Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Design, synthesis and the evaluation of cholinesterase inhibition and blood-brain permeability of daidzein derivatives or analogs.

In the present study, a series of derivatives and analogs of daidzein were designed and synthesized to investigate cholinesterase inhibition and blood-brain barrier permeability. The enzyme assay showed that most of the compounds containing a tertiary amine group exhibit moderate cholinesterase inhibition, 7-hydroxychromone derivatives (absence of B ring of daidzein scaffold) only have a weaker bioactivity, while those compounds without the tertiary amine group have no bioactivity. Among them compound 15a (4'-N,N-dimethylaminoethoxy-7-methoxyisoflavone) appeared the best inhibitory activity (IC50 : 2.14 ± 0.31 µmol/L) and higher selectivity for AChE over BuChE (Ratio: 7.07). It was selected for the further investigation by UPLC-MS/MS. The results show that CBrain/Serum of compound 15a in mice was more than 2.87 within 240 min. This discovery may provide worthy information for the future development of central nervous drugs including but not limited to cholinesterase inhibitors.

A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

Chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance: A case report and literature review.

BACKGROUND: Study of the molecular biological characteristics of chronic neutrophilic leukemia complicated with plasma cell disorder (CNL-PCD) and lymphocytic proliferative disease (CNL-LPD). METHODS: The clinical data of a patient with chronic neutrophilic leukemia complicated with monoclonal gammopathy of undetermined significance (CNL-MGUS) in our hospital were reviewed, and the Chinese and/or English literature about CNL-PCD and CNL-LPD in PubMed and the Chinese database CNKI in the past 10 years was searched to analyze the molecular biological characteristics of this disease. RESULTS: A 73-year-old male had persistent leukocytosis for 18 months. The white blood cell count was 46.77 × 109/L and primarily composed of mature neutrophils; hemoglobin: 77 g/L; platelet count: 189 × 109/L. Serum immunofixation electrophoresis showed IgG-λ monoclonal M protein. A CT scan showed splenomegaly. Next-generation sequencing (NGS) showed that CSF3R T618I, ASXL1 and RUNX1 mutations were positive. It was diagnosed as CNL-MGUS. We summarized 10 cases of CNL-PCD and 1 case of CNL-LPD who underwent genetic mutation detection reported in the literature. The CSF3R mutational frequency (7/11, 63.6%) was lower than that of isolated CNL. The ASXL1 mutations were all positive (3/3), which may represent a poor prognostic factor. The SETBP1 mutation may promote the progression of CNL-PCD. We also found JAK2, RUNX1, NRAS, etc. in CNL-PCD. CONCLUSIONS: Chronic neutrophilic leukemia may be more inclined to coexist with plasma cell disorder. The CSF3R mutation in CNL-PCD is still the most common mutated gene compared with isolated CNL. Mutations in SETBP1 and ASXL1 may be poor prognostic factors for CNL-PCD.

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with PRF1 c.65delC/c.163C>T compound heterozygous mutations: A case report.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review. CASE SUMMARY: We report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation. CONCLUSION: The delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.

Design and synthesis of new disubstituted benzoxazolone derivatives that act as iNOS inhibitors with potent anti-inflammatory activity against LPS-induced acute lung injury (ALI).

Acute lung injury (ALI) is a pulmonary disease that acts as a severe acute inflammatory response with no specific drugs. iNOS, a catalyst of the excessive production of NO, has been demonstrated to participate in the inflammatory process, and targeting iNOS may be a promising therapeutic pathway to alleviate ALI. In our research, eighteen new disubstituted benzoxazolone derivatives were synthesized, characterized, and evaluated for activity against NO production in an LPS-induced RAW264.7 cell. The results showed that these compounds could obviously inhibit the over-generation of NO and disubstitution at the 4, N-position of the benzoxazolone ring, presenting better potency than substitution only at the 4-position. Among the analogues generated, compounds 2c, 2d, and 3d showed NO inhibitory activity with IC50 values of 16.43, 14.72, and 13.44 µM and iNOS inhibitory activity with IC50 values of 4.605, 3.342, and 9.733 µM, respectively. Meanwhile, compounds 2c, 2d, and 3d could also inhibit the release of IL-6, IL-1ß in vitro and suppress xylene-induced ear edema in vivo to realize anti-inflammatory activity. Furthermore, compound 2d could significantly protect the LPS-induced ALI, presenting as decreased inflammatory cytokines and obvious pathological changes. Immunohistochemistry and molecular modeling demonstrated that compound 2d significantly inhibited the expression of iNOS in vivo and interacted with iNOS through two hydrogen bindings with the MET368 and ILE195 residues of the iNOS protein. These results demonstrated that compound 2d could be a promising lead structure for iNOS inhibitors, with anti-inflammatory activity to treat LPS-induced acute lung injury.

Nitrogen-containing flavonoid and their analogs with diverse B-ring in acetylcholinesterase and butyrylcholinesterase inhibition.

In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone, 2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing 6 or 7-substituted tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results indicated that the alteration of aromatic ring connecting to chromone scaffold brings about a significant impact on biological activity. Compared with flavones, the inhibitory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE significantly decreased, while that of 2-biphenyl chromone derivatives with 7-substituted tertiary amine side chain is better than relative flavones derivatives. For all new synthesized compounds, the position of tertiary amine side chain obviously influenced the activity of inhibiting AChE. The results above provide great worthy information for the further development of new AChE inhibitors. Among the newly synthesized compounds, compound 5a is potent in AChE inhibition (IC50 = 1.29 ± 0.10 µmol/L) with high selectivity for AChE over BChE (selectivity ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a mixed-type inhibitory effect against AChE.

CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis.

Non-small cell lung cancer (NSCLC) is a common type of lung cancer, characterized by a poor prognosis. In the last several years, more and more studies have demonstrated the significant roles played by circular RNAs (circRNAs) in different human tumors progression including NSCLC. The present study was to explore the mechanism of hsa_circ_101237 in regulating non-small cell lung cancer (NSCLC). Totally 303 NSCLC cases were enrolled. A549 and H1299 cells were transfected. Cells viability, migration and invasion were determined by CCK-8 assay and transwell experiment, respectively. Luciferase reporter gene assay and RNA immunoprecipitation (RIP) assay were performed. hsa_circ_101237, miR-490-3p and MAPK1 expression in tissues/cells were detected by qRT-PCR. The study found an elevation in the expression of Hsa_circRNA_101237 in both NSCLC tissues and cell line. High Hsa_circRNA_101237 expression predicted poor survival in NSCLC. Meanwhile, we found that hsa_circRNA_101237 expression sponged miR-490-3p to enhance MAPK1 expression, thus significantly promoting NSCLC cell lines proliferation, migration, and invasion. MAPK1 restoration prevented NSCLC cells proliferation, migration, and invasion to be repressed due to hsa_circRNA_101237 knockdown. To sum up, as revealed by the study, hsa_circRNA_101237 promoted the expression of MAPK1 via miRNA-490-3p sponge, thus affecting the NSCLC as an important onco-circRNA.

MicroRNA-96-5p represses breast cancer proliferation and invasion through Wnt/ß-catenin signaling via targeting CTNND1.

Low miR-96-5p expression is characteristic of many cancers but its role in breast cancer (BCa) remains poorly defined. Here, the role of miR-96-5p in BC development was assessed. We demonstrate that exogenously expressing miR-96-5p inhibits the proliferative, migratory and invasive capacity of BCa cells. Mechanistically, miR-96-5p in BCa cells was found to target and downregulate catenin delta 1 (CTNND1) leading to decreased ß-catenin expression, a loss of WNT11 signaling, reduced cyclin D1 levels and lower MMP7 expression. Exogenously expressing CTNND1 alleviated these effects. In summary, we are the first to reveal that miR-96-5p inhibits the proliferative, invasive and migratory phenotypes of BCa cells the targeting of CTNND1 and subsequent Wnt/ß-catenin signaling. These data highlight miR-96-5p as a novel target for BC treatment.

Birth prevalence of orofacial clefts among perinatal infants: A register-based study in Bao'an district, Shenzhen, China.

BACKGROUND: The birth prevalence of orofacial clefts (OFCs) has been widely studied, but results are considerable varied, and epidemiological studies in southern China are few in numbers. To address this gap, we carried out a register-based study to estimate the birth prevalence of OFCs in Bao'an district, Shenzhen, China. METHODS: Data of perinatal infants born between 2003 and 2017 were extracted from Shenzhen Maternal and Child Health Management System. The overall OFCs birth prevalence with 95% confidence interval (CI) as well as subgroup analysis based on selected demographic factors was conducted. Cochran-Armitage trend tests were applied to evaluate the time trend by 5-year intervals. RESULTS: The overall birth prevalence of OFCs, cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) was 1.30 (95% CI 1.21-1.39), 1.00 (95% CI 0.92-1.08), and 0.30 (95% CI 0.25-0.34) per 1,000 births, respectively. An overall declining tendency was observed in the OFCs (from 1.83 to 1.04 per 1,000 births), specifically CL/P (from 1.53 to 0.69 per 1,000 births) birth prevalence over 5-year intervals, with statistical significance (p < 0.01). Subgroup analysis revealed that the CL/P and CPO birth prevalence was differed by infant gender, household registration, maternal age, and parity. CONCLUSION: Our findings had firstly reported the birth prevalence of OFCs in Bao'an district, and might help other researchers to plan more comprehensive public health strategies to reduce the occurrence of OFCs in further generation.

Structure-activity study of fluorine or chlorine-substituted cinnamic acid derivatives with tertiary amine side chain in acetylcholinesterase and butyrylcholinesterase inhibition.

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a-9d) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a-3f) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC50 = 1.11 ± 0.08 µmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.

[Rapid characterization of chemical constituents and rat metabolites of Fufang Gancao Tablets by UHPLC-LTQ-Orbitrap mass spectrometer].

Ultra-high-performance liquid chromatography coupled with tandem high-resolution mass spectrometry (UHPLC-HR-MSn ) method was used to analyze the constituents of Fufang Gancao Tablets and its main metabolites in rat plasma. Rat plasma was collected both before and after oral administration of Fufang Gancao Tablets. After solid phase extraction, ACQUITY UHPLC BEH C18 (2.1 mm×100 mm, 1.7 µm) was used with 0.1% formic acid-acetonitrile solution as the mobile phase for gradient elution. The chemical components in Fufang Gancao Tablets and their prototypes and metabolites in plasma samples were analyzed by LTQ-Orbitrap equipped with an ESI ion source in a positive ion mode. Based on the accurate mass measurements, the retention time and mass fragmentation patterns, a total of 55 compounds were tentatively identified from Fufang Gancao Tablets, including 42 flavonoids, 9 triterpenes and 4 alkaloids. Furthermore, metabolites in rat plasma after oral administration of Fufang Gancao Tablets were also analyzed. A total of 26 compounds were identified, including 20 prototypes and 6 metabolites mainly through metabolic pathways of hydroxylation, glucuronide conjugation, and sulfate conjugation, etc. Our results showed that the ultra-high-performance liquid chromatography coupled with linear ion trap quadrupole Orbitrap high resolution mass spectrometry (UHPLC-LTQ-Orbitrap) could comprehensively elucidate the chemical constituents of Fufang Gancao Tablets and their migrating components in rat plasma, providing scientific basis for further studying the metabolism process and pharmacodynamic substance of Fufang Gancao Tablets.

Structure-activity relationship investigation of coumarin-chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors.

Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. The nature and position of the chalcone substituents had major effects on inhibitory activity as well as selectivity for AChE over BChE. Compounds with para-substituted chalcone fragments in which the substituents were choline-like had potent activity against AChE and poor activity against BChE, while ortho-substituted analogs exhibited an opposite effect. Replacement of the terminal amine groups by amide, alkyl or alkenyl groups abrogated activity. Compound 5e showed potent inhibitory activity [Formula: see text]) and good selectivity for AChE over BChE (ratio 27.4), and a kinetic study showed that 5e exhibited mixed-type inhibition against AChE. Computational docking results indicate that 5e binds to Trp 279, Tyr334 and Trp 84 in AChE, but only to Trp 82 in BChE. Overall, the results show that coumarin-chalcone hybrids with choline-like side-chains have promising activity and selectivity against AChE and be promising therapeutic leads for Alzheimer's disease.

Structure-activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors.

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a-4c and 7a-7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure-activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity (IC50: 2.49 ± 0.19 µM) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.

Microwave radiation leading to shrinkage of dendritic spines in hippocampal neurons mediated by SNK-SPAR pathway.

The popularization of microwave raised concerns about its influence on health including cognitive function which is associated greatly with dendritic spines plasticity. SNK-SPAR is a molecular pathway for neuronal homeostatic plasticity during chronically elevated activity. In this study, Wistar rats were exposed to microwaves (30 mW/cm2 for 6 min, 3 times/week for 6 weeks). Spatial learning and memory function, distribution of dendritic spines, ultrastructure of the neurons and their dendritic spines in hippocampus as well as the related critical molecules of SNK-SPAR pathway were examined at different time points after microwave exposure. There was deficiency in spatial learning and memory in rats, loss of spines in granule cells and shrinkage of mature spines in pyramidal cells, accompanied with alteration of ultrastructure of hippocampus neurons. After exposure to 30 mW/cm2 microwave radiation, the up-regulated SNK induced decrease of SPAR and PSD-95, which was thought to cause the changes mentioned above. In conclusion, the microwave radiation led to shrinkage and even loss of dendritic spines in hippocampus by SNK-SPAR pathway, resulting in the cognitive impairments.

Discovery of potent and selective acetylcholinesterase (AChE) inhibitors: acacetin 7-O-methyl ether Mannich base derivatives synthesised from easy access natural product naringin.

Naringin, as a component universal existing in the peel of some fruits or medicinal plants, was usually selected as the material to synthesise bioactive derivates since it was easy to gain with low cost. In present investigation, eight new acacetin-7-O-methyl ether Mannich base derivatives (1-8) were synthesised from naringin. The bioactivity evaluation revealed that most of them exhibited moderate or potent acetylcholinesterase (AChE) inhibitory activity. Among them, compound 7 (IC50 for AChE = 0.82 ± 0.08 µmol•L-1, IC50 for BuChE = 46.30 ± 3.26 µmol•L-1) showed a potent activity and high selectivity compared with the positive control Rivastigmine (IC50 for AChE = 10.54 ± 0.86 µmol•L-1, IC50 for BuChE = 0.26 ± 0.08 µmol•L-1). The kinetic study suggested that compound 7 bind to AChE with mix-type inhibitory profile. Molecular docking study revealed that compound 7 could combine both catalytic active site (CAS) and peripheral active site (PAS) of AChE with four points (Trp84, Trp279, Tyr70 and Phe330), while it could bind with BuChE via only His 20.

Tertiary amine derivatives of chlorochalcone as acetylcholinesterase (AChE) and buthylcholinesterase (BuChE) inhibitors: the influence of chlorine, alkyl amine side chain and α,ß-unsaturated ketone group.

A new series of tertiary amine derivatives of chlorochalcone (4a∼4l) were designed, synthesized and evaluated for the effect on acetylcholinesterase (AChE) and buthylcholinesterase (BuChE). The results indicated that all compounds revealed moderate or potent inhibitory activity against AChE, and some possessed high selectivity for AChE over BuChE. The structure-activity investigation showed that the substituted position of chlorine significantly influenced the activity and selectivity. The alteration of tertiary amine group also leads to obvious change in bioactivity. Among them, IC50 of compound 4l against AChE was 0.17 ± 0.06 µmol/L, and the selectivity was 667.2 fold for AChE over BuChE. Molecular docking and enzyme kinetic study on compound 4l suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Further study showed that the pyrazoline derivatives synthesized from chlorochalcones had weaker activity and lower selectivity in inhibiting AChE compared to that of chlorochalcone derivatives.

[Cellphone electromagnetic radiation damages the testicular ultrastructure of male rats].

OBJECTIVE: To investigate the influence of cellphone electromagnetic radiation (CER) on the testicular ultrastructure and the apoptosis of spermatogenic cells in male rats.atability, feasibility, applicability, and controllability in the construction of experimental animal models, we compared the major anatomic features of the penis of 20 adult beagle dogs with those of 10 adult men. Using microsurgical techniques, we performed cross-transplantation of the penis in the 20 (10 pairs) beagle dogs and observed the survival rate of the transplanted penises by FK506+MMF+MP immune induction. We compared the relevant indexes with those of the 10 cases of microsurgical replantation of the amputated penis. METHODS: Thirty adult male SD rats were equally randomized into a 2 h CER, a 4 h CER, and a normal control group, the former two groups exposed to 30 days of 900 MHz CER for 2 and 4 hours a day, respectively, while the latter left untreated. Then the changes in the ultrastructure of the testis tissue were observed under the transmission electron microscope and the apoptosis of the spermatogenic cells was determined by TUNEL. RESULTS: Compared with the normal controls, the rats of the 2 h CER group showed swollen basement membrane of seminiferous tubules, separated tight junction of Sertoli cells, increased cell intervals, apparent vacuoles and medullization in some mitochondria, and increased apoptosis of spermatogenic cells, mainly the apoptosis of primary spermatocytes (P<0.05 ). In comparison with the 2 h CER group, the animals of the 4 h CER group exhibited swollen basement membrane of seminiferous tubules, more separated tight junction of Sertoli cells, wider cell intervals, incomplete membrane of spermatogonial cells, fragments of cytoplasm, nuclear pyknosis and notch, slight dilation of perinuclear space, abnormalities of intracellular mitochondria with vacuoles, fuzzy structure, and fusion or disappearance of some cristae, and increased damage of mitochondria and apoptosis of spermatogenic cells, including the apoptosis of spermatogonial cells, primary spermatocytes, and secondary spermatocytes (P<0.05 ). CONCLUSIONS: CER can damage the testicular ultrastructure and increase the apoptosis of spermatogenic cells of the male rat in a time-dependent manner, and the apoptosis of spermatogenic cells may be associated with the damage to mitochondria.

Sedation and analgesia with fentanyl and etomidate for intrathecal injection in childhood leukemia patients.

In this study, we tried to find a safe as well as fast effective treatment for sedation and analgesia for intrathecal injection in childhood leukemia patients, relieving treatment difficulties and pain, increasing the success rate of single intrathecal injection.The patients were divided into the experimental group (fentanyl combined with etomidate) and the control group (lidocaine only) randomly. The experimental group was given fentanyl 1 to 2 µg/kg intravenously first, then etomidate 0.1 to 0.3 mg/kg intravenously after the pipe washed. The patients younger than 1.5 years or who did not achieve satisfied sedative and analgesic situation received an additional time of etomidate (0.1-0.3 mg/kg). The patients were given oxygen at the rate of 4-5 L/min during the whole operation, and the finger pulse oximeter was used simultaneously to detect the changes in heart rate (HR) and blood oxygen saturation (SpO2). The doctors who performed the procedures assessed the quality of sedation and analgesia.In the experimental group, the patients' HR increased slightly after given fentanyl combined with etomidate. The patients' SpO2 was stable. Most patients achieved a good sedative and analgesic state within 1 to 2 minutes, and no case of respiration depression or cardiac arrhythmias occurred during the whole operation. The wake-up time was 55.42 ±â€Š20.62 min. In the control group, the patients were not very cooperative during the intrathecal injection, which made the procedures very difficult.During intrathecal injection, pain obviously reduced and the success rate of single lumbar puncture increased. It is safe and effective to apply fentanyl combined with etomidate for sedation and analgesia.

Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino-Alkyl-Substituted Fluoro-Chalcones Derivatives.

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3a˜3l) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino-alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase (IC50  = 0.21 ± 0.03 µmol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE) = 65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme.