Article Reviews

Article Review 7

A Trp574 to Leu Amino Acid Substitution in the ALS Gene of Annuai Biuegrass (Poa annua) Is Associated with Resistance to ALS-lnhibiting Herbicides

ALS-inhibiting herbicides target the ALS enzyme, which controls branched chain amino acid (Val, Leu, Ile) synthesis, causing plant death. The most common mechanism of resistance in plants is a point mutation in the target gene, and 6 mutations have been associated with herbicide resistance in several weed species. Annual bluegrass is one of the most troublesome weeds, especially in the southeastern United States, and several resistant populations have recently been reported. The purpose of this study was to determine the mechanism of resistance in an annual bluegrass population from Alabama. Resistance was confirmed in the AL population compared with a susceptible population, and the ALS gene was then sequenced. The resistant population showed a mutation at Trp574, and a smaller amplicon surrounding the mutation was cloned and sequenced to look at different forms of ALS. The sequence confirmed the Trp to Leu mutation at position 574 in the ALS gene. This mutation has been shown to confer resistance to ALS-inhibiting herbicides in other plant populations, indicating that the mutation may be the cause of resistance in the AL population.

The authors sequenced 15 plaques at each stage of amplification, so the results should be reliable. The results also agree with previously published studies. The research is definitely relevant, as annual bluegrass is resistant to herbicides with many different mechanisms of action. There has not been much research into nonchemical mechanisms of control, so there may come a point where annual bluegrass has developed resistance to most or all herbicides. Recently, resistant populations have been found in Mississippi, Tennessee, and Georgia as well as the original population in Alabama.

More research should be done into nonchemical mechanisms of annual bluegrass control, as it develops resistance rapidly. Alternatively, more research could be done to develop an herbicide with a novel mechanism of action.

McElroy, J. Scott, et al. “A Trp574 To Leu Amino Acid Substitution In The ALS Gene Of Annual Bluegrass (Poa Annua) Is Associated With Resistance To ALS-Inhibiting Herbicides.” Weed Science 61.1 (2013): 21-25. Environment Complete. Web. 7 Nov. 2016.

Article Review 6

Global Methylation In The Placenta And Umbilical Cord Blood From Pregnancies With Maternal Gestational Diabetes, Preeclampsia, And Obesity.

Metabolic disorders such as global diabetes mellitus (GDM), preeclampsia, and obesity in pregnant women are risk factors for future diseases in the infant such as metabolic challenges and neurobehavioral impairments in childhood. While the biological mechanisms linking the metabolic problems in mothers to future diseases in the child have not yet been elucidated, epigenetic factors such as DNA methylation may play a part. This study investigates the relationships between global methylation in placenta and umbilical cord blood; maternal GDM, preeclampsia, and obesity; and newborn phenotypes such as weight, gestational age at birth, body length, and head circumference at birth. There was no correlation between global methylation in placenta and umbilical cord blood. There were no significant differences in global methylation levels in umbilical cord blood in women with metabolic disorders compared with controls. However, in women with GDM and preeclampsia, the global methylation levels in the placenta were lower than in controls, and in obese women, the methylation levels were higher than in controls. Methylation levels in umbilical cord blood were not associated with any infant phenotypes, but methylation levels in the placenta were associated with head circumference and body length. Specifically, a greater methylation level was associated with smaller head circumference and body length in the infants.

Metabolic disorders such as GDM and obesity have become more frequent as people consume more sugar, saturated fats, and processed foods. This research is, therefore, relevant to today’s world as more and more women will have metabolic disorders before and during their pregnancy. The sample size for this study was small, though it was only intended to be a preliminary study.

This study should be replicated with a larger sample of women and a longer follow up period for evaluation of development in the child. Additionally, gene-specific methylation studies should be performed on candidate genes to determine if there is correlation between methylation in either the placenta and umbilical cord blood and maternal metabolic disorders.

Nomura, Yoko, et al. “Global Methylation In The Placenta And Umbilical Cord Blood From Pregnancies With Maternal Gestational Diabetes, Preeclampsia, And Obesity.” Reproductive Sciences (Thousand Oaks, Calif.) 21.1 (2014): 131-137. MEDLINE. Web. 20 Oct. 2016.

Article Review 5

Cerebral Perfusion Pressure In Women With Preeclampsia Is Elevated Even After Treatment Of Elevated Blood Pressure

Maternal deaths from preeclampsia occur mainly due to cerebral infarction and hemorrhage, possibly due to increased cerebral perfusion pressure (CPP). High CPP has been linked to preeclamptic symptoms and eclamptic seizures. Labetalol and MgSO4, drugs used to control hypertension in preeclamptic patients, cause a decrease in CPP, while another antihypertensive drug, nimodipine, causes CPP to increase. Nimodipine is associated with more eclamptic seizures, possibly due to the increase in CPP. The purpose of the study was to evaluate the CPP in preeclamptic women with blood pressure controlled by antihypertensives. The CPP was calculated using zero-flow pressure and mean arterial blood pressure measurements. The zero flow pressure, arterial blood pressure, CPP, and CFI were all higher in preeclamptic women than control women. Additionally, a correlation was found between mean arterial blood pressure and CPP in preeclamptic patients, but not in controls.

As cerebrovascular complications are the main cause of death to preeclamptic women, and preeclampsia affects 3-8% of all pregnancies, this study is relevant. The authors used two methods to calculate the CPP, and, in both cases, the CPP was higher for preeclamptic women. Additionally, the authors report that the CPP calculated for the control patients was similar to that reported in other studies, which shows consistency between studies. The authors did, however, use non-invasive methods to measure the CPP, which have not been validated in humans. Nevertheless, they got similar results with both calculations of CPP.

Future studies could include trials with additional or alternative antihypertensive medications to bring the CPP to normal levels along with the blood pressure. The effect of lower CPP on the risk of cerebrovascular complications can then be observed. Additionally, studies could be done to validate the techniques for non-invasive measurement of CPP in humans.

Sonneveld, Milan J., et al. “Cerebral Perfusion Pressure In Women With Preeclampsia Is       Elevated Even After Treatment Of Elevated Blood Pressure.” Acta Obstetricia Et Gynecologica Scandinavica 93.5 (2014): 508-511. Academic Search Complete. Web. 20 Oct. 2016.

Article Review 4

CXCR4, CXCR7, and CXCL12 Are Associated with Trophoblastic Cells Apoptosis and Linked to Pathophysiology of Severe Preeclampsia

The purpose of this paper was to examine the expression of the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, in placental tissues and primary trophoblasts from preeclamptic and normal pregnancies. CXCL12 and its receptors are involved not only in the immune system, but also in various other processes, including remodeling the spiral arteries to form the placenta. CXCL12 and CXCR4 have been shown to be involved in trophoblast proliferation and invasion and decidual stromal cell migration and motility; lack of either of these functions is associated with preeclampsia. The authors examined the association between these proteins and preeclampsia.

Placentas were obtained after a cesarean section (21 normal pregnant, 11 mild preeclamptic, and 18 severe preeclamptic). A scanning electron microscope was used to observe morphological changes of trophoblast cells in preeclamptic placentas that caused a significant tendency towards apoptosis. Immunohistochemistry showed that there were lower levels of CXCR4, CXCR7, and CXCR12 were lower in severe preeclamptic placentas than in normal placentas. RT-qPCR was used to show that the same pattern was true for mRNA expression of the proteins, and Western blot analysis confirmed for protein expression levels in trophoblasts. The authors concluded that apoptosis of the cytotrophoblast cells may be regulated by expression of CXCR4, CXCR7, and CXCL12.

All three proteins have been shown to be important for proper placenta formation, so I think the research to compare expression between normal and preeclamptic patients is necessary and relevant. I think the study was well designed, especially by using different techniques to confirm results. However, the number of samples was small, only 50 in total, probably because the placenta was required for testing.

It would be interesting to see if the results in this study were replicated in a future study with more samples. While the study observes a decrease in the three proteins studied, more studies are required to understand the how they relate to the pathophysiology of preeclampsia. Additional studies should be done to understand the mechanism of cytotrophoblast invasion and how CXCL12 and its receptors relate to this.

 

Lu, Jing, et al. “CXCR4, CXCR7, And CXCL12 Are Associated With Trophoblastic Cells Apoptosis And Linked To Pathophysiology Of Severe Preeclampsia.” Experimental And Molecular Pathology 100. (2016): 184-191. ScienceDirect. Web. 9 Oct. 2016.

Article Review 3

An RGS2 3’UTR Polymorphism is Associated With Preeclampsia in Overweight Women

Preeclampsia is a pregnancy-associated syndrome initiated by poor placental perfusion which, together with maternal genetic and metabolic risk factors, cause the maternal response. The regulation of G-protein signaling 2 (RGS2) gene has been implicated in blood pressure regulation by inhibiting vasoconstriction mediated by G protein-coupled receptors. Low RGS2 levels is associated with hypertension and obesity. One cause of low RGS2 levels is the 3’ UTR C1114G polymorphism in the RGS2 gene (mutation rs4606). This study used obstetric and perinatal data to classify pregnancies as preeclamptic or normal control and as normal, overweight, or obese based on the mother’s pre-pregnancy body mass index. The rs4606 mutation was in Hardy-Weinberg equilibrium, though no association between preeclampsia and the rs4606 mutation was found under a dominant, recessive, or additive model. However, the CG and GG genotypes were significantly associated with preeclampsia in overweight women. The researchers concluded that RGS2 function could contribute to the increased rate of preeclampsia in overweight women.

All of the study participants had extensive clinical background information available for admission into the study and for classification of the pregnancies. Since the study included women from all Finnish university hospitals, the participants were representative of the Finnish population. The critical value for the statistical tests was 0.05, which is generally accepted as statistically significant data. Additionally, over 1300 preeclamptic and 600 normal pregnancies were included in the study, which is a decent size.

The rs4606 mutation in the RGS2 gene is associated with metabolic syndrome in white European men, weight gain in young hypertensive men, personality traits and brain function linked to anxiety disorders, and lower benefit from sertraline treatment to social anxiety disorder. Therefore, women with the mutation could be at higher risk of postpartum depression in addition to the known cardiovascular and insulin resistance problems after pregnancy. More research should be done to determine the role of RGS2 and the effect of the rs4606 mutation on that role.  Similar studies should include data on participants’ personality traits and anxiety disorders to determine if this mutation could explain some of the link between preeclampisa and anxiety/depression.

Karppanen, Tina, et al. “An RGS2 3’UTR Polymorphism is Associated With Preeclampsia in Overweight Women.” BMC Genetics 17. (2016): 1-7. Academic Search Complete. Web. 9 Oct. 2016.

Article Review 2

FtsZ protein determines the point of cell division in bacteria by polymerizing into fibers that form the Z-ring, or the site of cell division.  Cinnamaldehyde has previously been shown to have bactericidal effects while being non-toxic to humans.  The authors studied the effect of cinnamaldehyde on FtsZ protein binding.  To show that cinnamaldehyde inhibited the GTPase activity of FtsZ, a light-scattering assay and GTP hydrolysis assay were used.  Electron microscopy of FtsZ showed that cinnamaldehyde inhibited the formation of protofibrils, which inhibited the formation of Z rings, and resulted in longer cells, as was shown in E. coli cell.  Additionally, the binding of cinnamaldehyde to FtsZ was shown through favorable enzyme kinetics, epitope mapping of cinnamaldehyde, and in silico molecular modeling of binding.

As explained in the paper, compounds targeting FtsZ have the potential to be very useful as antibiotic agents with a new mode of action.  Cinnamaldehyde can also inhibit methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic resistant bacteria, so it could be used as a last resort against infections.  Therefore, this research is very relevant to today’s scientific research.  The experimental approach is also sound, in my opinion, because they use multiple assays/approaches for measuring each aspect of the FtsZ/cinnamaldehyde interaction the paper was focused on.

Future research in this area should include compounds that are stable in air, since cinnamaldehyde can be oxidized to cinnamic acid, which does not have the same bactericidal properties; this would be prohibitive to developing cinnamaldehyde as a useful antibacterial agent.  However, since the authors of this study explored the binding site structure of cinnamaldehyde, similar drugs could be designed that would bind to FtsZ to block polymerization.  Cinnamaldehyde could be a good starting point for future research.

Works Cited

Domadia, Prerna, et al. “Inhibition of Bacterial Cell Division Protein FtsZ by Cinnamaldehyde.” Biochemical Pharmacology 74. (2007): 831-340. ScienceDirect. Web. 16 Sept. 2016.

Article Review 1

Preeclampsia is characterized by new onset hypertension and proteinuria after 20 weeks gestation.  Though the pathophysiology has not been fully defined, preeclampsia is thought to begin when the fetal trophoblastic cells and maternal endothelial cells fail to adequately remodel to supply blood to the fetus.  This placental ischemia results in the release of maternal factors such as cytokines – those studied in this paper are adiponectin and leptin.  Both of these are released by white adipose tissue and, during pregnancy, are involved in trophoblastic invasion.  These cytokines are mediated by metalloproteinases (MMPs) such as MMP2 and MMP9 and their inhibitors (TIMP1 and TIMP2).

In this study, adiponectin, leptin, MMP2, MMP9, TIMP1, and TIMP2 plasma concentrations were compared between healthy pregnancies and preeclamptic pregnant groups.  ELISA kits were used to measure the concentrations and Student’s t-test, the chi-squared test, and the Pearson’s correlation test were performed on the data.  Maternal age, BMI, MMP9 levels, MMP9/TIMP1 and MMP2/TIMP2 ratios were not statistically different from each other.  Both systolic and diastolic blood pressure were higher, and gestational age at sampling, delivery, and newborn weight were lower in the preeclamptic group compared to the HP group. Leptin, adiponectin, TIMP1, TIMP2, and MMP2 were higher in the preeclamptic group as well.

I think the paper is relevant and the experimental approach is sound.  The significance point for the data is P<0.05, which is not different from many other papers published in various journals.  The paper’s authors say comment that, to their knowledge, “This is the first study to measure correlation between circulating adiponectin and leptin and MMP/TIMP concentrations in preeclamptic patients, even though both have been shown to be related to trophoblast invasion” (Eleuterio, et al. 2015).  The results show that the study is relevant and matches the stated objective of the paper in the abstract.  All the cytokines and metalloproteinases measured were higher in preeclamptic patients, showing that, clearly, the study was needed.

Future studies could either block the production or interfere with the activity of adiponectin, leptin, or the metalloproteinases in animal models of preeclampsia or in endothelial cell cultures.  These studies could monitor the effects on the other cytokines and proteinases or on the symptoms such as placental ischemia.  The authors also suggested that adiponectin may contribute to higher levels of MMP2 and TIMP2, so studies could be done to elucidate that relationship.

Works Cited

Eleuterio, Nibia Mariana, et al.  “Positive Correlations Between Circulating Adiponectin and MMP2 in Preeclampsia Pregnant.”  Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 5. (2015): 205-208.  ScienceDirect.  Web.  9 Sept. 2016.