Varroa destructor is a honey bee (Apis mellifera) parasite identified as one of the leading causes of overwintering colony loss in New Zealand. It has been shown that a naturally occurring heritable ...trait, "Varroa Sensitive Hygiene" (VSH), confers an advantage to colonies by increasing behaviours that limit the survival and reproduction of Varroa mites. The SNP 9-9224292 is an adenine/guanine (A/G) polymorphism on chromosome 9 of Apis mellifera where the G allele was observed to be associated with VSH behaviour in North American honey bees. In this study, we sought to determine if selection for the G allele of SNP 9-9224292 could decrease Varroa mite infestation of New Zealand honey bee (Apis mellifera ligustica) colonies. We genotyped queens and tracked their colonies over summer before measuring Varroa levels at the point of autumn Varroa treatment. The mean Varroa population level in colonies headed by queens that carry two copies of VSH associated G allele of SNP 9-9224292 was 28.5% (P<0.05) lower compared with colonies headed by queens with two copies of non-VSH associated A alleles. Although a significant reduction in mite infestation was achieved in treatment colonies, conventional Varroa treatment was still required for adequate Varroa control. Considering the open mating of queens used and a lack of drift control in this study, this VSH SNP shows promise for marker assisted selection of New Zealand honey bees when aiming for innate Varroa control traits.
Hepcidin, the liver-produced peptide hormone, is a principal regulator of iron homeostasis. Abnormal hepcidin production has emerged as a causative factor in several common iron disorders. Hepcidin ...insufficiency results in iron overload in hereditary hemochromatosis and iron-loading anemias, whereas hepcidin excess causes or contributes to the development of iron-restricted anemias in inflammatory diseases, infections, some cancers and chronic kidney disease. Not surprisingly, hepcidin and related pathways have become the target for the development of novel therapeutics for iron disorders. In this review, we will summarize the strategies and development programs that have been devised for agonizing or antagonizing hepcidin and its receptor ferroportin.
The actions of extracellular Ca
2+
in regulating parathyroid gland and kidney functions are mediated by the extracellular calcium receptor (CaR), a G protein-coupled receptor. The CaR is one of the ...essential molecules maintaining systemic Ca
2+
homeostasis and is a molecular target for drugs useful in treating bone and mineral disorders. Ligands that activate the CaR are termed calcimimetics and are classified as either agonists (type I) or positive allosteric modulators (type II); calcimimetics inhibit the secretion of parathyroid hormone (PTH). Cinacalcet is a type II calcimimetic that is used to treat secondary hyperparathyroidism in patients receiving dialysis and to treat hypercalcemia in some forms of primary hyperparathyroidism. The use of cinacalcet among patients with secondary hyperparathyroidism who are managed with dialysis effectively lowers circulating PTH levels, reduces serum phosphorus and FGF23 concentrations, improves bone histopathology, and may diminish skeletal fracture rates and the need for parathyroidectomy. A second generation type II calcimimetic (AMG 416) is currently under regulatory review. Calcilytics are CaR antagonists that stimulate the secretion of PTH. Several calcilytic compounds have been evaluated as orally active anabolic therapies for postmenopausal osteoporosis but clinical development of all of them has been abandoned because they lacked clinical efficacy. Calcilytics might be repurposed for new indications like autosomal dominant hypocalcemia or other disorders beyond those involving systemic Ca
2+
homeostasis.
The genus Achillea consists of about 140 perennial herbs native to the Northern hemisphere. Traditional indications of their use include digestive problems, liver and gall-bladder conditions, ...menstrual irregularities, cramps, fever, wound healing. The Commission E approves its internal use for loss of appetite and dyspeptic ailments (gastric catarrh, spastic discomfort), externally it is used in form of sitz bath or as a compress against skin inflammation, slow healing wounds, bacterial or fungal infections. In the last decades, pharmacological studies became intensive, although human clinical investigations are still rare. Recent findings have confirmed several traditional uses. The largest number of data accumulated for antioxidant and anti-inflammatory effects. There are positive results on the analgesic, anti-ulcer, choleretic, hepatoprotective and wound healing activities. First results on other interesting therapeutical areas - antihypertensive, antidiabetic, antitumor, antispermatogenic activities -need confirmation. Yarrow can be used also as an insect repellent. Contact dermatitis as adverse effect may be connected to sesquiterpenes. The diversity and complexity of the effective compounds of yarrow species explains the broad spectrum of their activity. According to the literature the pharmacological effects are mainly due to the essential oil, proazulenes and other sesquiterpene lactones, dicaffeoylquinic acids and flavonoids. Synergistic actions of these and other compounds are also supposed. Achillea species have different chemical and therapeutical values. Despite of numerous data, correct evaluation of the results is difficult because of missing generally accepted taxonomical nomenclature. The used chemical-analytical methods and bio-assays are utmost diverse, making the comparison complicated. Further research on the activity is needed using exactly defined plant material, standardized methods and chemical analysis.
Summary
Hepatic hormone hepcidin is a principal regulator of iron homeostasis and a pathogenic factor in common iron disorders. Hepcidin deficiency causes iron overload in hereditary hemochromatosis ...and iron‐loading anemias, whereas hepcidin excess causes or contributes to the development of iron‐restricted anemia in inflammatory diseases, infections, some cancers, and chronic kidney disease. Because of this, hepcidin may become a useful tool for diagnosis and management of iron disorders. Furthermore, a number of strategies that target hepcidin, its receptor, and its regulators are under development as novel therapeutic approaches for diseases associated with iron dysregulation.
Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the ...transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose transporter) or SLC2A (Solute carrier 2A) families represent the main glucose transporters in mammalian cells, originally described as plasma membrane transporters. Glucose transport through intracellular membranes has not been elucidated yet; however, glucose is formed in the lumen of various organelles. The glucose-6-phosphatase system catalyzing the last common step of gluconeogenesis and glycogenolysis generates glucose within the lumen of the endoplasmic reticulum. Posttranslational processing of the oligosaccharide moiety of glycoproteins also results in intraluminal glucose formation in the endoplasmic reticulum (ER) and Golgi. Autophagic degradation of polysaccharides, glycoproteins, and glycolipids leads to glucose accumulation in lysosomes. Despite the obvious necessity, the mechanism of glucose transport and the molecular nature of mediating proteins in the endomembranes have been hardly elucidated for the last few years. However, recent studies revealed the intracellular localization and functional features of some glucose transporters; the aim of the present paper was to summarize the collected knowledge.
Beyond its general role as antioxidant, specific functions of ascorbate are compartmentalized within the eukaryotic cell. The list of organelle-specific functions of ascorbate has been recently ...expanded with the epigenetic role exerted as a cofactor for DNA and histone demethylases in the nucleus. Compartmentation necessitates the transport through intracellular membranes; members of the GLUT family and sodium-vitamin C cotransporters mediate the permeation of dehydroascorbic acid and ascorbate, respectively. Recent observations show that increased consumption and/or hindered entrance of ascorbate in/to a compartment results in pathological alterations partially resembling to scurvy, thus diseases of ascorbate compartmentation can exist. The review focuses on the reactions and transporters that can modulate ascorbate concentration and redox state in three compartments: endoplasmic reticulum, mitochondria and nucleus. By introducing the relevant experimental and clinical findings we make an attempt to coin the term of ascorbate compartmentation disease.
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•Ascorbate/dehydroascorbic acid (AA/DHA) is needed in all subcellular compartments.•SVCTs and GLUTs transport AA/DHA into subcellular compartments.•Decreased transport or increased consumption reduces subcellular AA/DHA pools.•Reduced AA/DHA pools may cause ascorbate compartmentation diseases.
Parathyroid hormone (PTH) is the key endocrine factor regulating systemic Ca(2+) homeostasis. Elevated levels of circulating PTH increase bone turnover and, depending on the duration of elevation, ...will result in net anabolic or catabolic effects on the skeleton. Secretion of PTH from the parathyroid glands is regulated by small changes in circulating levels of Ca(2+) which are detected by a Ca(2+) receptor on the surface of parathyroid cells. This G protein-coupled receptor is the primary molecular entity used by parathyroid cells to regulate secretion of PTH. As such, the Ca(2+) receptor is a unique molecular target for new drugs capable of increasing or decreasing circulating levels of PTH. Compounds which activate the Ca(2+) receptor are termed calcimimetics and they inhibit the secretion of PTH; a calcimimetic compound is in late stage clinical trials for the treatment of both primary and secondary hyperparathyroidism. Conversely, calcilytic compounds, which are Ca(2+) receptor antagonists, stimulate secretion of PTH; a calcilytic compound is in early clinical development for the treatment of osteoporosis.
GLUT10 belongs to a family of transporters that catalyze the uptake of sugars/polyols by facilitated diffusion. Loss-of-function mutations in the
gene encoding GLUT10 are responsible for arterial ...tortuosity syndrome (ATS). Since subcellular distribution of the transporter is dubious, we aimed to clarify the localization of GLUT10. In silico GLUT10 localization prediction suggested its presence in the endoplasmic reticulum (ER). Immunoblotting showed the presence of GLUT10 protein in the microsomal, but not in mitochondrial fractions of human fibroblasts and liver tissue. An even cytosolic distribution with an intense perinuclear decoration of GLUT10 was demonstrated by immunofluorescence in human fibroblasts, whilst mitochondrial markers revealed a fully different decoration pattern. GLUT10 decoration was fully absent in fibroblasts from three ATS patients. Expression of exogenous, tagged GLUT10 in fibroblasts from an ATS patient revealed a strict co-localization with the ER marker protein disulfide isomerase (PDI). The results demonstrate that GLUT10 is present in the ER.
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