Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and ...oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease.
To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation.
Sixty-four BALBc mice, were divided into eight groups (
= 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 μg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28).
Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4
, CD8
, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-β, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (
< 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-β, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (
< 0.05).
Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.
A major challenge in the design of biocidal drugs is to identify compounds with potential action on microorganisms and to understand at the molecular level their mechanism of action. In this study, ...thymol, a monoterpenoid found in the oil of leaves of Lippia sidoides with possible action in biological surfaces, was incorporated in lipid monolayers at the air–water interface that represented cell membrane models. The interaction of thymol with dipalmitoylphosphatidylcholine (DPPC) at the air–water interface was investigated by means of surface pressure–area isotherms, Brewster angle microscopy (BAM), polarization-modulation reflection–absorption spectroscopy (PM-IRRAS), and molecular dynamics simulation. Thymol expands DPPC monolayers, decreases their surface elasticity, and changes the morphology of the lipid monolayer, which evidence the incorporation of this compound in the lipid Langmuir film. Such incorporation could be corroborated by PM-IRRAS since some specific bands for DPPC were changed upon thymol incorporation. Furthermore, potential of mean force obtained by molecular dynamics simulations indicates that the most stable position of the drug along the lipid film is near the hydrophobic regions of DPPC. These results may be useful to understand the interaction between thymol and cell membranes during biochemical phenomena, which may be associated with its pharmaceutical properties at the molecular level.
Being an atomically thin material, graphene is known to be extremely susceptible to its environment, including defects and phonons in the substrate on which it is placed as well as gas molecules that ...surround it. Thus, any device design using graphene has to take into consideration all surrounding components, and device performance needs to be evaluated in terms of environmental influence. However, no methods have been established to date to readily measure the density and distribution of external perturbations in a quantitative and non-destructive manner. Here, we present a rapid and non-contact method for visualizing the distribution of molecular adsorbates on graphene semi-quantitatively using terahertz time-domain spectroscopy and imaging. We found that the waveform of terahertz bursts emitted from graphene-coated InP sensitively changes with the type of atmospheric gas, laser irradiation time, and ultraviolet light illumination. The terahertz waveform change is explained through band structure modifications in the InP surface depletion layer due to the presence of localized electric dipoles induced by adsorbed oxygen. These results demonstrate that terahertz emission serves as a local probe for monitoring adsorption and desorption processes on graphene films and devices, suggesting a novel two-dimensional sensor for detecting local chemical reactions.
Natural monoterpenes were isolated from the essential oil of Piper cernuum Vell. (Piperaceae) leaves. The crude oil and the individual monoterpenes were tested for cytotoxicity in human tumor cell ...lineages and B16F10-Nex2 murine melanoma cells. In the present work we demonstrate the activity of camphene against different cancer cells, with its mechanism of action being investigated in vitro and in vivo in murine melanoma. Camphene induced apoptosis by the intrinsic pathway in melanoma cells mainly by causing endoplasmic reticulum (ER) stress, with release of Ca2+ together with HmgB1 and calreticulin, loss of mitochondrial membrane potential and up regulation of caspase-3 activity. Importantly, camphene exerted antitumor activity in vivo by inhibiting subcutaneous tumor growth of highly aggressive melanoma cells in a syngeneic model, suggesting a promising role of this compound in cancer therapy.
Hypothalamic kisspeptin neurons are the primary modulators of gonadotropin-releasing hormone (GnRH) neurons. It has been shown that circadian rhythms driven by the suprachiasmatic nucleus (SCN) ...contribute to GnRH secretion. Kisspeptin neurons are potential targets of SCN neurons due to reciprocal connections with the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) and the arcuate nucleus of the hypothalamus (ARH). Vasoactive intestinal peptide (VIP), a notable SCN neurotransmitter, modulates GnRH secretion depending on serum estradiol levels, aging or time of the day. Considering that kisspeptin neurons may act as interneurons and mediate VIP's effects on the reproductive axis, we investigated the effects of VIP on hypothalamic kisspeptin neurons in female mice during estrogen negative feedback. Our findings indicate that VIP induces a TTX-independent depolarization of approximately 30% of AVPV/PeN kisspeptin neurons in gonad-intact (diestrus) and ovariectomized (OVX) mice. In the ARH, the percentage of kisspeptin neurons that were depolarized by VIP was even higher (approximately 90%). An intracerebroventricular infusion of VIP leds to an increased percentage of kisspeptin neurons expressing the phosphoSer133 cAMP-response-element-binding protein (pCREB) in the AVPV/PeN. On the other hand, pCREB expression in ARH kisspeptin neurons was similar between saline- and VIP-injected mice. Thus, VIP can recruit different signaling pathways to modulate AVPV/PeN or ARH kisspeptin neurons, resulting in distinct cellular responses. The expression of VIP receptors (VPACR) was upregulated in the AVPV/PeN, but not in the ARH, of OVX mice compared to mice on diestrus and estradiol-primed OVX mice. Our findings indicate that VIP directly influences distinct cellular aspects of the AVPV/PeN and ARH kisspeptin neurons during estrogen negative feedback, possibly to influence pulsatile LH secretion.
•VIP directly depolarizes 30% of AVPV/PeN kisspeptin neurons in diestrus mice.•VIP directly depolarizes approximately 90% of ARH kisspeptin neurons of diestrus females.•Central VIP infusion increases pCREB levels only in AVPV/PeN kisspeptin neurons.•VPACR expression is upregulated in the AVPV/PeN of OVX mice.•VIP responsiveness in AVPV/PeN kisspeptin neurons is similar in diestrus and OVX mice.
Growth hormone (GH) is a key factor in the regulation of body growth, as well as a variety of other cellular and metabolic processes. Neurons expressing kisspeptin and leptin receptors (LepR) have ...been shown to modulate the hypothalamic-pituitary-gonadal (HPG) axis and are considered GH responsive. The presence of functional GH receptors (GHR) in these neural populations suggests that GH may regulate the HPG axis via a central mechanism. However, there have been no studies evaluating whether or not GH-induced intracellular signaling in the brain plays a role in the timing of puberty or mediates the ovulatory cycle. Toward the goal of understanding the influence of GH on the central nervous system as a mediator of reproductive functions, GHR ablation was induced in kisspeptin and LepR-expressing cells or in the entire brain. The results demonstrated that GH signaling in specific neural populations can potentially modulate the hypothalamic expression of genes related to the reproductive system or indirectly contribute to the progression of puberty. GH action in kisspeptin cells or in the entire brain was not required for sexual maturation. On the other hand, GHR ablation in LepR cells delayed puberty progression, reduced serum leptin levels, decreased body weight gain and compromised the ovulatory cycle in some individuals, while the lack of GH effects in the entire brain prompted shorter estrous cycles. These findings suggest that GH can modulate brain components of the HPG axis, although central GH signaling is not required for the timing of puberty.
Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in ...hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1-expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhrlit/lit mice). Interestingly, although Ghrhrlit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhrlit/lit mice. Despite presenting dwarfism, the majority of Ghrhrlit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1-expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice.
•Neonatal-induced ARH lesions compromise the kisspeptin system and the somatotropic axis.•Kisspeptin expression in the rostral hypothalamus is sufficient for HPG axis maturation.•Kisspeptin expression in the arcuate nucleus of the hypothalamus is essential for male fertility.•Growth hormone deficiency does not compromise the kisspeptin system.
The dineutron correlation is systematically studied in three different Borromean nuclei near the neutron dripline, 11Li, 14Be and 17B, via the (p,pn) knockout reaction measured at the RIBF facility ...in RIKEN. For the three nuclei, the correlation angle between the valence neutrons is found to be largest in the same range of intrinsic momenta, which can be associated to the nuclear surface. This result reinforces the prediction that the formation of the dineutron is universal in environments with low neutron density, such as the surface of neutron-rich Borromean nuclei.
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