Role of serum cholinesterase and inflammatory markers in the prognosis of stage ⅠA -ⅢA breast cancer / 国际肿瘤学杂志

Objective:To analyze the preoperative and postoperative serum cholinesterase (CHE) levels in patients with stage ⅠA-ⅢA breast cancer who underwent surgical treatment, and to explore the roles of them and peripheral blood inflammatory markers in the prognostic prediction of stage ⅠA-ⅢA breast cancer.Methods:The relevant blood indicators of 152 patients with stage ⅠA-ⅢA breast cancer who underwent surgery and postoperative adjuvant therapy from January 2012 to December 2017 at Affiliated Huai'an Hospital of Xuzhou Medical University were retrospectively studied. The optimal cut-off values of serum CHE levels and peripheral blood inflammatory markers [systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) ] were calculated using X-tile 3.6.1 software. Patients were categorized into low and high value groups based on the optimal cutoff values. Kaplan-Meier curves and Cox regression analysis were used to assess the correlation between CHE and peripheral blood inflammation indexes and disease-free survival (DFS). Spearman correlation coefficient and Wilcoxon test were used to assess the correlation and changes of CHE and inflammation indexes before and after treatment. In addition to this, a nomogram prediction model was conscturcted based on independent prognostic factors by R software, which was validated by Bootstrap method.Results:The CHE levels of patients before and after treatment was 8 645.0 (7 251.3, 10 229.3) and 9 309.0 (7 801.0, 10 835.3) U/L, respectively, with a statistically significant difference ( Z=2.73, P=0.006) .The optimal cut-off values for postoperative CHE (Post-CHE), postoperative SII (Post-SII), and postoperative SIRI (Post-SIRI) associated with patients' DFS, being 7 773 U/L, 741, and 0.9, respectively. Univariate analysis showed that tumor size (≤2 cm vs.>2 cm and ≤5 cm: HR=2.55, 95% CI: 1.30-4.99, P=0.006; ≤2 cm vs. >5 cm: HR=8.95, 95% CI: 4.15-19.32, P<0.001), number of positive lymph nodes ( HR=3.84, 95% CI: 2.24-6.58, P<0.001), clinical stage (stage Ⅰ vs. stage Ⅱ: HR=1.52, 95% CI: 0.68-3.39, P=0.309, stage Ⅰ vs. stage Ⅲ: HR=8.12, 95% CI: 3.76-17.55, P<0.001), Ki-67 expression ( HR=2.19, 95% CI: 1.24-3.84, P=0.007), whether radiotherapy ( HR=2.05, 95% CI: 1.19-3.53, P=0.010), Post-CHE ( HR=6.81, 95% CI: 3.94-11.76, P<0.001), Pre-neutrophil to lymphocyte ratio (NLR) ( HR=1.11, 95% CI: 1.02-1.21, P=0.014), Post-NLR ( HR=5.23, 95% CI: 2.78-9.85, P<0.001), Pre-platelet to lymphocyte ratio (PLR) ( HR=2.08, 95% CI: 1.01-4.26, P=0.046), Post-PLR ( HR=7.11, 95% CI: 3.78-13.37, P<0.001), Pre-lymphocyte to monocyte ratio (LMR) ( HR=0.37, 95% CI: 0.20-0.66, P<0.001), Post-LMR ( HR=0.23, 95% CI: 0.13-0.41, P<0.001), Pre-SII ( HR=1.81, 95% CI: 1.05-3.12, P=0.033), Post-SII ( HR=6.12, 95% CI: 3.48-10.76, P<0.001), Pre-SIRI ( HR=2.12, 95% CI: 1.24-3.63, P=0.006), and Post-SIRI ( HR=4.93, 95% CI: 2.87-8.48, P<0.001) were associated with DFS in patients with stage ⅠA-ⅢA breast cancer. Multivariate analysis showed that tumor size (≤2 cm vs. >2 cm and ≤5 cm: HR=2.86, 95% CI: 1.41-5.78, P=0.003; ≤2 cm vs. >5 cm: HR=3.72, 95% CI: 1.50-9.26, P=0.005), number of positive lymph nodes ( HR=4.66, 95% CI: 2.28-9.54, P<0.001), Ki-67 expression ( HR=2.13, 95% CI: 1.15-3.94, P=0.016), Post-CHE ( HR=0.18, 95% CI: 0.10-0.33, P<0.001), Post-SII ( HR=2.71, 95% CI: 1.39-5.29, P=0.004), and Post-SIRI ( HR=3.77, 95% CI: 1.93-7.36, P<0.001) were independent influencing factors for DFS in patients with stage ⅠA-ⅢA breast cancer. Kaplan-Meier survival curve analysis showed that the median DFS of patients in the Ki-67<30% group was not reached, and the median DFS of patients in the Ki-67≥30% group was 89.0 months, and the 3- and 5-year DFS rates were 84.9% vs. 75.9% and 80.8% vs. 64.3%, respectively, with a statistically significant difference ( χ2=7.65, P=0.006) ; the median DFS of patients in the tumor size≤2 cm group was not reached, the median DFS of the 2 cm<tumor size≤5 cm group was 93.5 months, and the median DFS of the tumor size>5 cm group was 26.3 months, and the 3- and 5-year DFS rates were 95.5% vs. 74.6% vs. 42.1%, 86.3% vs. 68.6% vs. 25.3%, with a statistically significant difference ( χ2=40.46, P<0.001) ; the median DFS of patients in the group with the number of positive lymph nodes<4 was not reached, and the median DFS of the group with the number of positive lymph nodes≥4 was 30.7 months, and the 3- and 5-year DFS rates were 87.9% vs. 46.4% and 81.4% vs. 28.6%, respectively, with a statistically significant difference ( χ2= 47.34, P<0.001) ; the median DFS of patients in the Post-CHE<7 773 U/L group was 47.3 months, and the median DFS of patients in the Post-CHE≥7 773 U/L group was not reached, and the 3- and 5-year DFS rates were 52.8 % vs. 88.6% and 27.8% vs. 81.2%, respectively, with a statistically significant difference ( χ2=62.17, P<0.001) ; the median DFS was not achieved in patients in the Post-SII<741 group, and the median DFS was 30.5 months in the Post-SII≥741 group, with 3- and 5-year DFS rates of 88.1% vs. 38.5% and 80.1% vs. 30.8%, respectively, with a statistically significant difference ( χ2=50.78, P<0.001) ; the median DFS of patients in Post-SIRI<0.9 group was not reached, the median DFS of Post-SIRI≥0.9 group was 33.3 months, and the 3- and 5-year DFS rates were 93.5% vs. 46.7% and 84.9% vs. 39.9%, respectively, with a statistically significant difference ( χ2=40.67, P<0.001). Spearman correlation analysis revealed that Post-CHE was not correlated with Post-SII ( r=-0.111, P=0.175), and Post-CHE was negatively correlated with Post-SIRI ( r=-0.228, P=0.005). Post-treatment CHE was elevated compared to preoperative and the median DFS was not reached in patients with elevated CHE group and 61.8 months in patients with reduced CHE group after treatment, with a statistically significant difference ( χ2=25.67, P<0.001). The nomogram based on independent prognostic factors had good predictive performance, with a C-index of 0.893. Conclusion:The serum CHE level exhibited a significant increase following treatment. Postoperative serum CHE combined with SII and SIRI can effectively predict DFS in patients with stage ⅠA-ⅢA breast cancer, and the prognosis of patients with elevated CHE after treatment is better. The nomogram constructed based on independent prognostic factors has good predictive performance for DFS in breast cancer patients.

The role of serum cholinesterase in the prognosis assessment of patients with acute decompensated heart failure / 中华急诊医学杂志

Objective:To explore the role of serum cholinesterase (CHE) levels in the prognosis of patients with acute decompensated heart failure (ADHF).Methods:Total of 244 consecutive patients with ADHF who were admitted to the emergency department and were successfully discharged were prospectively enrolled from January 2018 to June 2020. Patients were divided into groups according to the first and third quartile of CHE level and the clinical data, laboratory tests and other nutritional indices were recorded after discharge, and then were followed up. The primary end points were the composites of cardiovascular death and hospitalization for worsening HF (composite end points). The secondary end points were all-cause mortality and cardiovascular death. Cox proportional risk analysis, time-dependent Cox regression model or stratified cox regression were used to identify the risk of primary and secondary endpoints. Clinical, biomarker and the compound models of clinical and biomarker were constructed. Kaplan-Meier method was used to plot the survival curves of different groups and compare their differences. Receiver Operating characteristics (ROC) curves were used to compare the area under the curve for CHE levels and other nutritional or prognostic indicators to identify composite end-point events.Results:During a follow-up period of 350(100,683) days, 158 patients reached the composite end points. In the multivariable Cox analysis, cholinesterase level was significantly associated with the composite end points after adjustment for major confounders. Cox proportional risk analysis or time-dependent Cox regression model showed that CHE level was significantly associated with the composite end points, all-cause mortality and cardiovascular mortality in both clinical, biomarker and composite models (all P< 0.05). A Kaplan–Meier analysis revealed that patients with low cholinesterase levels had significantly greater risk of reaching the composite end points than those with middle or high cholinesterase levels (78.1% vs 66.7% vs. 46.7%, P<0.001); Cholinesterase level showed the largest area under the receiver operating characteristic curve (AUROC) of 0.736 (95% CI, 0.664-0.888) for prediction of the composite end points among other nutritional indices. The AUROC of the Global Meta-Analysis Group Chronic Heart Failure (MAGGIC) Risk Score for prediction of the composite end points was increased from 0.704 to 0.762 ( P=0.038), when cholinesterase level was added. Conclusions:Cholinesterase may serve as a simple and effective prognostic marker for predicting adverse outcomes in ADHF patients.

Working Hours and Personal Protective Equipment Effect on Blood Cholinesterase Levels of Tobacco Plantation Workers

@#Introduction: Tobacco production is increasing in certain regions of Indonesia due to its high economic value. Tobacco and its products can have harmful effects on the health of consumers, producers and processing workers. Analysis of blood samples has shown that tobacco farmers are at risk of developing occupational diseases related to pesticide exposure and nicotine absorption through the epidermis of wet tobacco leaves. The aim of this study was to compare blood cholinesterase levels in tobacco plantation workers in relation to their working hours and use of personal protective equipment (PPE). Methods: This cross-sectional observational study was conducted in ten subdistricts in Jember district, Indonesia, and included 50 participants selected using proportional sampling. Spearman’s test was used to analyse the relationship between variables. Results: The significance value of the relationship based on Spearman’s test between working hours and blood cholinesterase levels of tobacco farmers in Jember was 0.058 > α (0.05). Meanwhile, the significance value of the relationship between working hours and complete blood count, specifically mean corpuscular haemoglobin concentration (MCHC), was 0.00 < α (0.05), and between PPE use and blood cholinesterase levels was 0.035 < α (0.05). Conclusion: Working hours were not associated with blood cholinesterase levels, but were associated with blood MCHC levels. Meanwhile, the use of PPE was found to be associated with cholinesterase levels in tobacco farmers.

Synthesis and biological activity evaluation of phthalimide-donepezil hybrids / 药学学报

A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.

Niveles de colinesterasa sérica en agricultores de San Pablo de Borbur, Boyacá, expuestos a organofosforados

Introducción: Las colinesterasas son enzimas que se encargan de hidrolizar la acetilcolina en ácido acético y colina, poniéndole fin a la transmisión nerviosa a lo largo de la sinapsis de las uniones neuromusculares. La medición de la actividad de la colinesterasa sérica constituye un indicador del efecto causado por la exposición prolongada a los organofosforados. Objetivo: Determinar los niveles de colinesterasa sérica y factores relacionados con la exposición a organofosforados en agricultores de la vereda de Páramo Lagunas de San Pablo de Borbur, Boyacá, Colombia. Metodología: Estudio prospectivo, de corte transversal, con una muestra de 57 trabajadores. A cada individuo se le aplicó una encuesta de datos sociodemográficos y factores laborales, posteriormente se les tomó una muestra de sangre venosa en ayuno de 8-12 horas; con el fin de determinar las concentraciones de colinesterasa sérica (kit Colinesterasa Butiriltiocolina Biosystems®) con el equipo automatizado de química clínica A-15 de Biosystems®. Resultados: El rango de edad de los participantes estuvo entre los 22 y 64 aflos, el 72 % de los individuos pertenecía al sexo masculino. El 3,5 % (2 varones) presentó valores inferiores al intervalo biológico de referencia (IBR), el 88 % de las personas afirmó realizar tareas con plaguicidas y el 54 % afirmó no utilizar los elementos de protección personal (EPP) al trabajar con estas sustancias. Conclusiones: Se evidenció la falta de escolaridad y la ausencia del acompaflamiento técnico en esta zona, lo que induce a que estos agricultores realicen procesos agrícolas relacionados con la aplicación de plaguicidas sin el adecuado conocimiento y sin la utilización adecuada de EPP.

Introduction: Cholinesterases are enzymes responsible for hydrolyzing acetylcholine in acetic acid and choline, which ends nerve transmission along the synapse of neuromuscular junctions. Measurement of serum cholinesterase activity acts as an indicator of the effect caused by prolonged exposure to organophosphates and carbamates Objective: To determine serum cholinesterase levels and factors related to exposure to organophosphates in farmers from the county of Páramo Lagunas in San Pablo de Borbur, Boyacá, Colombia. Methodology: Prospective, cross-sectional study, with a sample of 57 agricultural workers, a survey of sociodemographic data and labor factors was applied to each individual and a venous blood sample was taken in an 8-12 hour fasting, Serum cholinesterase concentrations were determined (Biosystems® Butyrylthiocholine Cholinesterase kit), by means of the Biosystems® A-15 automated clinical chemistry kit. Results: The age range of the participants was between 22 and 64 years old, 72% of the individuals belonged to the male sex. 3.5% (2 male individuals) presented values lower than the biological reference interval (BRI); 88% of the people affirmed to carry out tasks with pesticides and 54% of them affirmed not to use personal protective equipment (PPE) when working with these substances. Conclusions: The lack of schooling was evidenced in most of the farmers, as well as the absence of technical support to this area, which induces these farmers to carry out agricultural processes such as pesticide application, without adequate knowledge and without the proper use of PPE.

Investigation on health status of workers exposed to glyphosate / 中华劳动卫生职业病杂志

Objective: To analyze the concentrations of glyphosate and its metabolites in occupational exposed workers and their possible effects on human health, so as to provide a reference for improving the safe use of glyphosate and toxicity research. Methods: From April to December 2020, 247 workers directly exposed to glyphosate in 5 enterprises were selected as the contact group, and 237 workers who were not exposed to glyphosate and other pesticides in the same enterprise were selected as the control group. Questionnaire survey and occupational health examination were conducted on objects, and the concentrations of glyphosate and its metabolites in the air of workplaces and biological samples were detected. The correlation between the concentrations and the difference of health examination between the two groups were analyzed. Results: The urine glyphosate concentration (0.022-47.668 mg/L), the rate of exceeding the standard (60.32%, 149/247) and the urine aminomethyl phosphonic acid concentration (<0.010-1.624 mg/L) in the contact group were higher than those in the control group [urine glyphosate concentration (<0.020-4.482 mg/L), the rate of exceeding the standard (2.53%, 6/237) and the urine aminomethyl phosphonic acid concentration (<0.010-0.524 mg/L) ], respectively (P<0.001). The exceeding standard rate of glyphosate concentration in the workplace was 33.67% (33/98). The concentration of glyphosate in the workplace was positively correlated with the concentrations of glyphosate and aminomethylphosphonic acid in urine (r(s)=0.804, 0.238, P<0.001), and the concentration of glyphosate in urine was positively correlated with the concentration of aminomethylphosphonic acid in urine (r(s)=0.549, P<0.001). The alanine aminotransferase (ALT), white cell ratio, creatinine, uric acid, the abnormal rates of ALT and total protein (TP) in the contact group were higher than those in the control group, and TP was lower than that in the control group, the differences were statistically different (P<0.05). The abnormal rates of overall liver function, overall renal function, blood routine test, urine routine test, electrocardiogram, liver B ultrasound and blood lipid in the contact group were significantly higher than those in the control group (P<0.05) . Conclusion: The concentration of glyphosate in the workplace is related to the concentrations of glyphosate and aminomethyl phosphonic acid in the urine of workers, and exposure to glyphosate may have some harmful effects on human health.

Effects of nimodipine on cognitive function in patients with Alzheimer's disease / 中国基层医药

Objective:To investigate the effects of nimodipine on cognitive function in patients with Alzheimer's disease.Methods:A total of 200 patients with Alzheimer's disease who received treatment in Shuangqiao Hospital from January 2019 to January 2022 were included in this study. They were randomly divided into a control group and an observation group ( n = 100/group). The control group was treated with Donepezil. The observation group was treated with nimodipine and Donepezil. Before and 2 months after treatment, mental status and cognitive function were evaluated in each group. Results:After treatment, total response rate in the observation group was significantly higher than that in the control group [95% (95/100) vs. 81% (81/100), χ2 = 9.58, P < 0.05]. Alzheimer's disease assessment scale cognitive subscale score was significantly lower after treatment compared with before treatment in each group ( P < 0.05). Mini-mental State Examination score was significantly higher after treatment compared with before treatment in each group ( P < 0.05). Alzheimer's disease assessment scale cognitive subscale score in the observation group was significantly lower than that in the control group [(17.38 ± 1.95) points vs. (29.63 ± 3.39) points, t = -3.26, P < 0.05]. Mini-mental State Examination score in the observation group was significantly higher than that in the control group [(23.47 ± 4.59) points vs. (18.68 ± 3.91) points, t = 2.14, P < 0.05]. Conclusion:Nimodipine can improve cognitive function in patients with Alzheimer's disease.

Association between serum cholinesterase and insulin resistance in patients with type 2 diabetes mellitus / 中华内分泌代谢杂志

Objective:To investigate the association of serum cholinesterase(ChE) with insulin resistance(IR) in patients with type 2 diabetes mellitus(T2DM).Methods:General information and laboratory results of 376 hospitalized patients with type 2 diabetes were collected from the Endocrinology Department of Xuzhou Medical University Affiliated Hospital from June 2020 to November 2022. Based on quartile levels of serum cholinesterase(ChE), the patients were divided into four groups: Q1 group(≤7 912 IU/L), Q2 group(7 913-9 083 IU/L), Q3 group(9 084-10 304 IU/L), and Q4 group(≥10 305 IU/L). The Homeostasis model was used to evaluate insulin resistance(HOMA-IR) for each group, and the correlation between ChE and HOMA-IR was analyzed. Results:As ChE levels increased, HOMA-IR levels significantly increased( P<0.05). Spearman correlation analysis showed that ChE was positively correlated with body mass index, diastolic blood pressure, high-sensitivity C-reactive protein, HbA 1C, total cholesterol, triglycerides, low density lipoprotein-cholesterol(LDL-C), aspartate aminotransferase, alanine aminotransferase(ALT), glutamyl transpeptidase, prealbumin, albumin, uric acid, and HOMA-IR( P<0.05). ChE was negatively correlated with age, duration of diabetes, and blood urea nitrogen( P<0.05). Multivariat stepwise linear regression analysis showed that disease duration, body mass index, HbA 1C, ALT, and ChE were independent influencing factors of HOMA-IR( P<0.01). Logistic regression analysis showed that compared to the Q1 group, the risks of developing IR in the Q4, Q3, and Q2 groups were 3.969(1.791-8.797), 2.100(1.059-4.164), and 2.026(1.071-3.833), respectively. Conclusion:Serum ChE is closely associated with IR in patients with T2DM.

Treatment of post-stroke cognitive impairment / 国际脑血管病杂志

Post stroke cognitive impairment (PSCI) is the most common complication in stroke patients, which seriously affects their quality of life. Early comprehensive treatment to intervene in mild cognitive impairment caused by stroke is of great significance in reducing and delaying the occurrence of dementia. This is a review on the latest treatment progress of PSCI.

Rare Cases of Hepatitis B Virus Infection Combined with Severe Cholinesterase Deficiency not Caused by Liver Dysfunction:Two Case Reports and Literature Review / 昆明医科大学学报

Objective To analyze the hepatitis B virus infection with extreme reduction of cholinesterase(CHE)not caused by liver synthesis dysfunction,and to explore its clinical significance.Methods The clinical data of 2 rare cases hospitalized in the 3rd people's hospital of Kunming in July 2021 and February 2022,including liver function,coagulation function,hepatitis B markers,hepatitis B virus volume,and whole exon sequencing,were collected and analyzed,and literature was reviewed.Results CHE was extremely reduced in 2 patients with HBV infection,liver synthesis function was good,and whole exon sequencing showed the presence of butyrylcholinesterase(BCHE)gene mutation.Conclusion The extremely low CHE in this case is not due to liver function disorder.Exon sequencing detected mutations in the BCHE gene in two patients.Screening for BCHE mutations may be necessary in patients with extremely low cholinesterase levels not due to liver dysfunction.

Pyridostigmine bromide causes myocardial infarction in myasthenia gravis： a case report and literature review / 中风与神经疾病杂志

@#Myasthenia gravis is an autoimmune disease，which is usually mediated by antibodies to acetylcholine receptors at the neuromuscular junction. It is commonly treated with cholinesterase inhibitors such as pyridostigmine bromide. Although cardiovascular events with the drug are rare，it is very important to early recognize disease changes and be alert to potential cardiovascular events in patients with myasthenia gravis. Therefore，we report a case of an elderly female patient with myasthenia gravis developing acute myocardial infarction and then sudden cardiac death following anticholinesterase therapy，and discuss the possible causes of adverse cardiovascular events based on this case.

Organophosphorus poisoning: study of evaluation of clinically relevant indicators

Background:POP scale andserum cholinesterase estimation are purported to be meaningful indicators for mortality prediction in the cases of organophosphorus poisoning. The present study was undertaken to substantiate the correlation ofPOP scale score and serum cholinesterase levels in acute OP poisoning with mechanical ventilation requirement and mortality in our setting. Methods:Data of 150 eligible participants was collected, with POP scale andserum cholinesterase levels being assessed during initial presentation in each of them. Clinical course of the cases was monitored anddocumented. Results:The observed case fatality rate was 32.7%. POP scale scoring revealed 30out of 75 patients to be from moderate group and 19 out of 22 patients to be from severe group. Forty nine outof 75 in moderate group & all patients in severe group required ventilator support. With respect to Serum Cholinesterase level; 20 out of 23 and 29 out of 77 patients died in the severe & moderate poisoning categories respectively. Forty eight out of 77 in moderate poisoning andall patients in severe poisoning required ventilator support. Conclusions: POP scale scoring and serum Cholinesterase level assessments are clinically relevant indicators in acute OP poisoning cases and are of great utility towards assessment ofmechanical ventilation requirement and mortality prediction.

Identification of potential AChE inhibitors through combined machine-learning and structure-based design approaches-Supplementary data

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterised by dementia.The depletion of acetylcholine (ACh) is involved the synaptic cleft is responsible for dementia due to neuronal loss. The acetylcholinesterase (AChE) enzyme isinvolved in the hydrolytic degradation of ACh and its inhibition is therapeutically beneficial for the treatment in memory loss.The use of machine learning (ML) for the identification of enzyme inhibitors has recently become popular. It identifies important patterns in the reported inhibitors to predict the new molecules. Hence, in this study, a set of support vector classifier-based ML models were developed,validated and employed to predict AChE inhibitors. Further, 247 predicted compounds obtained through PAINS and molecular property filters were docked on the AChE enzyme. The docking study identified compounds AAM132011183, ART21232619 and LMG16204648 as AChE inhibitors with suitable ADME properties. The selected compounds produced stable interactions with enzymes in molecular dynamics studies. The novel inhibitors obtained from the study may be proposed as active leads for AChE inhibition.

Identification of potential AChE inhibitors through combined machine-learning and structure-based design approaches-Supplementary data

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterised by dementia.The depletion of acetylcholine (ACh) is involved the synaptic cleft is responsible for dementia due to neuronal loss. The acetylcholinesterase (AChE) enzyme isinvolved in the hydrolytic degradation of ACh and its inhibition is therapeutically beneficial for the treatment in memory loss.The use of machine learning (ML) for the identification of enzyme inhibitors has recently become popular. It identifies important patterns in the reported inhibitors to predict the new molecules. Hence, in this study, a set of support vector classifier-based ML models were developed,validated and employed to predict AChE inhibitors. Further, 247 predicted compounds obtained through PAINS and molecular property filters were docked on the AChE enzyme. The docking study identified compounds AAM132011183, ART21232619 and LMG16204648 as AChE inhibitors with suitable ADME properties. The selected compounds produced stable interactions with enzymes in molecular dynamics studies. The novel inhibitors obtained from the study may be proposed as active leads for AChE inhibition.

Identification of potential AChE inhibitors through combined machine-learning and structure-based design approaches

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease characterised by dementia.The depletion of acetylcholine (ACh) is involved the synaptic cleft is responsible for dementia due to neuronal loss. The acetylcholinesterase (AChE) enzyme isinvolved in the hydrolytic degradation of ACh and its inhibition is therapeutically beneficial for the treatment in memory loss.The use of machine learning (ML) for the identification of enzyme inhibitors has recently become popular. It identifies important patterns in the reported inhibitors to predict the new molecules. Hence, in this study, a set of support vector classifier-based ML models were developed,validated and employed to predict AChE inhibitors. Further, 247 predicted compounds obtained through PAINS and molecular property filters were docked on the AChE enzyme. The docking study identified compounds AAM132011183, ART21232619 and LMG16204648 as AChE inhibitors with suitable ADME properties. The selected compounds produced stable interactions with enzymes in molecular dynamics studies. The novel inhibitors obtained from the study may be proposed as active leads for AChE inhibition.

CRP COMPARISON WITH RDW AS A PROGNOSTIC MARKER FOR OUTCOME OF OP POISONING

Background: Organophosphate (OP) compounds are frequently used as pesticides in countries. This ease of availability of the OP compounds has resulted in a gradual increase in unintentional and 1 suicidal poisoning, mainly in developing countries . Elevated RDW is associated with systemic in?ammation and oxidative stress More severe poisoning means more production of free radicals and more oxidative stress. In AOPP, toxins may cause 2,5 lesions in tissues and organs in the body, leading to increased plasma CRP levels . Aim: 1-To measure CRP, serum acetylcholinesterase, red cell distribution width, in acute organophosphorus poisoning.2- To analyze the correlation between these biochemical parameters and serum acetylcholinesterase levels. 3-To analyze the validity of these biochemical parameters in prediction of severity and prognosis in op poisoning. Hospital based Methods: prospective study was conducted from OP compound consumption patients attending casualty and admitted patients in S. Nijalingappa Medical College Hospital and Research center, BAGALKOT. Patients less than 18 years, Co-ingestion of organophosphorus with other agents, Pre hospital cardiac arrest, Prior history of Iron de?ciency anemia, Vitamin B12 de?ciency and folate de?ciency anemia, Recent hemorrhage, Chronic liver disease, Prior chemotherapy, Patient on oral contraceptive pills, Patient on estrogen therapy is excluded. Results: a total of 60 patients who diagnosed with history of poisoning were involved in the study among them 29 (48.3%) were male and 31 (51.7%) were female. 75% of study population has attempted suicide by taking the poisoning and 10% of study population had accidental consumption of poisoning, and 5% of study population had occupational exposure. There is negative correlation between the cholinesterase, RDW and CRP as cholinesterase in Conclusion: creases RDW and CRP decreases and severity of poisoning decreases and as cholinesterase decreases RDW and CRP increases and severity of op poisoning increases and morbidity and mortality increases.

Efficacy of Xiaoshuan Changrong Capsules combined with donepezil hydrochloride in the treatment of patients with vascular dementia and their effects on serum cytokines and oxidative stress / 中国基层医药

Objective:To investigate the efficacy of Xiaoshuan Changrong Capsules combined with donepezil hydrochloride in the treatment of patients with vascular dementia and their effects on serum cytokines and oxidative stress. Methods:A total of 102 patients with vascular dementia who received treatment in Hangzhou Seventh People's Hospital, China between January 2019 and January 2021 were included in this study. They were randomly divided into control and observation groups, with 51 patients per group. The control group was treated by oral donepezil hydrochloride. The observation group was given oral Xiaoshuan Changrong Capsules combined with oral donepezil hydrochloride. All patients were treated for 12 weeks. Efficacy was compared between the two groups. The Clinical Dementia Rating score, the Mini-Mental State Examination score, and serum levels of interleukin 6, insulin-like growth factor-1, tumor necrosis factor-α, superoxide dismutase and malondialdehyde were compared between before and after treatment. Results:Total response rate in the observation group was significantly higher than that in the control group [90.20% (46/51) vs. 70.59% (36/51), χ 2 = 6.22, P < 0.05]. At 12 weeks after treatment, the Clinical Dementia Rating score in the observation group was significantly lower than that in the control group [(1.34 ± 0.27) points vs. (1.89 ± 0.31) points, t = 9.55, P < 0.05]. At 12 weeks after treatment, the Mini-Mental State Examination score in the observation group was significantly higher than that in the control group [(25.45 ± 1.98) points vs. (22.32 ± 2.10) points, t = 7.74, P < 0.05]. At 12 weeks after treatment, interleukin-6, insulin-like growth factor-1, and tumor necrosis factor-α levels in the observation group were (31.28 ± 7.35) ng/L, (0.34 ± 0.08) ng/L and (9.46 ± 2.27) ng/L, respectively, which were significantly lower than those in the control group [(46.43 ± 6.28) ng/L, (0.48 ± 0.07) ng/L, (20.98 ± 3.56) ng/L, t = 11.19, 9.40, 19.48, all P < 0.05]. At 12 weeks after treatment, superoxide dismutase in the observation group was significantly higher than that in the control group [(98.91 ± 7.25) U/L vs. (86.59 ± 5.63) U/L, t = 9.58, P < 0.05] . At 12 weeks after treatment, malondialdehyde in the observation group was significantly lower than that in the control group [(3.25 ± 0.50) mmol/L vs. (4.81 ± 0.35) mmol/L, t = 18.25, P < 0.05]. Conclusion:Xiaoshuan Changrong Capsules combined with donepezil hydrochloride is highly effective on vascular dementia. It can reduce cellular inflammatory response and improve oxidative stress response. This study is of great innovation and science.

Association of plasma cholinesterase and triglyceride level in patients with newly diagnosed type 2 diabetes / 中华内分泌代谢杂志

Objective:To investigate the relationship of plasma cholinesterase (ChE) with triglyceride (TG) levels in newly diagnosed patients with type 2 diabetes (T2DM).Methods:Clinical data and biochemical parameters of 321 patients with newly diagnosed T2DM admitted to the Department of Endocrinology of People′s Hospital of Shanghai Putuo from January 2018 to June 2020 were retrospectively collected. The patients were classified into four groups based on the plasma ChE level: Q1group ( n=81, <6 915 U/L), Q2 group ( n=80, 6 916-8 268 U/L), Q3 group ( n=80, 8 269-9 578 U/L), and Q4 group ( n=80, ≥9 579 U/L). The correlation of plasma ChE with TG level was analyzed. Results:With the increased ChE level, TG level significantly increased ( P<0.001). Correlation analysis showed that ChE was positively correlated with body weight, body mass index (BMI), TG, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), uric acid (UA), alanine aminotransferase (ALT), aspartate aminotransferase (AST)( r=0.35, 0.39, 0.35, 0.31, 0.27, 0.24, 0.25, 0.11, P<0.05, P<0.01 or P<0.001)while negatively correlated with age, systolic blood pressure, blood urea nitrogen (BUN), creatinine, and glycated albumin (GA)( r=-0.46、-0.14、-0.20、-0.14、-0.21, P<0.05 or P<0.001). Multivariate stepwise regression analysis showed that ChE was an independent risk factor for TG ( β=0.270, P<0.001). Logistic Multivariate regression analysis showed that after adjustment for sex, age, body weight, hemoglobin, leukocytes, total protein, albumin, globulin, ALT, BUN, creatinine, uric acid, smoking history, drinking history, HbA 1C, GA, TC, and LDL-C, the risk of hypertriglyceridemia in Q4 was 6.024 folds higher than Q1 group ( P=0.011). With the TG (1.70 mmol/L) as cut-off value, the optimal cut-off point of the ChE was 7 801 U/L, as calculated by receiver operating characteristic(ROC) curve analysis of ChE and hypertriglyceridemia. Conclusions:ChE level is positively correlated with TG in newly diagnosed patients with T2DM.

Synthesis, cholinesterase inhibition and hepatotoxicity of tacrine-phenol-bifendate hybrids / 药学学报

A series of tacrine-phenol-bifendate hybrids (7a-7e, 8a-8e) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs) with low hepatotoxicity. All the compounds had potent ChEs inhibitory activity with half-inhibitory concentration (IC50) values at the nanomolar range. Compound 8d exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC50 value of 156.39 nmol·L-1 and compound 7b showed the most potent inhibition for butyrylcholinesterase with IC50 value of 16.33 nmol·L-1. Kinetic and molecular modeling studies showed that 8d targeted both the catalytic active site and the peripheral anionic site of AChE. In addition, these compounds showed low toxicity to hepatocytes, and compound 8d did not increase the level of reactive oxygen species in HepG2 cells.

Synthesis of ferulic acid derivatives and their inhibition of cholinesterase inhibitory activity / 中国药科大学学报

@#Ferulic acid (FA), a natural product of phenylpropanoids containing phenolic hydroxyl groups, has a wide range of pharmacological activities and some therapeutic effect on Alzheimer's disease (AD).Using FA as the raw material, the ferulic acid carbamate aniline derivatives were first synthesized by 4-step esterification reaction, splicing carbamate active functional groups, hydrolysis reaction and amide condensation.These FA derivatives were evaluated for in vitro cholinesterase inhibition activity by the Ellman method.A total of 15 novel FA derivatives were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and ESI-MS.Cholinesterase activity tests showed that compounds 5c, 5f, 5j, 5g, 5m possessed good acetylcholinesterase inhibition activity.Except for 5l, 5m, almost all compounds have inhibition activity on butyrylcholinesterase, which is much higher than that on acetylcholinesterase.In conclusion, compounds 5c, 5f, 5j and 5g can be used as potential anti-AD inhibitors targeting cholinesterase..