Description:
Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 mu M while displaying good selectivity, with an IC50 of 37.9 mu M for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
Description:
MicroRNA-181a binds to the 3’ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure.
Description:
A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
Description:
The study is aimed at investigating access to primary health care by examining various access parameters such as availability, accessibility, and affordability in Meander Valley, Northern Tasmania, Australia. Qualitative research design and data analysis were adopted. Semi-structured interviews were conducted with 30 people that were recruited through convenience sampling. The findings indicated that participants generally expressed relative satisfaction with local health care service provision, although a number of participants cited satisfaction with some services and dissatisfaction with others. The main issues of concern were the absence of specialised, dental and after-hours care, high cost of services, and issues of access to transport. The resourcefulness of people with chronic health issues and their carers emerged as important, as was the relationship between lifestyle choices, alternative and mainstream health care options. This study revealed major barriers to health care access by residents in rural Australia, which calls for urgent corrective measures. Further research should be directed to the exploration of the experience and expertise of carers and health professionals so as to obtain a more complete picture of access to health care services in rural settings. In addition, the study recommends a thorough investigation of the alternative health care options.
Description:
The study is aimed at investigating access to primary health care by examining various access parameters such as availability, accessibility, and affordability in Meander Valley, Northern Tasmania, Australia. Qualitative research design and data analysis were adopted. Semi-structured interviews were conducted with 30 people that were recruited through convenience sampling. The findings indicated that participants generally expressed relative satisfaction with local health care service provision, although a number of participants cited satisfaction with some services and dissatisfaction with others. The main issues of concern were the absence of specialised, dental and after-hours care, high cost of services, and issues of access to transport. The resourcefulness of people with chronic health issues and their carers emerged as important, as was the relationship between lifestyle choices, alternative and mainstream health care options. This study revealed major barriers to health care access by residents in rural Australia, which calls for urgent corrective measures. Further research should be directed to the exploration of the experience and expertise of carers and health professionals so as to obtain a more complete picture of access to health care services in rural settings. In addition, the study recommends a thorough investigation of the alternative health care options.
Description:
Primary health care plays a significant role in the well-being of individuals and communities, yet access to these services can vary. Factors such as socio-economic status and location of residence can impact this access. A study was conducted to investigate the relationship between location, utilisation, quality and health outcomes of primary health care services in the Meander Valley municipality of Tasmania, Australia. This paper reports the findings of the study which adopted a mixed-methods approach with multiple sources of data including government reports, survey questionnaires and interviews. The regional socio-economic disadvantage reflected not only the health disparities and poorer health conditions, but also the affordability to seek care. This was compounded by the lower levels of available health services and private health insurance. The lack of local services or their low quality was the main motivation for many to seek care outside of the region, which was unaffordable and at times logistically impossible. On the basis of the findings, a number of recommendations are provided to guide the current and future health care services and to improve the well-being of the Meander Valley community.
Description:
Primary health care plays a significant role in the well-being of individuals and communities, yet access to these services can vary. Factors such as socio-economic status and location of residence can impact this access. A study was conducted to investigate the relationship between location, utilisation, quality and health outcomes of primary health care services in the Meander Valley municipality of Tasmania, Australia. This paper reports the findings of the study which adopted a mixed-methods approach with multiple sources of data including government reports, survey questionnaires and interviews. The regional socio-economic disadvantage reflected not only the health disparities and poorer health conditions, but also the affordability to seek care. This was compounded by the lower levels of available health services and private health insurance. The lack of local services or their low quality was the main motivation for many to seek care outside of the region, which was unaffordable and at times logistically impossible. On the basis of the findings, a number of recommendations are provided to guide the current and future health care services and to improve the well-being of the Meander Valley community.
Description:
A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1H-pyrazole-5-carboxamide derivative with an IC
Description:
Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE−/−) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE−/− mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE−/− mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE−/− mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE−/− mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE −/−mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE−/− mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1. •Quercetin is an important dietary flavonoid that can reduce atherosclerosis in animal models.•Dietary quercetin improved oxidant-induced vascular dysfunction in mice.•Quercetin reduced oxidative stress, increased endothelial eNOS activity, and increased heme oxygenase-1 protein expression in aortic tissue.•Protection against oxidant-induced vascular dysfunction was critically related to arterial induction of HO-1 expression.
An improved 3-(4,5-dmethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl )-2H-tetrazolium proliferation assay to overcome the interference of hydralazine
Description:
The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay is one of the most commonly used assays to assess cell proliferation and cytotoxicity, but is subject to interference by testing compounds. Hydralazine, an antihypertensive drug, is commonly investigated in multiple fields such as heart failure, cancer, and blood pressure research. This study reported interference of the MTS assay by hydralazine and a simple modification overcoming this interference. Vascular smooth muscle cells were cultured in the presence or absence of hydralazine (0, 10, 50,100, and 500 mu M) for 2 or 24 h. Cell numbers were analyzed using MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established, in which an additional step was added replacing the test medium, containing hydralazine, with fresh culture medium immediately before the addition of the MTS reagent. Culture with hydralazine at concentrations of 50, 100, and 500 mu M for 2 h increased absorbance (p< 0.05) in the standard MTS assay, whereas microscopy suggested no change in cell numbers. Culture with 500 mu m hydralazine for 24 h increased absorbance (p< 0.05) in the standard MTS assay, however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (>= 10 mu M) increased absorbance in a concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy. In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and may be useful to avoid interference from other tested compounds.
Description:
The MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay is one of the most commonly used assays to assess cell proliferation and cytotoxicity, but is subject to interference by testing compounds. Hydralazine, an antihypertensive drug, is commonly investigated in multiple fields such as heart failure, cancer, and blood pressure research. This study reported interference of the MTS assay by hydralazine and a simple modification overcoming this interference. Vascular smooth muscle cells were cultured in the presence or absence of hydralazine (0, 10, 50,100, and 500 mu M) for 2 or 24 h. Cell numbers were analyzed using MTS, trypan blue exclusion, or microscopic assays. A modified version of the standard MTS assay was established, in which an additional step was added replacing the test medium, containing hydralazine, with fresh culture medium immediately before the addition of the MTS reagent. Culture with hydralazine at concentrations of 50, 100, and 500 mu M for 2 h increased absorbance (p< 0.05) in the standard MTS assay, whereas microscopy suggested no change in cell numbers. Culture with 500 mu m hydralazine for 24 h increased absorbance (p< 0.05) in the standard MTS assay, however, trypan blue exclusion and microscopy suggested a decrease in cell numbers. In a cell-free system, hydralazine (>= 10 mu M) increased absorbance in a concentration-dependent manner. The modified MTS assay produced results consistent with trypan blue exclusion and microscopy. In conclusion, a simple modification of the standard MTS assay overcame the interference of hydralazine and may be useful to avoid interference from other tested compounds.
Description:
This study was supported by the resources at Federation University; no external funding was used to fund this study. We acknowledge the Caenorhabditis elegans Genetics Centre for the strains used in this study and Hannah Tatnell (Federation University) for technical assistance.
Description:
This study was supported by the resources at Federation University; no external funding was used to fund this study. We acknowledge the Caenorhabditis elegans Genetics Centre for the strains used in this study and Hannah Tatnell (Federation University) for technical assistance.