. 23.2±0.5; IL-1β/GAPDH: 9.4±0.2, 7.4±0.3, 2.2±0.3 vs. 13.4±0.1; IL-6/GAPDH: 36.2±4.4, 39.3±1.5, 26.2±2.1 vs. 51.4±1.4, all P < 0.05), the protein expression levels of above indexes in neural stem cell treatment group < those of EPO treatment group < those of ω-3 unsaturated fatty acid treatment group < those of hypoxic ischemic brain damage model group. ③ Apoptotic rates:after drug administration, the apoptotic rates of the ω-3 unsaturated fatty acid group, EPO treatment group, neural stem cell treatment group were obviously lower than the rate of model group [(3.7±0.3)%, (3.4±0.2)%, (2.5±0.1)% vs. (5.5±0.4)%, all P < 0.05]. Conclusion The mRNA expressions of Fas/FasL in the brain of neonatal rats with hypoxic-ischemic brain damage are high, and the treatment with each of the following agents; neural stem cells, EPO and ω-3 unsaturated fatty acid can reduce the mRNA expressions of Fas/FasL in such rats' brain tissues.

The effect of entinostat on NK killing effect on non-small cell lung cancer in vitro / 中国肿瘤临床

Objective: To investigate the Effects of entinostat on the expression of NKG2D ligands in the non-small cell lung cancer (NSCLC) cell lines, A549 and HCC-827, and to detect the effect of entinostat-mediated NK cell killing of A549 and HCC-827 cells. Meth-ods: The effect of entinostat on A549 and HCC-827 cell proliferation was measured by MTT assay. Flow cytometry was used to detect the expression of NKG2D ligands. mRNA levels of the ligands were detected by RT-PCR . The level of soluble MICA in cell culture super-natant was evaluated by ELISA. The cytotoxicity of NK cells against A549 and HCC-827 cell lines (treated with entinostat) was assessed using lactate dehydrogenase release assay. Results: Entinostat showed a time-and dose-dependent inhibition effect on the prolifera-tion of A549 and HCC-827 cell lines. The expression of NKG2D ligands and mRNA transcription levels of MICA and MICB were en-hanced after treatment with 0.5, 1μmol/L entinostat for 48 h. The soluble MICA level in A549 cell culture supernatant was increased by 1μmol/L entinostat. The sensitivity of HCC-827 cells to NK cells was enhanced upon treatment with 0.5, 1μmol/L entinostat. Con-clusions: entinostat enhanced the killing effect of NK cells on non-small cell lung cancer cells by up-regulating the expression of NKG2D ligands. This provides a new method and theory for the treatment of NSCLC.

SELEX screening of EpCAMGspecific nucleic acid aptamer targeting prostate cancer cells / 实用放射学杂志

Objective To investigate the methods of screening specific aptamers for (EpCAM)Gpositive prostate cancer (PCa)cells by cellGSELEX technique.Methods A random DNA library was designed to screen EpCAMGspecific DNA aptamers from human prostate cancer cells expressing EpCAM molecule by cellGSELEX technique.After 12 rounds of in vitro screening,DNA products were cloned and sequenced.Flow cytometry and cellular immunofluorescence were used to detect the specific binding ability of aptamers to target cells.Results Two aptamers of Ep1 and Ep2 were selected.Both of them could specifically bind to EpCAMGpositive cancer cells LNCap,PCG3 ,DU1 45 , and HEK293T cells transfected with target molecule.The binding rates of Ep1 were 61.0%,74.3%,5 9.1% and 60.3%.The binding rates of Ep2 were 65.1%,77.8%,54.2% and 58.3%.Neither of them could bind to HEK293T cells transfected with empty vector with the binding rate of 5.4% in Ep1 and 3.3% in Ep2,respectively.Flow cytometry analysis and confocal images indicated that the EpCAM aptamers could specifically recognize human PCa cells expressing EpCAM,but could not bind to EpCAMGnegative cells.Conclusion EpCAM aptamers derived from cellGSELEX technology can recognize and bind to EpCAMGpositive PCa cells specifically,which may provide new ideas for the specific diagnosis and targeted therapy of prostate cancer,and lay an experimental basis for the other specific diagnosis and treatment schemes of malignant tumors.

Progress of multi-target directed drugs based on tacrine and donepezil in alzheimer′s disease / 中国药学杂志

Alzheimer′s disease (AD) is a progressive multifactorial neurodegenerative disorder in elder people. Currently, the pathogenesis of AD is unclear, and it is presently incurable. In view of the complex network pathological features of AD, a single small molecule compound that can act simultaneously with multiple targets, called multi-target directed ligands (MTDLs), is considered to be an effective therapeutic strategy at present. Here, we review highlights recent MTDLs approach based cholinesterase inhibitors, antioxidant, metal chelator and neuroprotectant in the novel drug candidate prototypes for the treatment of AD.

Adsorption and availability of phosphorus in response to humic acid rates in soils limed with CaCO3 or MgCO3 / Adsorção e disponibilidade de fósforo em resposta a doses de ácido húmico em solos corrigidos por CaCO3 ou MgCO3

ABSTRACT Humic acid (HA) may reduce adsorption and increase soil P availability, however, the magnitude of this effect is different when Ca2+ prevails over Mg2+ in limed soils. The objective of this study was to evaluate the effects of HA rates and carbonate sources on the adsorption, phosphate maximum buffering capacity (PMBC), and P availability in two contrasting soils. Oxisol and Entisol samples were firstly incubated with the following HA rates: 0, 20, 50, 100, 200 and 400 mg kg-1, combined with CaCO3 or MgCO3, to evaluate P adsorption. In sequence, soil samples were newly incubated with P (400 mg kg-1) to evaluate P availability. The least P adsorption was found when 296 mg kg-1 of HA was added to Oxisol. Applying HA rates decreased maximum adsorption capacity, increased P binding energy to soil colloids and did not alter PMBC of Entisol. Available P contents in Oxisol increased with HA rates, but it did not change in Entisol. Choosing the right HA rate can decrease PMBC up to 40% and increase the Oxisol P availability by 17%. Application of MgCO3 instead of CaCO3 decreased P adsorption in both soils. Thus, a positive correlation between Ca2+ content and PMBC was verified. Optimum rate of HA and the preponderance of Mg2+ instead of Ca2+ in soil volume fertilized with P are effective practices to reduce adsorption and increase P availability, especially in clayey Oxisol.

RESUMO O ácido húmico (AH) pode reduzir a adsorção e aumentar a disponibilidade de P nos solos, entretanto, a magnitude desse efeito é diferente quando o Ca2+ prevalece sobre Mg2+ em solos com acidez corrigida. Objetivou-se avaliar os efeitos de doses de AH e fontes de carbonato na adsorção, fator capacidade de P máximo (FCPm) e disponibilidade de P em solos contrastantes. Amostras de Latossolo e Gleissolo foram primeiramente incubadas com as seguintes doses de AH: 0, 20, 50, 100, 200 e 400 mg kg-1, combinadas com CaCO3 ou MgCO3, para avaliar a adsorção de P. Em sequência, as amostras de solo foram novamente incubadas com P (400 mg kg-1), para determinar a disponibilidade de P. A aplicação de doses de AH reduziu a capacidade máxima de adsorção, aumentou a energia de ligação do P e não alterou a FCPm do Gleissolo. O teor de P disponível aumentou com o acréscimo das doses de AH no Latossolo, contudo, não foram alterados no Gleissolo. A escolha correta da dose de AH reduziu a FCPm em até 40% e aumentou a disponibilidade de P no Latossolo em 17%. A aplicação de MgCO3 em vez do CaCO3 reduziu a adsorção de P em ambos os solos. Assim, houve correlação positiva entre o teor de Ca2+ e a FCPm. A dose ótima de AH e a predominância de Mg2+ sobre Ca2+ no volume de solo adubado com P são práticas efetivas para reduzir a adsorção e aumentar a disponibilidade de P, especialmente, no Latossolo argiloso.

Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions?

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to µ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the β-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the β-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the µ receptor G protein pathway selective (µ-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased µ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.

Screening of nucleic acid aptamer of lung cancer cells based on cell exponential enrichment ligand system evolution and its application in tumor diagnosis and treatment / 生物医学工程学杂志

Nucleic acid aptamer is an oligonucleotide sequence screened by the exponential enrichment ligand system evolution technology (SELEX). Previous studies have shown that nucleic acid aptamer has a good application prospect in tumor diagnosis and treatment. Therefore, we reviewed the selection and identification of nucleic acid aptamer of lung cancer cells in recent years, and discussed the effect of aptamer as targeting drugs and targeting vectors on the diagnosis of tumors, which provide a new idea for early diagnosis and treatment of tumor.

Development of tau PET Imaging Ligands and their Utility in Preclinical and Clinical Studies / 대한핵의학회잡지

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.

Ligand-Independent Epidermal Growth Factor Receptor Overexpression Correlates with Poor Prognosis in Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients’ survival with CRC. MATERIALS AND METHODS: The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH. RESULTS: Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands–/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis. CONCLUSION: Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.