Curcumin as a Potent and Selective Inhibitor of 11β-Hydroxysteroid Dehydrogenase 1: Improving Lipid Profiles in High-Fat-Diet-Treated Rats

Background

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11β-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11β-HSD1 have not been reported.

Methodology

Curcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11β-HSD1 with selectivity against 11β-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months.

Results and Conclusions

Curcumin exhibited inhibitory potency against human and rat 11β-HSD1 in intact cells with IC₅₀ values of 2.29 and 5.79 µM, respectively, with selectivity against 11β-HSD2 (IC₅₀, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11β-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11β-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC₅₀ values of 93 and 184 nM for human and rat 11β-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11β-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11β-HSD1 with selectivity against 11β-HSD2.     

Enzymatic Characterization of Insecticide Resistance Mechanisms in Field Populations of Malaysian Culex quinquefasciatus Say (Diptera: Culicidae)

Background

There has been no comprehensive study on biochemical characterization of insecticide resistance mechanisms in field populations of Malaysian Culex quinquefasciatus. To fill this void in the literature, a nationwide investigation was performed to quantify the enzyme activities, thereby attempting to characterize the potential resistance mechanisms in Cx. quinquefasciatus in residential areas in Malaysia.

Methodology/Principal Findings

Culex quinquefasciatus from 14 residential areas across 13 states and one federal territory were subjected to esterases, mixed function oxidases, glutathione-S-transferase and insensitive acetylcholinesterase assays. Enzyme assays revealed that α-esterases and β-esterases were elevated in 13 populations and 12 populations, respectively. Nine populations demonstrated elevated levels of mixed function oxidases and glutathione-S-transferase. Acetylcholinesterase was insensitive to propoxur in all 14 populations. Activity of α-esterases associated with malathion resistance was found in the present study. In addition, an association between the activity of α-esterases and β-esterases was also demonstrated.

Conclusions/Significance

The present study has characterized the potential biochemical mechanisms in contributing towards insecticide resistance in Cx. quinquefasciatus field populations in Malaysia. Identification of mechanisms underlying the insecticide resistance will be beneficial in developing effective mosquito control programs in Malaysia.     

Evaluation of Hepatitis A Vaccine in Post-Exposure Prophylaxis,The Netherlands, 2004-2012

Background

The secondary attack rate of hepatitis A virus (HAV) among contacts of cases is up to 50%. Historically, contacts were offered immunoglobulin (IG, a human derived blood product) as post-exposure prophylaxis (PEP). Amid safety concerns about IG, HAV vaccine is increasingly recommended instead. Public health authorities’ recommendations differ, particularly for healthy contacts ≥40 years old, where vaccine efficacy data is limited. We evaluated routine use of HAV vaccine as an alternative to immunoglobulin in PEP, in those considered at low risk of severe infection in the Netherlands.

Methods

Household contacts of acute HAV cases notified in Amsterdam (2004-2012) were invited ≤14 days post-exposure, for baseline anti-HAV testing and PEP according to national guidelines: immunoglobulin if at risk of severe infection, or hepatitis A vaccine if healthy and at low risk (aged <30, or, 30-50 years and vaccinated <8 days post-exposure). Incidence of laboratory confirmed secondary infection in susceptible contacts was assessed 4-8 weeks post-exposure. In a vaccinated subgroup, relative risk (RR) of secondary infection with estimated using Poisson regression.

Results

Of 547 contacts identified, 191 were susceptible to HAV. Per-protocol, 167 (87%) were vaccinated (mean:6.7 days post-exposure, standard deviation(sd)=3.3) and 24 (13%) were given immunoglobulin (mean:9.7 days post-exposure, sd=2.8). At follow-up testing, 8/112 (7%) had a laboratory confirmed infection of whom 7 were symptomatic. All secondary infections occurred in vaccinated contacts, and half were >40 years of age. In healthy contacts vaccinated per-protocol ≤8 days post-exposure, RR_{ref. ≤15 years} of secondary infection in those >40 years was 12.0 (95%CI:1.3-106.7).

Conclusions

Timely administration of HAV vaccine in PEP was feasible and the secondary attack rate was low in those <40 years. Internationally, upper age-limits for post-exposure vaccination vary. Pending larger studies, immunoglobulin should be considered PEP of choice in people >40 years of age and those vulnerable to severe disease.     

LncRNA LEF1-AS1 promotes osteogenic differentiation of dental pulp stem cells via sponging miR-24-3p

Molecular and Cellular Biochemistry - Alzheimer’s disease (AD) is the leading cause of dementia, which characterized by toxic senile plaques is composed of amyloid-β (Aβ)....     

An efficient protocol for Agrobacterium-mediated genetic transformation of Antirrhinum majus

Snapdragon (Antirrhinum majus L.) is a popular ornamental and model plant species, and the recently released reference genome could greatly boost its utilization in fundamental research. However, the lack of an efficient genetic transformation system is still a major limiting factor for its full application in genetic and molecular studies. In this study, a simple method for quick regeneration and efficient Agrobacterium-mediated transformation of snapdragon was developed. Cotyledon petiole and hypocotyl explants derived from two-week-old seedlings were cultured on MS media supplemented with 2 mg/L zeatin (ZT), 0.2 mg/L 1-naphthaleneacetic acid (NAA), and 2 mg/L AgNO₃, and adventitious shoots were regenerated through organogenesis with an average regeneration of 48.00% and 41.33%, respectively. By contrast, the regeneration frequency was only 22.67% for cotyledon petiole and 25.67% for hypocotyl explants in the absence of AgNO₃. Moreover, the application of AgNO₃ promoted indirect shoot organogenesis, while direct shoot organogenesis occurred in the absence of AgNO₃ from both hypocotyl or cotyledon petiole explants. Agrobacterium-mediated genetic transformation systems were developed with this high-efficient regeneration system. The transformation efficiency has been improved from 0 to 1% through the direct shoot organogenesis to 3 to 4% via the indirect shoot organogenesis. This efficient regeneration and genetic transformation method could be important for future use of snapdragon as a model plant to address some fundamental questions which are hard to be solved by using other model plant species, and to accelerate the breeding process through CRISPR/Cas9 genome editing.

     

Inhibitory mechanism of Penicillin V on mushroom tyrosinase

Molecular Biology Reports - Penicillin V is a bacteriolytic β-lactam antibiotic drug. In the present work, we investigated the inhibitory effect of Penicillin V on the activity of mushroom...     

MicroRNA-203a regulates pancreatic β cell proliferation and apoptosis by targeting IRS2

Molecular Biology Reports - The main pathogenesis of type 1 diabetes mellitus (T1DM) is autoimmune-mediated apoptosis of pancreatic islet β cells. We sought to characterize the function of...