Niemann-Pick disease type C (NP-C) is a neurovisceral lipid storage disorder. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. NP-C is transmitted in an autosomal recessive manner and is caused by mutations in either the NPC1 (95% of families) or NPC2 gene. The estimated disease incidence is 1 in 120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. Variants of adenosine triphosphatase (ATPase) subunit 6 and ATPase subunit 8 (ATPase6/8) in mitochondrial DNA (mtDNA) have been reported in different types of genetic diseases including NP-C. In the present study, the blood samples of 22 Iranian patients with NP-C and 150 healthy subjects as a control group were analyzed. The DNA of the blood samples was extracted by the salting out method and analyzed for ATPase6/8 mutations using polymerase chain reaction sequencing. Sequence variations in mitochondrial genome samples were determined via the Mitomap database. Analysis of sequencing data confirmed the existence of 11 different single nucleotide polymorphisms (SNPs) in patients with NP-C1. One of the most prevalent polymorphisms was the A8860G variant, which was observed in both affected and non-affected groups and determined to have no significant association with NP-C incidence. Amongst the 11 polymorphisms, only one was identified in the ATPase8 gene, while 9 including A8860G were observed in the ATPase6 gene. Furthermore, two SNPs, G8292A and C8792A, located in the non-coding region of mtDNA and the ATPase6 gene, respectively, exhibited significantly higher prevalence rates in NP-C1 patients compared with the control group (P<0.01). The present study suggests that there may be an association between mitochondrial ATPase6/8 mutations and the incidence of NP-C disease. In addition, the mitochondrial SNPs identified maybe pathogenic mutations involved in the development and prevalence of NP-C. Furthermore, these results suggest a higher occurrence of mutations in ATPase6 than in ATPase8 in NP-C patients.

In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs). In other transfected or native cells, GPCRs have been demonstrated to establish physical receptor-receptor interactions (RRIs) with formation of homo/hetero-complexes (dimers or receptor mosaics) in a dynamic monomer/oligomer equilibrium. RRIs modulate ligand binding, signaling, and internalization of GPCR protomers and they are considered of relevance for physiology, pharmacology, and pathology of the nervous system. We hypothesize that RRI may also occur in the different structural elements of the CB (type I cells, type II cells, and afferent fibers), with potential implications in chemoreception, neuromodulation, and tissue plasticity. This 'working hypothesis' is supported by literature data reporting the contemporary expression, in type I cells, type II cells, or afferent terminals, of GPCRs which are able to physically interact with each other to form homo/hetero-complexes. Functional data about cross-talks in the CB between different neurotransmitters/neuromodulators also support the hypothesis. On the basis of the above findings, the most significant homo/hetero-complexes which could be postulated in the CB include receptors for dopamine, adenosine, ATP, opioids, histamine, serotonin, endothelin, galanin, GABA, cannabinoids, angiotensin, neurotensin, and melatonin. From a methodological point of view, future studies should demonstrate the colocalization in close proximity (less than 10 nm) of the above receptors, through biophysical (i.e., bioluminescence/fluorescence resonance energy transfer, protein-fragment complementation assay, total internal reflection fluorescence microscopy, fluorescence correlation spectroscopy and photoactivated localization microscopy, X-ray crystallography) or biochemical (co-immunoprecipitation, in situ proximity ligation assay) methods. Moreover, functional approaches will be able to show if ligand binding to one receptor produces changes in the biochemical characteristics (ligand recognition, decoding, and trafficking processes) of the other(s). Plasticity aspects would be also of interest, as development and environmental stimuli (chronic continuous or intermittent hypoxia) produce changes in the expression of certain receptors which could potentially invest the dynamic monomer/oligomer equilibrium of homo/hetero-complexes and the correlated functional implications.

The ribosome-associated GTPase HflX acts as an antiassociation factor upon binding to the 50S ribosomal subunit during heat stress in Escherichia coli Although HflX is recognized as a guanosine triphosphatase, several studies have shown that the N-terminal domain 1 of HflX is capable of hydrolyzing adenosine triphosphate (ATP), but the functional role of its adenosine triphosphatase (ATPase) activity remains unknown. We demonstrate that E. coli HflX possesses ATP-dependent RNA helicase activity and is capable of unwinding large subunit ribosomal RNA. A cryo-electron microscopy structure of the 50S-HflX complex in the presence of nonhydrolyzable analogues of ATP and guanosine triphosphate hints at a mode of action for the RNA helicase and suggests the linker helical domain may have a determinant role in RNA unwinding. Heat stress results in inactivation of the ribosome, and we show that HflX can restore heat-damaged ribosomes and improve cell survival.

Background -Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. Methods -180 aspirin-treated stable CAD patients, who were planned to undergo elective PCI in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg (T90) or 60mg twice-daily (T60), both with 180mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and post-dose at 1 month, by adding adenosine 1 μmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30 and 60 seconds then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T (hsTnT) was measured pre- and 18-24 hours post-PCI. Results -174 patients underwent an invasive procedure, of which 162 patients received PCI (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen post-dose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15s, mean ± SD: clopidogrel 0.274 ± 0.101 μmol/L; T90 0.278 ± 0.134 μmol/L; T60 0.288 ± 0.149 μmol/L; P = 0.37). Similarly no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P > 0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow PRU, 1 month, mean ± SD: pre-dose, T60: 62 ± 47, T90: 40 ± 38, clopidogrel 181 ± 44; post-dose, T60: 34 ± 30, T90: 24 ± 21, clopidogrel 159 ± 57; all P < 0.0001 for ticagrelor vs clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow PRU>208, 1-month post-dose: 0%, 0% and 21%, respectively). Median (IQR) hsTnT increase was 16.9 (6.5-46.9) ng/l for clopidogrel, 22.4 (5.5-53.8) ng/L for T60 and 17.7 (8.1-43.5) ng/L for T90 (P = 0.95). There was a trend towards less dyspnea with T60 versus T90 (7.1% vs 19.0%; P = 0.09). Conclusions -Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release following PCI. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique Identifier: NCT02327624.

Obesity is a prominent risk factor for type 2 diabetes. Management of type 2 diabetes requires weight management in addition to glycemic parameters. For obese type 2 diabetes patients, metformin, Sodium-glucose co-transporter-2 inhibitors or Glucagon-Like Peptide-1 Receptor Agonists should be prescribed as the first priority for controlling both hyperglycemia and body weight or fat distribution. The Combination of these drugs with sulfonylureas, thiazolidinediones, and insulin may also be required in chronic cases. These drugs cause weight gain. Fortunately, many phytochemicals having a beneficial effect on diabetes and obesity, have minimum side-effects as compared to synthetic drugs. This review discusses the treatment strategies for controlling glycemia and weight management, with the focus on anti-diabetic drugs and phytochemicals. Glucagonostatic role, activation of Adenosine monophosphate activated protein kinase and adipocyte targeting potential of anti-diabetic drugs and phytochemicals are also discussed.