Rejected

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of approximately one-third of currently marketed drugs. In particular, adenosine A receptor (A AR) is an important therapeutic target for treating cardiac ischemia-reperfusion injuries, neuropathic pain, and renal diseases. As a prototypical GPCR, the A AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid-protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G-protein bound) A AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state. © 2019 Wiley Periodicals, Inc.

Fatty acid amide hydrolase (FAAH) is an important enzyme creditworthy of hydrolyzing endocannabinoids and related-amidated signalling lipids, discovery of which has pioneered novel arena of pharmacological canvasses to unwrap its curative potency in various diseased circumstances. It presents contemporary basis for understanding molecules regulating and mediating inflammatory reactions, pain, anxiety, depression, and neurodegeneration. FAAH inhibitors form vital approach for discovery of therapeutic agents that are concerned with local elevation of endocannabinoids under certain stimuli, debarring adverse/unwanted secondary effects from global activation of cannabinoid receptors by exogenous cannabimimetics. During past decades, several molecules with excellent potency developed through tailor-made approaches entered into clinical trials, but none could reach market. Hence, hunt for novel, non-toxic and selective FAAH inhibitors are on horizon. This review summarizes present perception on FAAH in conjunction with its structure, mechanism of catalysis and biological functions. It also foregrounds recent development of molecules belonging to diverse chemical classes as potential FAAH inhibitors bobbing up from in-depth chemical, mechanistic and computational studies published since 2015-November 2019, focusing on their potency. This review will assist readers to obtain rationale on FAAH as potential target for addressing various disease conditions, acquiring significant knowledge on recently established inhibitor scaffolds and their development potentials. New technologies including MD-MM simulations and 3D-QSAR studies allow mechanistic characterization of enzyme. Assessment of in-vitro and in-vivo efficacy of existing FAAH inhibitors will facilitate researchers to design novel ligands utilizing modern drug design methods. The discussions will also impose precaution in decision making process, quashing possibility of late stage failure.

Background Measurements of basal(b) calcitonin(CT) and calcium(Ca)-stimulated CT(Ca-sCT) levels are performed to identify medullary thyroid cancer(MTC) at an early stage when used as part of the diagnostic workup of thyroid nodules(CT-screening).Novel immunochemiluminometric assays (highly sensitive and specific for monomeric CT) have been introduced over the past decade.No prospectively generated data have so far become available to answer the frequently raised question as to whether Ca-sCT in contrast to bCT alone is helpful and therefore still indicated for the early detection of MTC. Methods Ca-stimulation tests were performed in 149 consecutive patients with thyroid nodules and elevated bCT.Regardless of Ca-sCT levels,all patients had an operation applying a uniform surgical protocol,including thyroidectomy and systematic lymph node surgery.Recently published sex-specific cut-off levels for the differentiation of MTC and other C-cell pathologies were used to compare the diagnostic performance of bCT or Ca-sCT alone and in combination using receiver-operating characteristic(ROC) analysis.Additionally,CT cut-off levels to predict lateral lymph node metastasis were evaluated for bCT compared to Ca-sCT.Follow-up for all patients was documented and correlated with initial CT levels. Results MTC was identified in 76(50.1%) patients,in 21/76(27.6%) with lymph node and in 4(5.3%) with distant metastasis.Using predefined cut-off levels,patients could effectively be subdivided into a group above the cut-off level with definitive diagnosis of MTC(100%) and below with a significant overlap of C-cell hyperplasia and MTC(all classified as pT1a;males:19/58[37.5%],females:7/41[17.1%]).The areas under the ROC curve(AUC) were excellent for the diagnosis of MTC in all tests.Determination of bCT proved to be superior for both diagnosing MTC in males(AUC bCT:0.894;AUC Ca-sCT:0.849) and females(bCT:0.935;Ca-sCT:0.868) and also for diagnosing lymph node metastasis in the lateral compartment(males:bCT:0.925;Ca-sCT:0.810; females:bCT:0.797;Ca-sCT:0.674).Combining both tests did not improve diagnostic accuracy.Using a cut-off level of>85pg/ml for females and>100pg/ml for males,the sensitivity for diagnosing lateral neck lymph node metastasis was 100%.Below these cut-off levels,no patient showed persistent or recurrent disease. Conclusion Predefined sex-specific bCT cut-off levels are helpful for the early detection of MTC and for predicting lateral neck lymph node metastasis.Ca-sCT did not improve preoperative diagnostics.bCT levels>43pg/ml and>100pg/ml for males and of >23pg/ml and >85pg/ml for females are relevant for advising patients and planning the extent of surgery.

Cluster headache (CR) is the most severe human headache and is chronic in 10%-20% of patients, and 10% can become refractory to all effective drugs. In this scenario, surgical procedures are indicated: radiofrequencies of the sphenopalatine ganglion ipsilateral to pain (RF-SPG), bilateral stimulation of the occipital nerves (NOM-S) and deep brain stimulation (DBS) of the ipsilateral posterior hypothalamus. The efficacy and safety of each of these procedures has been specifically analyzed, but the progress of a series of patients following this surgical route in order of aggressiveness has not been described.

In our earlier work, we found that intrauterine (i.u.) and intraperitoneal (i.p.) injection of LPS (10 μg serotype 0111:B4) induced preterm labor (PTL) with high pup mortality, marked systemic inflammatory response and hypotension. Here, we used both i.u. and i.p. LPS models in pregnant wild type (wt) and CCR2 knockout (CCR2-/-) mice on E16 to investigate the role played by the CCL2/CCR2 system in the response to LPS. Basally, lower numbers of monocytes and macrophages and higher numbers of neutrophils were found in the myometrium, placenta and blood of CCR2-/- vs. wt mice. After i.u. LPS, parturition occurred at 14 hours in both groups of mice. At 7 hours post injection, 70% of wt pups were dead vs. 10% of CCR2-/- pups, but at delivery 100% of wt and 90% of CCR2-/- pups were dead. Myometrial and placental monocytes and macrophages were generally lower in CCR2-/- mice, but this was less consistent in the circulation, lung and liver. At 7 hours post LPS, myometrial ERK activation was greater and JNK and p65 lower and the mRNA levels of chemokines were higher and of inflammatory cytokines lower in CCR2-/- vs. wt mice. Pup brain and placental inflammation was similar. Using the IP LPS model, we found that all measures of arterial pressure increased in CCR2-/- but declined in wt mice. These data suggest that the CCL2/CCR2 system plays a critical role in the cardiovascular response to LPS and contributes to pup death but does not influence the onset of inflammation-induced PTL.

Electroconvulsive therapy (ECT) is effective in treating adolescents with severe psychiatric disorders. This study examined the knowledge, experiences and attitudes of adolescents with severe psychiatric disorders and their caregivers towards ECT in China.

The natural course of chronic pancreatitis(CP) and its complications has been inadequately explored. We aimed to describe the natural history and factors affecting the progression of alcoholic(ACP), idiopathic juvenile(IJCP) and idiopathic senile(ISCP) variants of CP.

Fibromyalgia (FM) is the most common chronic pain disease in middle-aged women. Patients may also complain of migraine, irritable bowel syndrome and depression, which seriously affect their work and life, causing huge economic losses to society. However, the pathogenesis of FM is still controversial and the effect of the current treatment is far from satisfactory.

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

The content of selected major nitrogen compounds including nucleosides and their derivatives was evaluated in 75 samples of seven varieties of honey (heather, buckwheat, black locust, goldenrod, canola, fir, linden) by targeted ultra-high performance liquid chromatography-diode array detector – high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-DAD-QqTOF-MS) and determined by UHPLC-DAD. The honey samples contained nucleosides, nucleobases and their derivatives (adenine: 8.9 to 18.4 mg/kg, xanthine: 1.2 to 3.3 mg/kg, uridine: 17.5 to 51.2 mg/kg, guanosine: 2.0 to 4.1 mg/kg; mean amounts), aromatic amino acids (tyrosine: 7.8 to 263.9 mg/kg, phenylalanine: 9.5 to 64.1 mg/kg; mean amounts). The amounts of compounds significantly differed between some honey types. For example, canola honey contained a much lower amount of uridine (17.5 ± 3.9 mg/kg) than black locust where it was most abundant (51.2 ± 7.8 mg/kg). The presence of free nucleosides and nucleobases in different honey varieties is reported first time and supports previous findings on medicinal activities of honey reported in the literature as well as traditional therapy and may contribute for their explanation. This applies, e.g., to the topical application of honey in herpes infections, as well as its beneficial activity on cognitive functions as nootropic and neuroprotective, in neuralgia and is also important for the understanding of nutritional values of honey.