170,104 research outputs found
Towards a therapy for mitochondrial disease: an update
No full textPreclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different
approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field
C terminus-mediated control of voltage and cAMP gating of hyperpolarization-activated cyclic nucleotide-gated channels
No full textThe hyperpolarization-activated cyclic nucleotidegated
(HCN) family of “pacemaker” channels includes 4
isoforms, the kinetics and cAMP-induced modulation of
which differ quantitatively. Because HCN isoforms are
highly homologous in the central region, but diverge
more substantially in the N and C termini, we asked
whether these latter regions could contribute to the determination
of channel properties. To this aim, we analyzed
activation/deactivation kinetics and the response
to cAMP of heterologously expressed isoforms mHCN1
and rbHCN4 and verified that mHCN1 has much faster
kinetics and lower cAMP sensitivity than rbHCN4. We
then constructed rbHCN4 chimeras by replacing either
the N or the C terminus, or both, with the analogous
domains from mHCN1. We found that: 1) replacement of
the N terminus (chimera N1–4) did not substantially
modify either the kinetics or cAMP dependence of wildtype
channels; 2) replacement of the C terminus, on the
contrary, resulted in a chimeric channel (4-C1), the kinetics
of which were strongly accelerated compared
with rbHCN4, and that was fully insensitive to cAMP; 3)
replacement of both N and C termini led to the same
results as replacement of the C terminus alone. These
results indicate that the C terminus of rbHCN4 contributes
to the regulation of voltage- and cAMP-dependent
channel gating, possibly through interaction with other
intracellular regions not belonging to the N terminus
MtDNA-maintenance defects: syndromes and genes
No full textA large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions.
Communicated by: Shamima Rahman
Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Rome, Italy, September 6–9, 201
Introduction: Locating the Mediterranean
No full textIn recent years, the Mediterranean region has reasserted itself in the world: popular uprisings have unsettled long-standing political regimes, economic crises have generated precarity, and nationalist movements have reified some borders while condemning others. The circulation and stagnation of people, ideas, and objects provoked by these events draw attention to regional connections and separations that, in turn, challenge strict geopolitical renderings of Europe, the Middle East, and North Africa. In considering this resurgence of interest in the Mediterranean, this introduction asks: what role does ‘location’ play in our conception of region and region-formations? What kinds of locations are generated in the contemporary Mediterranean? How do historical, legal, political, and social connections and separations shape the experience of being located somewhere in particular? Furthermore, the introduction explores how, by placing in dialogue diverse approaches and traditions, this collective volume works on two levels at once. First, each contribution posits its own Mediterranean ‘constellation’. Second, the collective volume presents a wider understanding of what historically inclined anthropologists might conceive of as a Mediterranean ‘constellation’. In doing this, the introduction proposes a theoretical apparatus through which we can understand cultural and historical values of region and region-making in and beyond the Mediterranean
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Breathe: Your Mitochondria Will Do the Rest… If They Are Healthy!
No full textDysfunctions of the mitochondrial electron transport chain cause severe, currently untreatable, diseases in humans. A new study by Jain et al. (2019) reports increased oxygen levels in the brain of complex-I-deficient mice. Reducing the O2 levels by hypoxia, carbon monoxide, or anemia, improved the clinical phenotype and prolonged the lifespan of the mouse model
Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers.
No full textBACKGROUND: Rifaximin is an antibiotic, acting locally in the gastrointestinal
tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form.
METHODS: Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry.
RESULTS: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications.
CONCLUSION: Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic
SULODEXIDE FOR USE IN THE TREATMENT OF PATHOLOGIES WHEREIN METALLOPROTEINASES ARE INVOLVED
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