Design,synthesis and anti-melanogenic effect of cinnamamide derivatives

Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-β-phenyl-α,β-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25?µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-β-phenyl-α,β-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.     

高血压基底节区脑出血患者血清CXCL1、CXCL10与神经损伤指标和微创穿刺引流术后预后的关系研究

摘要 目的：探讨高血压基底节区脑出血（HBGH）患者血清CXC趋化因子配体1（CXCL1）、CXC趋化因子配体10（CXCL10）与神经损伤指标和微创穿刺引流术后预后的关系。方法：选取2020年2月~2023年4月聊城市人民医院东院区收治的行微创穿刺引流术治疗的HBGH患者162例纳入研究组,选取体检健康的志愿者110例纳入对照组。检测对比两组血清CXCL1、CXCL10和神经损伤指标[神经元特异性烯醇化酶（NSE）、胶质纤维酸性蛋白（GFAP）、S100β蛋白]水平。采用Pearson检验分析血清CXCL1、CXCL10与神经损伤指标的相关性。所有患者均随访3个月,根据改良Rankin量表（mRS）评分分为预后良好组和预后不良组。采用多因素Logistic回归模型分析HBGH患者微创穿刺引流术后预后的影响因素。结果：研究组的血清CXCL1、CXCL10水平高于对照组（P<0.05）。研究组的血清NSE、GFAP、S100β蛋白水平高于对照组（P<0.05）。Pearson检验分析结果显示,血清CXCL1、CXCL10与NSE、GFAP、S100β蛋白均呈正相关（P<0.05）。单因素分析结果显示,预后不良与年龄、甘油三酯（TG）、低密度脂蛋白（LDL）、凝血酶原时间（PT）、C反应蛋白（CRP）、血肿破入脑室、血肿体积、术后24 h内血肿清除率、尿激酶冲管次数、术后颅内出血再发、CXCL1、CXCL10有关（P<0.05）。多因素Logistic回归分析结果显示,年龄偏大、LDL偏高、血肿体积偏大、术后24 h内血肿清除率偏低、尿激酶冲管次数偏多、CXCL1偏高、CXCL10偏高是HBGH患者微创穿刺引流术后预后不良的危险因素（P<0.05）。结论：HBGH患者血清CXCL1、CXCL10水平升高可能导致神经损伤和不良预后。年龄、LDL、血肿体积、术后24 h内血肿清除率、尿激酶冲管次数、CXCL1、CXCL10是HBGH患者术后预后不良的危险因素,值得引起重视。     

Catalytic DNA and RNA for Targeting MDR1 mRNA

Abstract

Design, synthesis and properties of catalytic NAs for targeting MDR1 mRNA are reported.     

Angelman syndrome and severe infections in a patient with de novo 15q11.2–q13.1 deletion and maternally inherited 2q21.3 microdeletion

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11–q13 (about 70–90%), but can also be caused by paternal uniparental disomy of chromosome 15q11–q13 (3–7%), an imprinting defect (2–4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5 Mb-deletion of chromosome 15q11.2–q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~ 364 kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2–q13.1 deletion contains genes critical for Prader–Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.     

2′-Functional group of adenosine in 10–23 DNAzyme promotes catalytic activity

10–23 DNAzyme is an artificially selected catalytic DNA molecule. Its great potential as genetic therapeutics promoted chemical modifications for more efficient DNAzymes. Here, 10–23 DNAzyme was modified on its six deoxyadenosine residues (A5, A9, A11, A12, A15 in the catalytic domain and A0 of the recognition arm next to the cleavage site) with compound 1, an adenosine analogue with 2′-O-[N-(aminoethyl)carbamoyl]methyl group. A positive effect of compound 1 at A15 was observed (HJDS-05, k_obs = 0.0111 min⁻¹). Compared to the effect of 2′-H and 2′-OMe at A15, this result provided an approach for more efficient DNAzyme by combining 2′-substituted amino group of adenosine with A15 as the lead structure.     

Design,synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14

A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with?～15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.     

Analytical similarity assessment of rituximab biosimilar CT-P10 to reference medicinal product

CT-P10 (Truxima?) was recently approved as the world's first rituximab biosimilar product in the European Union (EU) and South Korea. To demonstrate biosimilarity of CT-P10 with the reference medicinal product (RMP), extensive 3-way similarity assessment has been conducted between CT-P10, EU-Rituximab and US-Rituximab, focusing on the physicochemical and biological quality attributes. A multitude of state-of-the-art analyses revealed that CT-P10 has identical primary and higher order structures compared to the original product. Purity/impurity profiles of CT-P10 measured by the levels of aggregates, fragments, non-glycosylated form and process-related impurities were also found to be comparable with those of RMPs. In terms of the post-translational modification, CT-P10 contains slightly less N-terminal pyro-glutamate variant, which has been known not to affect product efficacy or safety. Oligosaccharide profiling has revealed that, although CT-P10 contains the same conserved glycan species and relative proportion with the RMPs, the content of total afucosylated glycan in CT-P10 was slightly higher than in EU- or US-Rituximab. Nevertheless, the effect of the observed level of afucosylation in CT-P10 drug product on Fc receptor binding affinity or antibody-dependent cell-mediated cytotoxicity was found to be negligible based on the spiking study with highly afucosylated sample. Arrays of biological assays representative of known and putative mechanisms of action for rituximab have shown that biological activities of CT-P10 are within the quality range of RMPs. Recent results of clinical studies have further confirmed that the CT-P10 exhibits equivalent clinical efficacy and safety profiles compared to EU- and US-Rituximab. The current 3-way similarity assessment together with clinical study results confidently demonstrate that CT-P10 is highly similar with EU- and US-Rituximab in terms of physicochemical properties, biological activities, efficacy, and safety for its final approval as a biosimilar product.