Buspirone attenuated methotrexate-induced hippocampal toxicity in rats by regulating Nrf2/HO-1, PPAR-γ, NF-κB/nNOS,and ROS/NLRP3/caspase-1 signaling pathways

Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX-induced hippocampal neurotoxicity is a well-defined dose-limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX-induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5-HT1a receptor (5-HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti-inflammatory effects. The current study investigated BSP's potential anti-inflammatory and antioxidant effects in attenuating MTX-induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch-like ECH-associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase-1, and peroxisome proliferator-activated receptor expression. BSP dampened inflammation by reducing NO₂⁻, tumor necrosis factor-alpha, IL-6, and interleukin 1 beta levels mediated by downregulating NF-κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved-caspase-1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX.     

Iterative Most-Likely Point Registration (IMLP): A Robust Algorithm for Computing Optimal Shape Alignment

We present a probabilistic registration algorithm that robustly solves the problem of rigid-body alignment between two shapes with high accuracy, by aptly modeling measurement noise in each shape, whether isotropic or anisotropic. For point-cloud shapes, the probabilistic framework additionally enables modeling locally-linear surface regions in the vicinity of each point to further improve registration accuracy. The proposed Iterative Most-Likely Point (IMLP) algorithm is formed as a variant of the popular Iterative Closest Point (ICP) algorithm, which iterates between point-correspondence and point-registration steps. IMLP’s probabilistic framework is used to incorporate a generalized noise model into both the correspondence and the registration phases of the algorithm, hence its name as a most-likely point method rather than a closest-point method. To efficiently compute the most-likely correspondences, we devise a novel search strategy based on a principal direction (PD)-tree search. We also propose a new approach to solve the generalized total-least-squares (GTLS) sub-problem of the registration phase, wherein the point correspondences are registered under a generalized noise model. Our GTLS approach has improved accuracy, efficiency, and stability compared to prior methods presented for this problem and offers a straightforward implementation using standard least squares. We evaluate the performance of IMLP relative to a large number of prior algorithms including ICP, a robust variant on ICP, Generalized ICP (GICP), and Coherent Point Drift (CPD), as well as drawing close comparison with the prior anisotropic registration methods of GTLS-ICP and A-ICP. The performance of IMLP is shown to be superior with respect to these algorithms over a wide range of noise conditions, outliers, and misalignments using both mesh and point-cloud representations of various shapes.     

Connecting to the oceans: supporting ocean literacy and public engagement

Improved public understanding of the ocean and the importance of sustainable ocean use, or ocean literacy, is essential for achieving global commitments to sustainable development by 2030 and beyond. However, growing human populations (particularly in mega-cities), urbanisation and socio-economic disparity threaten opportunities for people to engage and connect directly with ocean environments. Thus, a major challenge in engaging the whole of society in achieving ocean sustainability by 2030 is to develop strategies to improve societal connections to the ocean. The concept of ocean literacy reflects public understanding of the ocean, but is also an indication of connections to, and attitudes and behaviours towards, the ocean. Improving and progressing global ocean literacy has potential to catalyse the behaviour changes necessary for achieving a sustainable future. As part of the Future Seas project (https://futureseas2030.org/), this paper aims to synthesise knowledge and perspectives on ocean literacy from a range of disciplines, including but not exclusive to marine biology, socio-ecology, philosophy, technology, psychology, oceanography and human health. Using examples from the literature, we outline the potential for positive change towards a sustainable future based on knowledge that already exists. We focus on four drivers that can influence and improve ocean literacy and societal connections to the ocean: (1) education, (2) cultural connections, (3) technological developments, and (4) knowledge exchange and science-policy interconnections. We explore how each driver plays a role in improving perceptions of the ocean to engender more widespread societal support for effective ocean management and conservation. In doing so, we develop an ocean literacy toolkit, a practical resource for enhancing ocean connections across a broad range of contexts worldwide.

     

Bacterial denitrifying nitric oxide reductases and aerobic respiratory terminal oxidases use similar delivery pathways for their molecular substrates

The superfamily of heme?copper oxidoreductases (HCOs) include both NO and O₂ reductases. Nitric oxide reductases (NORs) are bacterial membrane enzymes that catalyze an intermediate step of denitrification by reducing nitric oxide (NO) to nitrous oxide (N₂O). They are structurally similar to heme?copper oxygen reductases (HCOs), which reduce O₂ to water. The experimentally observed apparent bimolecular rate constant of NO delivery to the deeply buried catalytic site of NORs was previously reported to approach the diffusion-controlled limit (10⁸–10⁹?M^?1?s^?1). Using the crystal structure of cytochrome-c dependent NOR (cNOR) from Pseudomonas aeruginosa, we employed several protocols of molecular dynamics (MD) simulation, which include flooding simulations of NO molecules, implicit ligand sampling and umbrella sampling simulations, to elucidate how NO in solution accesses the catalytic site of this cNOR. The results show that NO partitions into the membrane, enters the enzyme from the lipid bilayer and diffuses to the catalytic site via a hydrophobic tunnel that is resolved in the crystal structures. This is similar to what has been found for O₂ diffusion through the closely related O₂ reductases. The apparent second order rate constant approximated using the simulation data is ~5?×?10⁸?M^?1?s^?1, which is optimized by the dynamics of the amino acid side chains lining in the tunnel. It is concluded that both NO and O₂ reductases utilize well defined hydrophobic tunnels to assure that substrate diffusion to the buried catalytic sites is not rate limiting under physiological conditions.     

Updates in the pathophysiological mechanisms of Parkinson's disease: Emerging role of bone marrow mesenchymal stem cells

AIM: To explore the approaches exerted by mesenchymal stem cells(MSCs) to improve Parkinson's disease(PD) pathophysiology.METHODS: MSCs were harvested from bone marrowof femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group(1) was control, Groups(2) and(3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group(2) was left untreated, while Group(3) was treated with single intravenous dose of bone marrow derived MSCs(BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1(TGF-β1), monocyte chemoattractant protein-1(MCP-1) and brain derived neurotrophic factor(BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase(TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done.RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1(489.7 ± 13.0 vs 691.2 ± 8.0, P 0.05) and MCP-1(89.6 ± 2.0 vs 112.1 ± 1.9, P 0.05) levels associated with significant increase in serum BDNF(3663 ± 17.8 vs 2905 ± 72.9, P 0.05) and brain DA(874 ± 15.0 vs 599 ± 9.8, P 0.05) levels as well as brain TH(1.18 ± 0.004 vs 0.54 ± 0.009, P 0.05) and nestin(1.29 ± 0.005 vs 0.67 ± 0.006, P 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin(293.2 ± 15.9 vs 271.5 ± 15.9, P 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs. CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.     

The HIV core protein p24 inhibits interferon-gamma-induced increase of HLA-DR and cytochrome b heavy chain mRNA levels in the human monocyte-like cell line THP1

Cells from the human monocytic cell-line THP1 were incubated prior to activation with IFN-gamma or LPS with varying amounts of p24, the main product of the HIV gag gene and the major component of the virus core. The IFN-gamma-dependent increase of mRNA for HLA-DR and for the heavy chain of cytochrome b was markedly decreased by p24 but not by gp120. This effect was abrogated by anti-p24 antibodies. On the other hand, preincubation of THP1 cells with p24 did not affect the accumulation of the LPS-dependent mRNA for TNF alpha and IL1-beta. These results indicate that p24 at concentrations similar to those found in the serum of HIV-infected individuals specifically affects IFN-gamma-induced activation markers.     

Metabolomics reveals ionones upregulation in MeJA elicited Cinnamomum camphora (camphor tree) cell culture

Plant Cell, Tissue and Organ Culture (PCTOC) - Cell suspension culture offers an approach for elucidating secondary metabolites biosynthetic pathways and its regulatory mechanism. In this work,...