基于网络药理学与分子对接技术的清瘟护肺颗粒防治新型冠状病毒肺炎(COVID-19)的潜在药效物质研究

本文通过网络药理学和分子对接技术探讨清瘟护肺颗粒防治新型冠状病毒肺炎(COVID-19)的潜在药效物质。首先,通过TCMSP数据库,BATMAN-TCM数据库及TCMIP数据库检索清瘟护肺颗粒中十六味药的化学成分及作用靶点,利用GeneCards和OMIM数据库检索COVID-19的相关疾病靶点。然后,通过venny2.1.0获取清瘟护肺颗粒防治COVID-19的潜在靶点,利用R语言对潜在靶点进行GO功能和KEGG通路富集分析,并结合文献对富集所得通路进行分析。最后,利用Cytoscape3.7.1软件构建网络图,采用AutoDock4.2.1软件评价清瘟护肺颗粒中潜在药效成分和新型冠状病毒SARS-CoV-23CL水解酶、血管紧张素转化酶II(ACE2)和RNA依赖的RNA聚合酶(RdRp)的结合作用。网络药理学得到清瘟护肺颗粒防治COVID-19的473个活性成分和123个靶点,KEGG结果及文献分析预测到清瘟护肺颗粒可通过调控MAPK、小细胞肺癌、肺结核、PI3K-AKT等多条信号通路而发挥作用,分子对接结果显示清瘟护肺颗粒中潜在药效成分和SARS-CoV-23CL水解酶、ACE2及RdRp具有良好的亲和性。本研究较为全面揭示了清瘟护肺颗粒治疗COVID-19“多成分、多靶点、多通路”的特点,为深入探讨清瘟护肺颗粒治疗COVID-19的作用机制提供参考依据。     

脓毒症患儿血清SAA、PCT、CRP水平与预后的关系及其诊断价值分析

摘要 目的：探讨脓毒症患儿血清淀粉样蛋白A（SAA）、降钙素原（PCT）、C反应蛋白（CRP）与预后的关系,并分析三者对脓毒症的诊断价值。方法：纳入我院于2016年8月～2020年6月期间收治的脓毒症患儿60例开展回顾性研究,作为脓毒症组,选取同期于我院进行体检的健康儿童40例作为对照组,比较两组血清SAA、PCT、CRP水平。根据脓毒症患儿1个月内的生存、死亡情况,分成生存组（n=42）、死亡组（n=18）,比较两组临床资料及血清SAA、PCT、CRP水平,经COX回归模型分析脓毒症患儿死亡的危险因素。绘制受试者工作特征（ROC）曲线分析血清SAA、PCT、CRP对脓毒症的诊断价值。结果：脓毒症组血清SAA、PCT、CRP水平显著高于对照组（P＜0.05）。死亡组器官障碍数量＞2个、脓毒性休克患儿占比分别为55.56%、44.44%,显著高于生存组的19.05%、9.52%（P＜0.05）;死亡组入院后1 h内使用抗菌治疗患儿占比为38.89%,显著低于生存组的69.05%（P＜0.05）;死亡组血清SAA、PCT、CRP水平高于生存组（P＜0.05）。COX多因素分析结果显示,器官障碍数量＞2、脓毒性休克及血清SAA、PCT、CRP水平升高是脓毒症患儿死亡的危险因素（P＜0.05）,而入院后1 h内使用抗菌治疗是脓毒症患儿死亡风险的保护性因素（P＜0.05）。血清SAA、PCT、CRP单独及三者联合诊断脓毒症的曲线下面积（AUC）分别为0.808、0.780、0.761、0.912。结论：脓毒症患儿血清SAA、PCT、CRP明显升高,三者升高均为脓毒症患儿死亡的危险因素,且对脓毒症具有一定诊断价值。     

入院时血清钙水平与高血压性脑出血血肿体积、神经功能及预后的关系研究

摘要 目的：探讨入院时血清钙水平与高血压性脑出血血肿体积、神经功能及预后的关系。方法：选择2018年9月-2020年4月我院收治的高血压性脑出血患者102例,根据患者入院时血清钙水平将其分为低血钙组（血清钙<2.1 mmol/L, n=34）、正常血钙组（2.1 mol/L≤血清钙≤2.7 mmol/L, n=39）和高血钙组（血清钙>2.7 mmol/L, n=29）,比较各组性别、血肿体积、入院美国国立卫生研究院卒中量表（NIHSS）评分等临床资料。所有患者随访1年,观察患者格拉斯哥预后量表（GOS）评分,根据患者预后情况将患者分为预后良好组（n=84）和预后不良组（n=18）,比较两组血清钙、血肿体积、入院NIHSS评分、GOS评分。应用受试者工作特征（ROC）曲线分析血清钙水平对患者预后的预测价值。结果：三组血肿体积、入院NIHSS评分、GOS评分、1年病死率、1年再出血率、总预后不良率比较有统计学差异（P<0.05）。预后不良组血清钙水平、GOS评分显著低于预后良好组,血肿体积、入院NIHSS评分显著高于预后良好组（P<0.05）。Pearson相关性分析显示：高血压性脑出血患者入院时血清钙水平与脑出血血肿体积、入院NIHSS评分呈负相关,与GOS评分呈正相关（P＜0.05）。ROC曲线分析显示入院时血清钙预测高血压脑出血不良预后的曲线下面积为0.129（95%CI：0.073~0.179）。结论：高血压性脑出血患者入院时血清钙水平与血肿体积、神经功能及预后存在一定关联,且入院时血清钙对高血压性脑出血不良预后具有一定预测价值。     

Therapeutic effects of Typha elephantina leave’s extract against paracetamol induced renal injury in rabbits

Present study focuses on ameliorative potential of Typha elephantina leave’s aqueous (TE.AQ) extract against Paracetamol (PCM) induced toxicity in rabbits. We fed the male rabbits with 300 mg PCM in alone and in combination with TE.AQ at different doses i.e. (100, 200 and 300 mg/kg body weight) or silymarin (100 mg/kg) daily for 21 days. PCM in alone significantly (P < 0.5) increased serum urea, uric acid, creatinine, total protein, albumin, globulin and blood urea nitrogen. Serum sodium, potassium and magnesium level were high. The glutathione, radical scavenging activity and Thiobarbituric acid reactive substances were significantly reduced. Treatment with TE.AQ at dose rate 300 mg/kg body weight and Silymarin significantly ameliorated all the parameters when compared with PCM administered group. The 100 and 200 mg of TE.AQ showed no significant effects. The histopathological examination confirmed the therapeutic potential of TE.AQ. These results established the presence of natural antioxidants in Typha elephantina leaves.     

Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A

Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.     

Alkaline phosphatase and acid phosphatase levels in saliva and serum of patients with healthy periodontium,gingivitis, and periodontitis before and after scaling with root planing: A clinico-biochemical study

Periodontitis is commonly diagnosed based on clinical parameters. However, the analysis of a few unique biomarkers of the disease process present in the saliva and blood can further assist the estimation of the rate of disease progression.AimThe present study attempted to correlate the alkaline phosphatase (ALP) and acid phosphatase (ACP) levels in saliva and serum between patients with healthy periodontium, gingivitis, and chronic periodontitis.Materials and methodsThe present study was conducted in 135 subjects between 20 and 55 years of age. The subjects were divided into three groups, namely healthy (Group A), gingivitis (Group B), and chronic periodontitis (Group C). The clinical parameters were recorded using the plaque index (PI), gingival index (GI), and probing depth (PD). Saliva and serum were analyzed for ALP and ACP levels using an auto analyzer. All patients underwent scaling and root planning (SRP) along with oral hygiene instructions. Patients were then recalled after four weeks, and blood and saliva samples were collected to estimate ALP and ACP levels prior to clinical examination.ResultsThe clinical parameters exhibited a statistically significant decrease in the PI and GI in both group B and group C after SRP. A significant change in the PD and attachment levels (AL) was observed in the periodontitis group after SRP. The mean salivary & serum ALP levels exhibited a statistically significant decrease in group B & C after SRP. The mean serum ACP levels exhibited a statistically significant decrease in group B & C after SRP However, the salivary ACP levels decrease after SRP was only statistically significant in group C.ConclusionSerum and salivary ALP and ACP levels were markedly decreased in the gingivitis and periodontitis groups after SRP and were positively correlated with the clinical parameters.     

Stimulatory and Inhibitory Actions of Proteins and Amino Acids On Copper-Catalysed Free Radical Generation in the Bulk Phase

The effect of a variety of proteins and amino acids was investigated on oxygen free radical activity as assessed by copper/hydrogen peroxide induced benzoate hydroxylation as well as copper-catalysed ascor-bate autoxidation. Serum albumins from a variety of species (human, bovine and dog) had both inhibitory and stimulatory effects depending on the molar copper to protein ratio; low ratios were inhibitory and high stimulatory. Some other proteins tested (lysozyme, soybean trypsin inhibitor and conalbumin) also had dual (inhibitory and stimulatory) effects, as did both histidine and polyhistidine, but all effects occurred at different molar ratios presumably dependent on the relative affinities for the copper ions. In contrast, metallolhioncin and cacruloplasmin, proteins specialised to bind copper in vivo had no stimulatory effects. In this paper we show that in addition to their fairly well documented inhibitory effects, under certain conditions some proteins also stimulate radical reactions. The possible role of this phenomenon in vivo is discussed.     

Glucose Accelerates Copper- and Ceruloplasmin-induced Oxidation of Low-density Lipoprotein and Whole Serum

Glucose at pathophysiological concentrations was able to accelerate copper-induced oxidation of isolated low-density lipoprotein (LDL) and whole serum. The efficiency of glucose was favored under the following circumstances: (a) when LDL oxidation was induced by low copper concentration, (b) when LDL was partly oxidized, i.e. enriched with lipid peroxides. The glucose derivative methyl- &#102 - d -glucoside was ineffective on Cu 2+ -induced LDL oxidation, pointing out the essential role of the reactivity of the aldehydic carbon for the pro-oxidative effect. When LDL oxidation was induced by a peroxyl radical generator, as a model of transition metal independent oxidation, glucose was ineffective. Glucose was found to stimulate oxidation of LDL induced by ceruloplasmin, the major copper-containing protein of human plasma. Thus, glucose accelerated oxidation of LDL induced by both free and protein bound copper. Considering the requirement for catalytically active copper and for the aldehydic carbon, the pro-oxidative effect of glucose is likely to depend on the increased availability of Cu + ; this is more efficient in decomposing lipid peroxide than Cu 2+ , accounting for acceleration of LDL oxidation. The possible biological relevance of our work is supported by the finding that glucose was able to accelerate oxidation of whole serum, which was assessed by monitoring low-level chemiluminescence associated with lipid peroxidation.     

Biochemical and cytogenetic biomarkers of pollutant exposure in marine fish (Aldrichetta forsteri Valenciennes and Sillago schomburgkii Peters) near industrial and metropolitan centres in South Australia

This project aimed to measure biochemical and cytogenetic biomarkers in marine fish (Aldrichetta forsteri and Sillago schomburgkii) associated with industrial and urban centres in South Australia. These sites were Port Pirie (affected by metal-contaminated outflows), Barker Inlet (adjacent to Metropolitan Adelaide), and Wills Creek (reference site). The biochemical biomarkers included sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) in serum, adenylate levels (ATP, ADP and AMP) and adenylate energy charge (AEC) in gill and liver, and sodium/potassium ATPase (Na⁺, K⁺-ATPase) in gill. Erythrocyte micronucleus frequency was a marker of cytogenetic effect. Serum enzyme levels were generally higher in fish from Port Pirie and Barker Inlet than in those from Wills Creek, with SDH demonstrating the clearest site-associated differences. Tissue adenylates were consistently lower at Port Pirie than elsewhere, suggesting a greater metabolic strain in fish at this site. AEC in gill and liver were consistently lower at Port Pirie than at Wills Creek, with Barker Inlet generally between these two. The reversed rank order was observed with erythrocyte micronucleus frequencies. Seasonal variations in the biomarkers may be attributed either to seasonal physiological changes in fish or changes in pollutant input levels or compositions. Na⁺, K⁺-ATPase did not differ between sites nor seasons in this study. This work shows that biochemical and cytogenetic differences occur in marine fish at specific locations in South Australia. It also shows that of these tests, serum SDH and erythrocyte micronuclei are potentially the most sensitive and reliable biomarkers of pollutants effects on marine fish. The results also suggest that these data may be used as a baseline against which future changes in marine water quality, and their consequent biological effects, can be compared.     

Allosteric regulation of pentameric ligand-gated ion channels: An emerging mechanistic perspective

Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communications in the nervous system by converting the binding of a chemical messenger—a neurotransmitter—into an ion flux through the postsynaptic membrane. They are oligomeric assemblies that provide prototypical examples of allosterically regulated integral membrane proteins. Here, we present an overview of the most recent advances on the signal transduction mechanism based on the X-ray structures of both prokaryotic and invertebrate eukaryotic pLGICs and on atomistic Molecular Dynamics simulations. The present results suggest that ion gating involves a large structural reorganization of the molecule mediated by two distinct quaternary transitions, a global twisting and the blooming of the extracellular domain, which can be modulated by ligand binding at the topographically distinct orthosteric and allosteric sites. The emerging model of gating is consistent with a wealth of functional studies and will boost the development of novel pharmacological strategies.