The Major Brain Endocannabinoid 2-AG Controls Neuropathic Pain and Mechanical Hyperalgesia in Patients with Neuromyelitis Optica

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.     

Epstein–Barr virus and thyroid cancer: The role of viral expressed proteins

Background : Thyroid cancer is a common endocrine malignancy whose incidence has increased in recent years. Several internal and external risk factors are involved in the development of this cancer, such as infectious agents. Evidence supporting the role of viral infection as an etiology for the invasiveness of thyroid cancer is increasing. The aim of this study was to determine the presence of the Epstein–Barr virus (EBV) and the association between viral gene products and thyroid tumor development. Methods : Fifty-seven thyroid cancer specimens were collected from the same number of patients as well as 18 samples from healthy controls. The presence of the EBV genome and the genotyping was examined by polymerase chain reaction (PCR). Also, an enzyme-linked immunosorbent assay and real-time PCR were used to measure the expression levels of viral and cellular genes. Results : The EBV DNA was detected in 71.9% of the samples, and it was also found that the presence of the EBV was associated with increasing development of thyroid tumor. Conclusion : Our results demonstrated that EBV infection may play a role in the development of thyroid tumor.     

Synthesis and urease inhibitory potential of benzophenone sulfonamide hybrid in vitro and in silico

This study deals with the synthesis of benzophenone sulfonamides hybrids (1–31) and screening against urease enzyme in vitro. Studies showed that several synthetic compounds were found to have good urease enzyme inhibitory activity. Compounds 1 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-4′′-nitrobenzenesulfonohydrazide), 2 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-3′′-nitrobenzenesulfonohydrazide), 3 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-4′′-methoxybenzenesulfonohydrazide), 4 (3′′,5′′-dichloro-2′′-hydroxy-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 6 (2′′,4′′-dichloro-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 8 (5-(dimethylamino)-N′-((4-hydroxyphenyl)(phenyl)methylene)naphthalene-1-sulfono hydrazide), 10 (2′′-chloro-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 12 (N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide) have found to be potently active having an IC₅₀ value in the range of 3.90–17.99?µM. These compounds showed superior activity than standard acetohydroxamic acid (IC₅₀?=?29.20?±?1.01?µM). Moreover, in silico studies on most active compounds were also performed to understand the binding interaction of most active compounds with active sites of urease enzyme. Structures of all the synthetic compounds were elucidated by ¹H NMR, ¹³C NMR, EI-MS and FAB-MS spectroscopic techniques.     

Sex and age related changes in the locomotor activity and phototactic behaviors of two closely related species of Camponotus ants

A virgin ant queen has only one opportunity in her lifetime to realize her reproductive fitness when she leaves her nest for a mating flight. After successful mating she sheds her wings, excavates a nest and starts laying eggs to initiate her own colony. Here we report the results of our study on two related species of Camponotus ants - day active Camponotus paria and night active Camponotus compressus - aimed at investigating (i) if there exist inter-species differences in the activity and phototactic behaviors of males and queens, (ii) whether these behaviors in the queen change after mating, and (iii) whether the activity rhythm of queens changes with age. We find that while activity profiles differ between C. paria and C. compressus virgin males and queens, such differences in queens disappear after mating. Once mated, the activity rhythm of queens shows little change with age; the rhythm in virgin queens, on the other hand, changes considerably. As virgins, C. paria queens are positively phototactic, while C. compressus queens are negatively phototactic. After mating, C. paria queens become less phototactic, particularly during the subjective night, while C. compressus queens remain negatively phototactic. These results indicate that there are considerable differences in the activity and phototactic behaviors of virgin queens of the two related species of Camponotus ants. Most of these differences disappear after mating, which suggests that these behaviors may have evolved primarily for the proper execution of pre-mating events.     

Or47b receptor neurons mediate sociosexual interactions in the fruit fly Drosophila melanogaster

In the fruit fly Drosophila melanogaster, social interactions especially among heterosexual couples have been shown to have significant impact on the circadian timing system. Olfaction plays a major role in such interactions; however, we do not know yet specifically which receptor(s) are involved. Further, the role of circadian clock neurons in the rhythmic regulation of such sociosexual interactions (SSIs) is not fully understood. Here, we report the results of our study in which we assayed the locomotor activity and sleep-wake behaviors of male-male (MM), female-female (FF), and male-female (MF) couples from several wild-type and mutant strains of Drosophila with an aim to identify specific olfactory receptor(s) and circadian clock neurons involved in the rhythmic regulation of SSI. The results indicate that Or47b receptor neurons are necessary for SSI, as ablation or silencing of these neurons has a severe impact on SSI. Further, the neuropeptide pigment dispersing factor (PDF) and PDF-positive ventral lateral (LN(v)) clock neurons appear to be dispensable for the regulation of SSI; however, dorsal neurons may be involved.     

Manipulation of estrous cycle in dwarf goat (Capra hircus) using estrumate under different management conditions

A study was conducted to elucidate the effectiveness of exogenous estrumate (prostaglandin F(2alpha)) treatment as a synchronizing agent for Dwarf goats and to establish the progesterone levels at different reproductive stages under two different environmental and nutritional conditions. Female Dwarf goats of various ages were raised, 10 each at two sites, viz. the Bio-Saline Research Substation (BSRS), Lahore and at the Nuclear Institute for Agriculture and Biology (NIAB), Faisalabad. The animals at the NIAB farm were reared on non-saline soil under normal grazing conditions, while the other animal lot was raised on salt-affected lands at the BSRS, Lahore and was fed on non-conventional fodders produced by salt-affected lands. The animals received two intramuscular doses (0.5 ml each) of estrumate (125 microg/ml) at 10 days interval. Nineteen of the 20 animals exhibited estrus after 56-72 h of the second injection of estrumate. The mean progesterone concentration in the NIAB and BSRS lots was 2.8 and 2.4 ng/ml, respectively, at the time of second injection and declined to the basal level (estrus) within 48 h. A gradual increase in the progesterone level occurred during the metestrus, reaching maximum during the luteal phase when it was 6.3 and 6.7 ng/ml in NIAB-lot and BSRS-lot, respectively. During the proestrous phase, the progesterone level decreased to the basal level (0.1 ng/ml) at the onset of the next estrus after 22 days. The length of the induced or natural estrous cycle (20+/-1 days) was not affected by the estrumate treatment, nor by the environmental and nutritional conditions. Breeding was allowed after the natural estrous cycle at the onset of third estrus and a high fertility rate (95%) was achieved. The progesterone concentrations remained at higher level (4.5-9.4 ng/ml) throughout the gestation period, declined gradually in the prepartum period, and dropped to the basal level at the completion of parturition. The results suggested that estrumate is an efficient synchronizing agent for the Dwarf goats kept under different environmental-nutritive conditions and that the progesterone profile is a useful indicator to assess the reproductive status of the goats.     

1,3,4-Oxadiazole-2(3H)-thione and its analogues: A new class of non-competitive nucleotide pyrophosphatases/phosphodiesterases 1 inhibitors

A series of 1,3,4-oxadiazole-2 (3H)-thiones and 1,3,4-thiadiazole-2 (3H)-thiones were synthesized and evaluated for their inhibitory activities against the two nucleotide pyrophosphatase phosphodiesterase 1 enzymes. Dixon, as well as Lineweaver–Burk plots, and their secondary replots have indicated that the inhibition was of pure non-competitive type, against both snake venom and pure human recombinant enzymes as the V_max values decreases without affecting the K_m values. 5-[4-(t-Butyldimethylsilyloxy)-phenyl]-1,3,4-thiadiazole-2 (3H)-thione (17) and [4-(t-butyldimethylsilyloxy)-phenyl]-1,3,4-oxadiazole-2 (3H)-thione (1) were found to be the most active compounds with IC₅₀ values 66.47 and 368 μM, respectively. The K_i values were 100 μM and 360 μM against the snake venom and human recombinant NPP1 enzyme, respectively. Most active compounds were found to be non-toxic in neutrophil viability assay.     

Oxazolones: new tyrosinase inhibitors; synthesis and their structure-activity relationships

The tyrosinase inhibitory potential of seventeen synthesized oxazolone derivatives has been evaluated and their structure-activity relationships developed in the present work. All the synthesized derivatives, 3-19, demonstrated excellent in vitro tyrosinase inhibitory properties having IC50 values in the range of 1.23+/-0.37-17.73+/-2.69 microM, whereas standard inhibitors l-mimosine and kojic acid have IC50 values 3.68+/-0.02 and 16.67+/-0.52 microM,, respectively. Compounds 4-8 having IC50 values 3.11+/-0.95, 3.51+/-0.25, 3.23+/-0.66, 1.23 +/- 0.37, and 2.15+/-0.75, respectively, were found to be very active members of the series, even better than both the standard inhibitors. However, compounds 3, 9-11, 13, 14, 16, 17, and 19 were found to be better than kojic acid but not l-mimosine. (2-Methyl-4-[E,2Z)-3-phenyl-2-propenyliden]-1,3-oxazol-5(4H)-one (7) bearing a cinnamyol residue at C-4 of oxazolone moiety and an IC50 = 1.23+/-0.37 microM was found to be the most active one among all tested compounds. These studies reveal that the substitution of functional group (s) at C-4 and C-2 positions plays a vital role in the activity of this series of compounds. It is concluded that compound 7 may act as a potential lead molecule to develop new drugs for the treatment of tyrosinase based disorders.     

Lentiviral transduction of dendritic cells confers protective antiviral immunity in vivo

Control of a viral infection in vivo requires a rapid and efficient cytotoxic-T-lymphocyte response. We demonstrate that lentivirus-mediated introduction of antigen in dendritic cells confers a protective antiviral immunity in vivo in a lymphocytic choriomeningitis virus model. Therefore, lentiviral vectors may be excellent vaccine candidates for viral infections.