Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.
Amino Acids ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; therapeutic use ; Drug Discovery ; Drug Resistance ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Hepatitis C ; drug therapy ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Serine Proteinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use

Antiviral Agents ; pharmacology ; therapeutic use ; Drug Design ; Herpesvirus 8, Human ; drug effects ; Humans ; Simplexvirus ; drug effects

Objective To evaluate the effect of isoflurane anesthesia on noise-induced hearing loss in guinea pigs.Methods Forty-eight healthy adult male guinea pigs,aged 3 months,weighing 400-500 g,were randomly divided into 4 groups (n =12 each) using a random number table:control group (C group),isoflurane group (I group),noise-induced hearing loss group (N group),and isoflurane + noise-induced hearing loss group (I + N group).Isoflurane was inhaled for 140 min at a concentration of 1％ in I and I + N groups.N and I + N groups were exposed to the noise of 4 kHz center frequency and 118-122 dB sound pressure level for 120 min starting from 20 min after administration.Mean arterial pressure (MAP) was recorded at 10,40,70,100 and 120 min of exposure to noise and cochlear blood flow (CoBF) was recorded before administration and at 10,40,70,100 and 120 min of exposure to noise.Auditory brainstem response (ABR) threshold was recorded before administration and at 1 h,72 h,and 10 days after the end of exposure to noise.Arterial blood samples were obtained and the plasma noradrenaline (NE) concentration was detected by HPLC before exposure to noise and immediately after the end of exposure to noise.Results Compared with group C,MAP and the change rate of CoBF were significantly decreased,and the plasma NE concentration was increased immediately after the end of exposure to noise in I group,and MAP was increased,the change rate of CoBF was decreased,and the plasma NE concentration immediately after the end of exposure,and ABR threshold after the end of exposure were increased in N and I + N groups.Compared with N group,MAP was significantly decreased,the change rate of CoBF was increased,the plasma NE concentration immediately after the end of exposure,and ABR threshold at 1 and 72 h after the end of exposure were increased,and no significant was found in ABR threshold at 10 days after the end of exposure in I + N group.Conclusion Isoflurane anesthesia exerts temporary but not permanent protective effects against noise-induced hearing loss in guinea pigs and partial inhibition of activation of sympathetic nerve and increased CoBF may be involved in the mechanism.

Objective To evaluate the relationship and screening value of percentage of body fat (BF%) and waist height ratio (WHtR) for hyperlipidemia in physical examination people. Methods A total of 2 668 objects taking physical examination in Henan Province People′s Hospital from September to December 2014 were included in this study. Values of height, body mass index (BMI), waist circumference, body composition and blood lipid level were detected. The receiver oper?ating characteristic curve (ROC) was used to analyze the screening rate of WHtR and BF%on hyperlipidemia with sensitivi?ty, specific and area under the curve (AUC). After stratified by age, waist circumference and BMI, multivariable logistic re?gression analysis was used to investigate the association between hyperlipidemia risk, BF% and WHtR. Results The screening accuracy rate on hyperlipidemia was higher for BF%, AUC was 0.79 in both female and male people. Among wom?en with BMI<18.5 kg/m2 and 18.5~<24 kg/m2, the risk of hyperlipidemia was higher in superfatted group than that of normal group. There was no correlation between WHtR and hyperlipidemia. Among men older than 40 y or with abnormal waist cir?cumference (≥85 cm), the risk of hyperlipidemia was higher in superfatted group than that of normal group, but not associat?ed with WHtR. Conclusion The BF%is a better screening indicator for hyperlipidemia compared with that of WHtR and BMI. Women with BMI<18.5 kg/m2 and 18.5~<24 kg/m2 and men older than 40 y or with waist circumference over 85 cm are suggested to do body composition tests to improve screening accuracy for hyperlipidemia.

BACKGROUND:Acute poisoning is frequently encountered at emergency department. This study was to investigate the epidemiology and characteristics of patients with acute poisoning who were treated at the Emergency Center, Fujian Provincial Hospital, China. METHODS:We retrospectively analyzed the gender, age, causes of poisoning, types of poisons, poisoning route, emergency diagnoses, outcomes, and prognoses of these patients. RESULTS:Altogether 2867 patients with acute poisoning were treated from January 2004 to December 2009. The ratio of male to female was 1:1.04, and their average age was 33.8 years. Of the 2867 patients, 76.39％ were between 18 and 40 years old. The incidence of acute poisoning was as high as 11.33％ in January each year. The incidence of poisoning was in a descending order:alcohol poisoning (54.55％), medication poisoning (25.95％), pesticide poisoning (5.65％), and drug poisoning (4.88％). Most (56.44％) of the patients with drug poisoning were under 25 years and their mean age was significantly lower than that of patients with medication poisoning or alcohol poisoning (P < 0.01). Approximately 69.54％ of the patients were followed up after emergency treatment, 30.39％ were hospitalized, and four patients died. CONCLUSIONS:Acute poisoning is largely alcohol poisoning and medication poisoning in a city. The emergency green channel "pre-hospital emergency care-emergency department-hospital treatment"can significantly improve the survival rate of patients with acute poisoning.

Compound Wuzhigan capsules is a compound preparation composed of Wuzhigan, Shidagonglao, Gangmei, Shanzhima. A Randomized, double-blind, multi-center, positive parallel control designed to evaluate the clinical efficacy and safety of compound Wuzhigan capsules on anemopyretic cold. One hundred and twenty anemopyretic cold patients were given compound Wuzhigan capsules (test group), 2 capsules one time, three times a day, 119 patients were given compound Wuzhigan tablets (control group) ,4 tablets one time, three times a day; three days of treatment The study showed, the markedly effective rate and total effective rate respectively were 63. 3% and 80% of the test group. For the control group, the markedly effective rate and total effective rate respectively were 72. 5% and 80. 7%. The difference was not statistically significant. Compound Wuzhigan capsules can reduce the dosage, and get better patient compliance.
Adult ; Capsules ; Common Cold ; complications ; drug therapy ; Double-Blind Method ; Drugs, Chinese Herbal ; adverse effects ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Safety ; Treatment Outcome ; Young Adult

Nine compounds were isolated from the n-butanol fraction of 95% ethanol extract of the fruit of Alpinia oxyphylla Miq. with a combination of various chromatographic approaches, including MDS resin, silica gel, reverse phase C18 and preparative HPLC. On the basis of spectroscopic data analysis, they were elucidated as (1R, 4R, 10R)-1β, 4α-dihydroxy-11, 12, 13-trinor-5, 6-eudesmen-7-one (1), 1β, 4β-dihydroxy-11, 12, 13-trinor-8, 9-eudesmen-7-one (2), oxyphyllenone A (3), oxyphyllenone B (4), rhamnocitrin (5), staphylionoside D (6), benzyl-1-O-β-D-glucopyranoside (7), 2-O-β-D-glucopyranosyl-(1S)-phenylethylene glycol (8), and (S)-1-phenylethyl-β-D-glucopyranoside (9). Among them, compound 1 is a new sesquiterpene, named as oxyphyllenone C; compounds 8 and 9 are new natural products; compounds 2 and 6 were isolated from the genus Alpinia for the first time, and compound 7 was isolated from A. oxyphylla for the first time.
1-Butanol ; Alpinia ; chemistry ; Chromatography, High Pressure Liquid ; Fruit ; chemistry ; Phytochemicals ; chemistry ; isolation & purification ; Sesquiterpenes ; chemistry ; isolation & purification

Robust and efficient control of therapeutic gene expression is needed for timing and dosing of gene therapy drugs in clinical applications. Ribozyme riboswitch provides a promising building block for ligand-controlled gene-regulatory system, based on its property that exhibits tunable gene regulation, design modularity, and target specificity. Ribozyme riboswitch can be used in various gene delivery vectors. In recent years, there have been breakthroughs in extending ribozyme riboswitch's application from gene-expression control to cellular function and fate control. High throughput screening platforms were established, that allow not only rapid optimization of ribozyme riboswitch in a microbial host, but also straightforward transfer of selected devices exhibiting desired activities to mammalian cell lines in a predictable manner. Mathematical models were employed successfully to explore the performance of ribozyme riboswitch quantitively and its rational design predictably. However, to progress toward gene therapy relevant applications, both precision rational design of regulatory circuits and the biocompatibility of regulatory ligand are still of crucial importance.
Animals ; Cell Line ; Gene Expression ; Gene Expression Regulation ; Genetic Therapy ; Humans ; Ligands ; Models, Theoretical ; RNA, Catalytic ; genetics ; Riboswitch ; genetics

Objective To investigate the effects of growth differentiation factor 11 ( GDF11 ) on β-cell function in db/db mice and its possible mechanism. Methods Twenty eight-week-old male db/db mice were randomizedtoi.p. administration of GDF11(0.3mg·kg-1·day-1)or equivalent PBS(n=10)for 6 weeks.10age-matched male db/m were used as normal control, received equivalent PBS injection for 6 weeks. Blood glucose levels, body weights and food intake were monitored weekly. IPGTT and glucose-stimulated insulin secretion ( GSIS) were analyzed. After 6 weeks of intervention, serum HbA1C , TG, TC, and FFA were measured respectively. The concentrations of hormones in serum and pancreas were evaluated. The mRNA expression of Pdx-1, MafA, Nkx6. 1, and insulin2 were determined by RT-PCR. The expression of phosphorylated Smd2 (P-Smad2), Smad2 in islet were examined by western blot. Results Compared with NC group, GDF11 administration decreased FBG, HbA1C , modified lipid profiles. GDF11 improved glucose tolerance and augmented GSIS. Moreover, GDF11 increased serum insulin and pancreatic insulin content, while decreased serum glucagon concentration. The expression of Pdx-1, MafA, Nkx6. 1, and Insulin2 were significantly increased in GDF11 group. GDF11 elevated the expression of P-Smad2 in islets. Conclusion s GDF11 may preserve β-cell function and facilitate the secretion and production of insulin. Diminishing the metabolic abnormalities, alleviating the secretion of glucagon, as well as maintaining the key transcript factor activation may contribute to the amelioration of β-cell function after GDF11 administration. Smad2 pathway may be related to the protective effects of GDF11.

OBJECTIVETo compare the effect of citric acid stimulation on salivary alpha-amylase (sAA), total protein (TP), salivary flow rate, and pH value between Pi deficiency (PD) children and healthy children, thereby providing evidence for Pi controlling saliva theory.

METHODSTwenty PD children were recruited, and 29 healthy children were also recruited at the same time. Saliva samples from all subjects were collected before and after citric acid stimulation. The sAA activity and amount, TP contents, salivary flow rate, and pH value were determined and compared.

RESULTS(1) Citric acid stimulation was able to significantly increase salivary flow rate, pH value, sAA activities, sAA specific activity and sAA amount (including glycosylated and non-glycosylated sAA amount) in healthy children (P<0.05), while it could markedly increase salivary flow rate, pH value, and glycosylated sAA levels in PD children (P<0.05); (2) Although there was no statistical difference in determined salivary indices between the two groups (P>0.05), salivary indices except salivary flow rate and glycosylated sAA levels decreased more in PD children. There was statistical difference in sAA activity ratio, sAA specific activity ratio, and the ratio of glycosylated sAA levels between PD children and healthy children (P<0.05).

CONCLUSIONPD children had decreased response to citric acid stimulation.