Effects of protease activated receptor (PAR)2 blocking peptide on endothelin-1 levels in kidney tissues in endotoxemic rat mode

Aims

Septic shock, the severe form of sepsis, is associated with development of progressive damage in multiple organs. Kidney can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of sepsis and its complications. Protease-activated receptors (PARs) are shown to play an important role in the interplay between inflammation and coagulation. We examined the time-dependent alterations of ET-1 and inflammatory cytokine, such as tumor necrosis factor (TNF)-α in kidney tissue in lipopolysaccharide (LPS)-induced septic rat model and the effects of PAR2 blocking peptide on the LPS-induced elevations of renal ET-1 and TNF-α levels.

Main methods

Male Wistar rats at 8 weeks of age were administered with either saline solution or LPS at different time points (1, 3, 6 and 10 h). Additionally, we treated LPS-administered rats with PAR2 blocking peptide for 3 h to assess whether blockade of PAR2 has a regulatory role on the ET-1 level in septic kidney.

Key findings

An increase in ET-1 peptide level was observed in kidney tissue after LPS administration time-dependently. Levels of renal TNF-α peaked (around 12-fold) at 1 h of sepsis. Interestingly, PAR2 blocking peptide normalized the LPS-induced elevations of renal ET-1 and TNF-α levels.

Significance

The present study reveals a distinct chronological expression of ET-1 and TNF-α in LPS-administered renal tissues and that blockade of PAR2 may play a crucial role in treating renal injury, via normalization of inflammation, coagulation and vaso-active peptide.     

Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis

Deleted in Breast Cancer 1 (DBC1) is an important metabolic sensor. Previous studies have implicated DBC1 in various cellular functions, notably cell proliferation, apoptosis, histone modification, and adipogenesis. However, current reports about the role of DBC1 in tumorigenesis are controversial and designate DBC1 alternatively as a tumor suppressor or a tumor promoter. In the present study, we report that polyoma small T antigen (PyST) associates with DBC1 in mammalian cells, and this interaction leads to the posttranslational downregulation of DBC1 protein levels. When coexpressed, DBC1 overcomes PyST-induced mitotic arrest and promotes the exit of cells from mitosis. Using both transient and stable modes of PyST expression, we also show that cellular DBC1 is subjected to degradation by LKB1, a tumor suppressor and cellular energy sensor kinase, in an AMP kinase-independent manner. Moreover, LKB1 negatively regulates the phosphorylation as well as activity of the prosurvival kinase AKT1 through DBC1 and its downstream pseudokinase substrate, Tribbles 3 (TRB3). Using both transient transfection and stable cell line approaches as well as soft agar assay, we demonstrate that DBC1 has oncogenic potential. In conclusion, our study provides insight into a novel signaling axis that connects LKB1, DBC1, TRB3, and AKT1. We propose that the LKB1–DBC1–AKT1 signaling paradigm may have an important role in the regulation of cell cycle and apoptosis and consequently tumorigenesis.     

Efficacy of triclabendazole against fascioloidiasis (Fascioloides magna) in naturally infected white-tailed deer (Odocoileus virginianus)

The efficacy of triclabendazole was evaluated in the treatment of naturally acquired Fascioloides magna infections in white-tailed deer (Odocoileus virginianus). Twenty white-tailed deer were captured on the Welder Wildlife Refuge (Sinton, San Patricio County, Texas, USA) and maintained in a 64 x 64 m deer enclosure. Ten deer were given a 5% suspension of triclabendazole orally at a dosage of 10 mg/kg body weight and 10 deer were given a placebo. Three wk later the deer were euthanized and examined for parasites. At necropsy 19 deer were infected. All specimens of F. magna from the tissues of the triclabendazole treated deer were dead or severely affected by the drug as indicated by changes in their size, color, movement and texture relative to those from control deer. The drug was considered 100% effective against this parasite. Adverse reactions of the deer to the drug were not observed.     

Timeline: Raising the profile of genetics in primary care

Primary care practitioners recognize that genetics is relevant to their daily practice, for example, for detecting and managing the risk of multifactorial disorders and genetic reproductive risks, and, in future, for targeted drug therapy. However, they lack confidence in their ability to apply genetic approaches. In fact, genetics is already ingrained in current practice, and the development of appropriate guidelines and web-based information resources will help practitioners to make personalized genetic risk assessment a part of holistic, patient-oriented primary health care.     

Three homopteran pests of citrus as prey for the convergent lady beetle: suitability and preference

The convergent lady beetle, Hippodamia convergens Guérin-Méneville (Coleoptera: Coccinellidae), is an important predator of soft-bodied insect pests in many regions of the United States, but generally uncommon in Florida citrus. Certain citrus producers in Florida recently initiated releases of commercially available H. convergens from California against the Asian citrus psyllid Diaphorina citri Kuwayama, vector of Huanglongbing or citrus greening disease. However, there is little information on potential efficacy of this predator against the psyllid or other pests of citrus. Preference, development, and reproduction by H. convergens was evaluated on freshly collected nymphs of D. citri, brown citrus aphid Toxoptera citricida Kirkaldy, green citrus aphid Aphis spiraecola Patch, and frozen eggs of the flour moth Ephestia kuehniella Zeller. Larvae preferred D. citri over T. citricida in two-way choice tests and consumed more D. citri or A. spiraecola than T. citricida in no-choice tests. Adults consumed equal numbers of all three species in both tests. Development times of larvae at 25.5±0.05°C on A. spiraecola were longer than on the other three diets. Larval survival and pupation times did not differ among diets. Females lived longer than males irrespective of diet, and longevity of both genders was greatly increased on E. kuehniella compared with D. citri and A. spiraecola. Life table analysis indicated that H. convergens should increase on all three species, with a greater potential on psyllids than aphids. Further studies are warranted to assess establishment and persistence of this potential biological control agent in the Florida citrus environment.     

An Augmented SMS Intervention to Improve Access to Antenatal CD4 Testing and ART Initiation in HIV-Infected Pregnant Women: A Cluster Randomized Trial

BackgroundLess than one-third of HIV-infected pregnant women eligible for combination antiretroviral therapy (ART) globally initiate treatment prior to delivery, with lack of access to timely CD₄ results being a principal barrier. We evaluated the effectiveness of an SMS-based intervention to improve access to timely antenatal ART.MethodsWe conducted a stepped-wedge cluster randomized trial of a low-cost programmatic intervention in 20 antenatal clinics in Gaborone, Botswana. From July 2011-April 2012, 2 clinics were randomly selected every 4 weeks to receive an ongoing clinic-based educational intervention to improve CD₄ collection and to receive CD₄ results via an automated SMS platform with active patient tracing. CD₄ testing before 26 weeks gestation and ART initiation before 30 weeks gestation were assessed.ResultsThree-hundred-sixty-six ART-naïve women were included, 189 registering for antenatal care under Intervention and 177 under Usual Care periods. Of CD₄-eligible women, 100 (59.2%) women under Intervention and 79 (50.6%) women under Usual Care completed CD₄ phlebotomy before 26 weeks gestation, adjusted odds ratio (aOR, adjusted for time that a clinic initiated Intervention) 0.87 (95% confidence interval [CI]0.47–1.63, P = 0.67). The SMS-based platform reduced time to clinic receipt of CD₄ test result from median of 16 to 6 days (P<0.001), was appreciated by clinic staff, and was associated with reduced operational cost. However, rates of ART initiation remained low, with 56 (36.4%) women registering under Intervention versus 37 (24.2%) women under Usual Care initiating ART prior to 30 weeks gestation, aOR 1.06 (95%CI 0.53–2.13, P = 0.87).ConclusionsThe augmented SMS-based intervention delivered CD₄ results more rapidly and efficiently, and this type of SMS-based results delivery platform may be useful for a variety of tests and settings. However, the intervention did not appear to improve access to timely antenatal CD₄ testing or ART initiation, as obstacles other than CD₄ impeded ART initiation during pregnancy.     

Metabolomics and Incidence of Atrial Fibrillation in African Americans: The Atherosclerosis Risk in Communities (ARIC) Study

Background

Atrial fibrillation (AF) is a common arrhythmia. Application of metabolomic approaches, which may identify novel pathways and biomarkers of disease risk, to a longitudinal epidemiologic study of AF has been limited.

Methods

We determined the prospective association of 118 serum metabolites identified through untargeted metabolomics profiling with the incidence of newly-diagnosed AF in 1919 African-American men and women from the Atherosclerosis Risk in Communities study without AF at baseline (1987–1989). Incident AF cases through 2011 were ascertained from study electrocardiograms, hospital discharge codes, and death certificates.

Results

During a median follow-up of 22 years, we identified 183 incident AF cases. In Cox proportional hazards models adjusted for age, sex, smoking, body mass index, systolic blood pressure, use of antihypertensive medication, diabetes, prevalent heart failure, prevalent coronary heart disease, and kidney function, two conjugated bile acids (glycolithocholate sulfate and glycocholenate sulfate) were significantly associated with AF risk after correcting for multiple comparisons (p<0.0004). Multivariable-adjusted hazard ratios (95% confidence intervals) of AF were 1.22 (1.12–1.32) for glycolithocholate sulfate and 1.22 (1.10–1.35) for glycocholenate sulfate per 1-standard deviation higher levels. Associations were not appreciably different after additional adjustment for alcohol consumption or concentrations of circulating albumin and liver enzymes.

Conclusion

We found an association of higher levels of two bile acids with an increased risk of AF, pointing to a potential novel pathway in AF pathogenesis. Replication of results in independent studies is warranted.     

The effects of neuropeptide Y on skeletal muscle contractile properties in streptozotocin diabetic rats

Diabetes induces changes in the structural, biochemical, electrical, and contractile properties of skeletal muscles. Neuropeptide Y (NPY) administered locally can induce angiogenesis in a rat ischemic limb model and restore the contractile function of the ischemic muscle. The effects of NPY on the contractile characteristics of limb skeletal muscles were examined in streptozotocin-induced diabetic rats. Rats were treated with sham pellets (control groups) or NPY-containing pellets (1 mg of NPY/pellet, 14 days releasing time) administered locally to the rat hind limb 2 months after induction of diabetes. Contractile properties and fatigability of the slow-twitch soleus and fast-twitch gastrocnemius medials muscle were compared in control (sham), control NPY, diabetic (sham), and diabetic NPY groups. In order to induce fatigue trains of repetitive tetanic stimulation were used (600 ms/1 s simulation-rest cycle per train, 112 trains at an 85-Hz fusion frequency). Two months of untreated diabetes significantly prolonged soleus contraction and slowed its relaxation, but had minimal effects on soleus tension. NPY ameliorated the diabetic effects on soleus speed-related contractile properties, restoring its contraction and relaxation times. Diabetes significantly reduced gastrocnemius medials tetanic tension, leaving its contractile characteristics mostly unaffected. NPY partially restored gastrocnemius tetanic tension production capacity. Diabetes significantly increased fatigability of both muscles, which was partially restored by NPY, as evidenced by restored endurance of soleus muscle. The results suggest that NPY administered locally tends to normalize muscle performance and improve fatigue resistance of skeletal muscles in streptozotocin diabetes. Further examination is needed to establish the mechanisms of local NPY action on muscle contractile properties in streptozotocin-induced diabetes.