While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been ...characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC
values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC
values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
The transport of pyruvate, the end product of glycolysis, into mitochondria is an essential process that provides the organelle with a major oxidative fuel. Although the existence of a specific ...mitochondrial pyruvate carrier (MPC) has been anticipated, its molecular identity remained unknown. We report that MPC is a heterocomplex formed by two members of a family of previously uncharacterized membrane proteins that are conserved from yeast to mammals. Members of the MPC family were found in the inner mitochondrial membrane, and yeast mutants lacking MPC proteins showed severe defects in mitochondrial pyruvate uptake. Coexpression of mouse MPC1 and MPC2 in Lactococcus lactis promoted transport of pyruvate across the membrane. These observations firmly establish these proteins as essential components of the MPC.
Biogenic amine transporters for serotonin, norepinephrine and dopamine (SERT, NET and DAT respectively), are the key players terminating transmission of these amines in the central nervous system by ...their high-affinity uptake. They are also major targets for many antidepressant drugs. Interestingly however, drugs targeted to a specific transporter do not appear to be as clinically efficacious as those that block two or all three of these transporters. A growing body of literature, reviewed here, supports the idea that promiscuity among these transporters (the uptake of multiple amines in addition to their "native" transmitter) may account for improved therapeutic effects of dual and triple uptake blockers. However, even these drugs do not provide effective treatment outcomes for all individuals. An emerging literature suggests that "non-traditional" transporters such as organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT) may contribute to the less than hoped for efficacy of currently prescribed uptake inhibitors. OCT and PMAT are capable of clearing biogenic amines from extracellular fluid and may serve to buffer the effects of frontline antidepressants, such as selective serotonin reuptake inhibitors. In addition, polymorphisms that occur in the genes encoding the transporters can lead to variation in transporter expression and function (e.g. the serotonin transporter linked polymorphic region; 5-HTTLPR) and can have profound effects on treatment outcome. This may be accounted for, in part, by compensatory adaptations in other transporters. This review synthesizes the existing literature, focusing on serotonin to illustrate and revive a model for the rationale design of improved antidepressants.
Friendly fire Snook, Scott A; Snook, Scott A
2011., 20110919, 2011, 2000-01-01
eBook
On April 14, 1994, two U.S. Air Force F-15 fighters accidentally shot down two U.S. Army Black Hawk Helicopters over Northern Iraq, killing all twenty-six peacekeepers onboard. In response to this ...disaster the complete array of military and civilian investigative and judicial procedures ran their course. After almost two years of investigation with virtually unlimited resources, no culprit emerged, no bad guy showed himself, no smoking gun was found. This book attempts to make sense of this tragedy--a tragedy that on its surface makes no sense at all.
The textbook description of mitochondrial respiratory complexes (RCs) views them as free-moving entities linked by the mobile carriers coenzyme Q (CoQ) and cytochrome c (cyt c). This model (known as ...the fluid model) is challenged by the proposal that all RCs except complex II can associate in supercomplexes (SCs). The proposed SCs are the respirasome (complexes I, III, and IV), complexes I and III, and complexes III and IV. The role of SCs is unclear, and their existence is debated. By genetic modulation of interactions between complexes I and III and III and IV, we show that these associations define dedicated CoQ and cyt c pools and that SC assembly is dynamic and organizes electron flux to optimize the use of available substrates.
The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby ...revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.
Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at ...an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.
The two major interfaces separating brain and blood have different primary roles. The choroid plexuses secrete cerebrospinal fluid into the ventricles, accounting for most net fluid entry to the ...brain. Aquaporin, AQP1, allows water transfer across the apical surface of the choroid epithelium; another protein, perhaps GLUT1, is important on the basolateral surface. Fluid secretion is driven by apical Na
-pumps. K
secretion occurs via net paracellular influx through relatively leaky tight junctions partially offset by transcellular efflux. The blood-brain barrier lining brain microvasculature, allows passage of O
, CO
, and glucose as required for brain cell metabolism. Because of high resistance tight junctions between microvascular endothelial cells transport of most polar solutes is greatly restricted. Because solute permeability is low, hydrostatic pressure differences cannot account for net fluid movement; however, water permeability is sufficient for fluid secretion with water following net solute transport. The endothelial cells have ion transporters that, if appropriately arranged, could support fluid secretion. Evidence favours a rate smaller than, but not much smaller than, that of the choroid plexuses. At the blood-brain barrier Na
tracer influx into the brain substantially exceeds any possible net flux. The tracer flux may occur primarily by a paracellular route. The blood-brain barrier is the most important interface for maintaining interstitial fluid (ISF) K
concentration within tight limits. This is most likely because Na
-pumps vary the rate at which K
is transported out of ISF in response to small changes in K
concentration. There is also evidence for functional regulation of K
transporters with chronic changes in plasma concentration. The blood-brain barrier is also important in regulating HCO
and pH in ISF: the principles of this regulation are reviewed. Whether the rate of blood-brain barrier HCO
transport is slow or fast is discussed critically: a slow transport rate comparable to those of other ions is favoured. In metabolic acidosis and alkalosis variations in HCO
concentration and pH are much smaller in ISF than in plasma whereas in respiratory acidosis variations in pH
and pH
are similar. The key similarities and differences of the two interfaces are summarized.
The respiratory chain has been proposed as an attractive target for the development of new therapies to tackle human fungal pathogens. This arises from the presence of fungal-specific electron ...transport chain components and links between respiration and the control of virulence traits in several pathogenic species. However, as the physiological roles of mitochondria remain largely undetermined with respect to pathogenesis, its value as a potential new drug target remains to be determined. The use of respiration inhibitors as fungicides is well developed but has been hampered by the emergence of rapid resistance to current inhibitors. In addition, recent data suggest that adaptation of the human fungal pathogen,
Candida albicans
, to respiration inhibitors can enhance virulence traits such as yeast-to-hypha transition and cell wall organisation. We conclude that although respiration holds promise as a target for the development of new therapies to treat human fungal infections, we require a more detailed understanding of the role that mitochondria play in stress adaption and virulence.
Without questioning the fact that to achieve efficiency emitters should pay for the true costs of their actions (a core principle of economic policies such as pollution taxes), we find sufficient ...evidence in the literature to demonstrate that many other policy instruments can be used in combination with taxes and permits to ensure that the transport needs of the present generation can be met without compromising the ability of future generations to meet any needs of their own.
The policies and policy aspects considered in this paper broadly fall into three categories: physical policies, soft policies, and knowledge policies. All three aim to bring about changes in consumers’ and firms’ behaviour, but in different ways. The first category includes policies with a physical infrastructure element: public transport, land use, walking and cycling, road construction, and freight transport. We also consider the particular challenges for mobility in developing countries, and how these may be addressed. Soft policies, on the other hand, are non-tangible aiming to bring about behavioural change by informing actors about the consequences of their transport choices, and potentially persuading them to change their behaviour. These measures include car sharing and car pooling, teleworking and teleshopping, eco-driving, as well as general information and advertising campaigns. Finally, knowledge policies emphasise the important role of investment in research and development for a sustainable model of mobility for the future.
The main findings can be summarised as follows.
An increase in the use of
public transport, combined with a decrease in the use of private cars, can reduce traffic congestion and, more importantly, carbon dioxide (CO
2) emissions, as public transport generally causes lower CO
2 emissions per passenger kilometre than private cars. Public transport fares are subsidised in most places, which can be justified by economies of scale and by the fact that public transport can reduce total road transport externalities. London, Singapore, Portland and Curitiba are all examples of good practice at government level, having achieved reliable, frequent and integrated public transport.
Policies to increase public transport use must be part of an
integrated policy. Integrated policy refers to integration across different modes of transport, different government objectives (such as the economy, health and the environment), considering the needs of different social groups, and coordinating action between the relevant government institutions. There is evidence that a lack of coordination can jeopardise the achievement of policy objectives.
A sustainable model for transport policy also requires integration with
land-use policies. These may be somewhat limited within the bounds of existing cities, but as cities grow and new cities are built, urban planners must put more emphasis on land use for sustainable transport in order to reduce congestion and CO
2 emissions. Sustainable land-use policy can direct urban development towards a form that allows public transport as well as walking and cycling to be at the core of urban mobility.
Walking and cycling, which improve general health and produce no tailpipe emissions, constitute an excellent alternative to motorised transport on short-distance trips within towns and cities. The policies which can incentivise walking and cycling include crime reduction to make streets safer, well-maintained and clean pavements, attractive street furniture, safe crossings with shorter waiting times, dedicated cycle paths, showers in offices, and lower speed limits, to name but a few.
Road construction and expansion used to be seen as one of the most promising ways to reduce traffic congestion. However, in the mid-1990s, the issue was reassessed and it was found that building and expanding roads, increased, rather than decreased, congestion, and ultimately induced higher levels of travel demand. The reason for this is that the extra capacity reduces the general cost of travelling and the less expensive the travel, the more it will be demanded. Regarding
freight modal shift, road transport is much more polluting than rail per tonne-km of goods transported and therefore a shift towards greater use of rail in freight transport is desirable. Inadequate infrastructure is the main obstacle preventing this modal shift taking place.
Developing countries face great mobility challenges: rural areas are often extremely poorly connected to transport infrastructure, such that, in contrast to the situation in developed countries, the benefits of road construction can strongly outweigh the total costs (including environmental ones). The main challenge, however, is to develop a solution to the problems arising from the combination of urbanisation and motorisation. Integration of transport and land-use policy will be key to rising to this challenge.
Car sharing and car clubs can also potentially reduce CO
2 emissions, although the aggregate reduction in congestion and emissions has not been measured with an adequate degree of precision in the literature.
Teleworking and teleshopping can potentially reduce congestion and also CO
2 emissions. However, the evidence for this reduction is rather mixed, as it is unclear whether these measures lead to overall reductions in road transport.
Eco-driving campaigns aim to inform and educate drivers in order to induce them to drive in a fuel-efficient and thus environmentally friendly way. There seems to be some consensus in the literature that eco-driving could lead to reductions in CO
2 emissions of around 10 per cent.
Information and education policies have often been advocated as instruments which may affect
behavioural change. We find in this paper that these types of measures are necessary, but not sufficient for behavioural change.
Advertising and marketing may go a long way in changing peoples’ behaviour. In California, for example,
Kahn (2007) finds the “Prius” effect: the Toyota Prius is preferred by consumers relative to other similarly green vehicles, probably due to extensive marketing and celebrity endorsements.
Family life changes are also found to trigger changes in behaviour (
Goodwin, 1989, 2008). People whose lives are being changed by some important development (birth of a child, retirement, etc) tend to respond more to changes in the relative attractiveness of different transport modes. Advertising campaigns promoting a modal shift towards public transport, for instance, may thus be more successful if targeted at people in the process of important life transitions.
Research and Development is crucial for developing sustainable and low-carbon transport for the future, and it is essential that governments provide incentives to undertake R&D, so that new low-carbon technologies in the transport sector can be demonstrated and applied at a large scale.
Finally, we consider the issue of
policy combination and integration. There is evidence that the combination and integration of policies can lead to positive side-effects and synergies. Policy integration is crucial in order to rise to the challenges we face in moving towards a sustainable mobility model. We conclude that classical economic policies may be successfully combined with a number of policy measures discussed in this paper in order to achieve sustainability in transport.
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