The Tumor Proteolytic Landscape: A Challenging Frontier in Cancer Diagnosis and Therapy

In recent decades, dysregulation of proteases and atypical proteolysis have become increasingly recognized as important hallmarks of cancer, driving community-wide efforts to explore the proteolytic landscape of oncologic disease. With more than 100 proteases currently associated with different aspects of cancer development and progression, there is a clear impetus to harness their potential in the context of oncology. Advances in the protease field have yielded technologies enabling sensitive protease detection in various settings, paving the way towards diagnostic profiling of disease-related protease activity patterns. Methods including activity-based probes and substrates, antibodies, and various nanosystems that generate reporter signals, i.e., for PET or MRI, after interaction with the target protease have shown potential for clinical translation. Nevertheless, these technologies are costly, not easily multiplexed, and require advanced imaging technologies. While the current clinical applications of protease-responsive technologies in oncologic settings are still limited, emerging technologies and protease sensors are poised to enable comprehensive exploration of the tumor proteolytic landscape as a diagnostic and therapeutic frontier. This review aims to give an overview of the most relevant classes of proteases as indicators for tumor diagnosis, current approaches to detect and monitor their activity in vivo, and associated therapeutic applications.     

The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.     

Decoding the Roles of Long Noncoding RNAs in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs.     

Omega-6支撑身体，Omega-3支撑大脑：均衡摄入对儿童大脑发育的影响（网络首发、推荐阅读）

人体大脑和身体的发育，需要从食物中摄取均衡的营养物质。人类大脑是区分人类和其他动物的特征。食物中的必需脂肪酸是机体组织结构和功能的必要组成部分。Omega-6（O6）亚油酸（LA6）是皮肤组织的组成成分，且是炎症、血栓形成、免疫和其他信号分子的前体；Omega-3（O3）α-亚麻酸（ALA3），特别是其长链代谢产物——二十二碳六烯酸（DHA3），是大脑、视网膜和部分神经组织中的关键组分。从富含LA6脂肪酸（缺乏O3脂肪酸）的植物籽中提取出的廉价而优质油脂，是20世纪的西方国家食品工业生产的主要脂肪来源。在代谢通路中，高浓度的LA6脂肪酸可拮抗O3脂肪酸代谢，造成O3脂肪酸不足，因此，在给怀孕动物的饲料中，只提供富含LA6但缺乏O3脂肪酸的油脂作为唯一的脂肪来源，会导致幼崽大脑发育不良。过去20~30年的研究表明，低含量LA6且含DHA3的油脂可改善大脑的功能。近年来的研究较多集中在营养因素对大脑发育的影响，最新研究数据表明，脂肪酸平衡对营养不良儿童的大脑发育尤为重要。世界卫生组织（WHO）越来越重视大脑的营养健康，通过其下属的食品法典委员会，建议用于治疗严重急性营养不良儿童的即食治疗食品中，使用含有均衡脂肪酸组成/构成的脂肪。同样，脂肪酸均衡对老年人可能也很重要。目前，业界已经有了调整油脂成分的方法，以确保脂肪酸均衡，从而维持人体整个生命周期的大脑健康。     

Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.     

Experimental Animal Model Systems for Understanding Salivary Secretory Disorders

Salivary secretory disorders are life-disrupting pathologic conditions with a high prevalence, especially in the geriatric population. Both patients and clinicians frequently feel helpless and get frustrated by the currently available therapeutic strategies, which consist mainly of palliative managements. Accordingly, to unravel the underlying mechanisms and to develop effective and curative strategies, several animal models have been developed and introduced. Experimental findings from these models have contributed to answer biological and biomedical questions. This review aims to provide various methodological considerations used for the examination of pathological fundamentals in salivary disorders using animal models and to summarize the obtained findings. The information provided in this review could provide plausible solutions for overcoming salivary disorders and also suggest purpose-specific experimental animal systems.     

DRD2和5-HTR2A基因多态性及其交互作用对奥氮平治疗精神分裂症疗效的影响

目的：探讨多巴胺D2受体（dopamine D2 receptor, DRD2）和5-羟色胺2A受体（5-hydroxytryptamine 2A receptor, 5-HTR2A）基因多态性及其交互作用与奥氮平治疗精神分裂症疗效的关系。方法：纳入147例接受单一奥氮平治疗的精神分裂症住院患者为研究对象，采用阳性与阴性症状量表（PANSS）评定药物疗效，按PANSS减分率≥50%和<50%，分为有效组和无效组。采用多重高温连接酶检测反应技术（iMLDR）检测DRD2（rs1799978、rs1800497）和5-HTR2A（rs6311、rs6313）基因多态性；采用多因素Logistic回归分析各基因型和奥氮平疗效的关联性，采用多因子降维法（MDR）分析基因-基因的交互作用。结果：有效组和无效组rs1799978、rs6313位点基因型和等位基因频率分布差异均有统计学意义（P<0.05），而两组rs1800497、rs6311位点基因型和等位基因频率分布差异均无统计学意义（P>0.05）；rs1799978位点GA和GG型患者奥氮平疗效较野生AA型好，其比值比（OR）及95%CI分别为5.101（1.118～23.267）、6.051（2.454～14.925）；rs6313位点CT和CC型患者奥氮平疗效较野生TT型好，其OR及95%CI分别为2.623（1.054～6.528）、3.412（1.180～9.869）；rs1799978、rs1800497和rs6313位点间存在交互作用，其交互模型为最优基因-基因交互作用模型（P<0.05），该模型检验样本准确度为0.727 3，交叉验证一致性为10/10。结论：DRD2（rs1799978）和5-HTR2A（rs6313）基因多态性可能与奥氮平治疗精神分裂症疗效相关，DRD2（rs1799978、rs1800497）和5-HTR2A（rs6313）对奥氮平疗效的影响存在交互作用。     

Site-Specific PEGylation of Therapeutic Proteins

The use of proteins as therapeutics has a long history and is becoming ever more common in modern medicine. While the number of protein-based drugs is growing every year, significant problems still remain with their use. Among these problems are rapid degradation and excretion from patients, thus requiring frequent dosing, which in turn increases the chances for an immunological response as well as increasing the cost of therapy. One of the main strategies to alleviate these problems is to link a polyethylene glycol (PEG) group to the protein of interest. This process, called PEGylation, has grown dramatically in recent years resulting in several approved drugs. Installing a single PEG chain at a defined site in a protein is challenging. Recently, there is has been considerable research into various methods for the site-specific PEGylation of proteins. This review seeks to summarize that work and provide background and context for how site-specific PEGylation is performed. After introducing the topic of site-specific PEGylation, recent developments using chemical methods are described. That is followed by a more extensive discussion of bioorthogonal reactions and enzymatic labeling.