Retracted: Icariin attenuates methotrexate chemotherapy-induced bone marrow microvascular damage and bone loss in rats

Methotrexate (MTX), a widely used antimetabolite in paediatric cancer to treatment, has been widely reported to cause bone loss and bone marrow (BM) microvascular (particularly sinusoids) damage. Investigations must now investigate how MTX-induced bone loss and microvasculature damage can be attenuated/prevented. In the present study, we examined the potency of icariin, an herbal flavonoid, in reducing bone loss and the dilation/damage of BM sinusoids in rats caused by MTX treatment. Groups of young rats were treated with five daily MTX injections (0.75 mg/kg) with and without icariin oral supplementation until Day 9 after the first MTX injection. Histological analyses showed a significant reduction in the bone volume/tissue volume (BV/TV) fraction (%) and trabecular number in the metaphysis trabecular bone of MTX-treated rats, but no significant changes in trabecular thickness and trabecular spacing. However, the BV/TV (%) and trabecular number were found to be significantly higher in MTX + icariin-treated rats than those of MTX alone-treated rats. Gene expression analyses showed that icariin treatment maintained expression of osteogenesis-related genes but suppressed the induction of adipogenesis-related genes in bones of MTX-treated rats. In addition, icariin treatment attenuated MTX-induced dilation of BM sinusoids and upregulated expression of endothelial cell marker CD31 in the metaphysis bone of icariin + MTX-treated rats. Furthermore, in vitro studies suggest that icariin treatment can potentially enhance the survival of cultured rat sinusoidal endothelial cells against cytotoxic effect of MTX and promote their migration and tube formation abilities, which is associated with enhanced production of nitric oxide.     

Load transfer along the bone–dental implant interface

In this paper the variation of normal and shear stresses along a path defined on the bone–dental implant interface is investigated. In particular, the effects of implant diameter, collar length and slope, body length, and the effects of four different types of external threads on the interfacial stress distribution are studied. The geometry of the bone is digitized from a CT scan of a mandibular incisor and the surrounding bone. The bone and the implant are assumed to be perfectly bonded. The finite element method with 2D plane strain assumption is used to compute interfacial stresses. Highest continuous interfacial stresses are encountered in the region where the implant collar engages the cortical region, and near the apex of the implant in the subcortical region. Stress concentrations in the interfacial stresses occur near the geometric discontinuities on the implant contour, and jumps in stress values occur where the elastic modulus of the bone transitions between the cortical and trabecular bone values. Among the six contour parameters, the slope and the length of the implant collar, and the implant diameter influence the interfacial stress levels the most, and the effects of changing these parameters are significantly noticed only in the cortical bone (alveolar ridge) area. External threads cause significant stress concentrations in interfacial stresses in otherwise smoothly varying regions. This work shows that the presence of external threads could cause significant variations in both normal and shear stresses along the bone–implant interface, but not reduction in shear stress as previously thought.     

Investigation of the effect of homocysteinylation of substance P on its binding to the NK1 receptor using molecular dynamics simulation

Substance P is a neurotransmitter or modulator in both the central and peripheral nervous systems. In this work, modifications of the lysine in SP by homocysteine and an acetyl group as well as the conformational dynamics of the native and modified SP peptides and their complexes with the NK1 receptor were studied via MD simulation. It was found that modifying SP stabilizes the peptide structure, but the modified SP peptides are less likely to bind to the NK1 receptor, so the resulting complexes are less stable. The RMSD of native SP (~0.33 nm) is about twice as large as that of the modified SP peptides (~0.18 nm), while the RMSD for the receptor complexed with native SP is ~0.3 nm, and that for the receptor complexed with either of the modified peptides is ~0.35 nm, which demonstrates the high stability of the modified SP peptides as well as the receptor complexed with native SP. Such behavior was also observed in other structural analyses. The binding free energies of the native and modified SP peptides with the NK1 receptor were also compared. The ΔG_bind values for the binding of homocysteinylated SP to the NK1 receptor and the binding of the acetylated SP and native SP to the NK1 receptor were ?38.89, ?64.46, and???264.52 kJ mol^?1, respectively. Modification of the lysine of SP decreases the binding affinity of the peptide to the NK1 receptor. In other words, homocysteinylation or acetylation of SP leads to weaker interactions of the peptide with the NK1 receptor compared to those between native SP and NK1. We propose that this phenomenon leads to increased levels of homocysteinylated SP in plasma in many diseases such as breast cancer.

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Graphical abstract Substance P (SP) is a neuropeptide which binds to the NK1 receptor. SP is of great pharmacological interest, as agonists and antagonists of SP can potentially be used to treat many chronic diseases. Therefore, in this work, the lysine (LYS) in SP was theoretically modified with a homocysteine or acetyl group to explore the effects of such a modification on the binding affinity of this peptide with the NK1 receptor and the structural dynamics of the resulting complex

     

Use of bacterial acc deaminase to increase oil (especially poly aromatic hydrocarbons) phytoremediation efficiency for maize (zea mays) seedlings

Oil presence in soil, as a stressor, reduces phytoremediation efficiency through an increase in the plant stress ethylene. Bacterial 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, as a plant stress ethylene reducer, was employed to increase oil phytoremediation efficiency. For this purpose, the ability of ACC deaminase-producing Pseudomonas strains to grow in oil-polluted culture media and withstand various concentrations of oil and also their ability to reduce plant stress ethylene and enhance some growth characteristics of maize and finally their effects on increasing phytoremediation efficiency of poly aromatic hydrocarbons (PAHs) in soil were investigated. Based on the results, of tested strains just P9 and P12 were able to perform oil degradation. Increasing oil concentration from 0 to 10% augmented these two strains population, 15.7% and 12.9%, respectively. The maximum increase in maize growth was observed in presence of P12 strain. Results of high-performance liquid chromatography (HPLC) revealed that PAHs phytoremediation efficiency was higher for inoculated seeds than uninoculated. The highest plant growth and PAHs removal percentage (74.9%) from oil-polluted soil was observed in maize inoculated with P12. These results indicate the significance of ACC deaminase producing bacteria in alleviation of plant stress ethylene in oil-polluted soils and increasing phytoremediation efficiency of such soils.     

A Microassay for Determination of the Cytopathogenicity of Human Immunodeficiency Virus Type-1 Isolates

Correlations between the in vitro biological properties of HIV strains isolated from patients and the prognosis of their disease have been reported. We developed a technique to study the phenotype of HIV strains isolated from patients. We used the P4 cell line, derived from HeLa cells, which has been transfected with receptor CD4 gene. HIV laboratory strain (HIV_LAI) and peripheral blood leukocytes (PBLs) from donors infected with HIV_LAI induce syncytium in P4 cell cultures in vitro. The presence of reporter gene (LacZ gene) under the control of the HIV-1 long terminal repeat (LTR) in these cells allows colorimetric visualization of syncytia in the cytoplasm using a β-galactosidase (βgal) assay in the presence of X-gal. We cocultivated 1 × 10⁶ patient PBLs with 2 × 10⁶ normal PHA-activated normal PBLs for 4 days in the presence of IL-2 in 24-well plates. Half of the medium was replaced twice a week and PHA-activated normal PBLs were added every 7 days. HIV-1 was isolated from cocultured PBLs of 18 patients with advanced-stage HIV infection as assessed by the production of HIV p24 detected with a commercially available HIV-1 p24 ELISA. Supernatant and 10⁵ cells were collected twice a week from cocultured PBLs and were added to P4 cells in 96-well microtiter plates. The cultures were observed every day for 3 days and then the βgal assay was performed. We did not observe any effect with cells and supernatant from 8 patients, harvested from cultures incubated for as long as 28 days. The phenotype of these isolates was called NC (noncytopathic). In cells from 2 patients, we obtained blue multinucleated giant cells; the phenotype of these strains was called SI (syncytium inducing). In cultures from 8 other patients, we obtained the death of P4 cells without syncytium formation, and the phenotype of these strains was called CI (cell-killing inducing). In every case, the cytopathic effect of HIV-1 isolates could be detected with cocultured PBLs collected as early as day 4 of culture. Cocultured PBLs from 13 healthy controls did not alter the P4 cells. We displayed the replication of CI strains of HIV-1, but not the one of NC strains in P4 cell line. Our micromethod allowed the detection of cytopathic effects of HIV isolates. Further investigations should define the clinical applications of this method.     

Integrated multi‐omics analysis supports role of lysophosphatidylcholine and related glycerophospholipids in the Lotus japonicus–Glomus intraradices mycorrhizal symbiosis

Interaction of plant roots with arbuscular mycorrhizal fungi (AMF) is a complex trait resulting in cooperative interactions among the two symbionts including bidirectional exchange of resources. To study arbuscular mycorrhizal symbiosis (AMS) trait variation in the model plant Lotus japonicus, we performed an integrated multi‐omics analysis with a focus on plant and fungal phospholipid (PL) metabolism and biological significance of lysophosphatidylcholine (LPC). Our results support the role of LPC as a bioactive compound eliciting cellular and molecular response mechanisms in Lotus. Evidence is provided for large interspecific chemical diversity of LPC species among mycorrhizae with related AMF species. Lipid, gene expression and elemental profiling emphasize the Lotus–Glomus intraradices interaction as distinct from other arbuscular mycorrhizal (AM) interactions. In G. intraradices, genes involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs were enhanced, while in Lotus, FA synthesis genes were up‐regulated during AMS. Furthermore, FAS protein localization to mitochondria suggests FA biosynthesis and elongation may also occur in AMF. Our results suggest the existence of interspecific partitioning of PL resources for generation of LPC and novel candidate bioactive PLs in the Lotus–G. intraradices symbiosis. Moreover, the data advocate research with phylogenetically diverse Glomeromycota species for a broader understanding of the molecular underpinnings of AMS.     

Innovative therapies for prostate cancer treatment

Androgen ablation is effective therapy for metastatic prostate cancer, but the majority of men eventually become refractory to this intervention. Cytotoxic chemotherapy offers palliation to symptomatic patients with hormone-refractory prostate cancer (HRPC); however, no chemotherapy regimen has yet been shown to prolong survival. There is a clear need for new agents and drug targets for the treatment of HRPC. A number of innovative therapeutic approaches that are rationally based and target driven are under investigation. This article reviews the development of antisense oligonucleotides that inhibit the anti-apoptotic bcL-2 protein. Approaches that target the epidermal growth factor receptor, the platelet derived growth factor receptor, and nuclear factor kappa-B are also discussed. There is much expectation that these therapies alone or in combination with cytotoxic chemotherapy will impact the clinical outcome of patients with HRPC.     

Cavin4 interacts with Bin1 to promote T-tubule formation and stability in developing skeletal muscle

The cavin proteins are essential for caveola biogenesis and function. Here, we identify a role for the muscle-specific component, Cavin4, in skeletal muscle T-tubule development by analyzing two vertebrate systems, mouse and zebrafish. In both models, Cavin4 localized to T-tubules, and loss of Cavin4 resulted in aberrant T-tubule maturation. In zebrafish, which possess duplicated cavin4 paralogs, Cavin4b was shown to directly interact with the T-tubule–associated BAR domain protein Bin1. Loss of both Cavin4a and Cavin4b caused aberrant accumulation of interconnected caveolae within the T-tubules, a fragmented T-tubule network enriched in Caveolin-3, and an impaired Ca²⁺ response upon mechanical stimulation. We propose a role for Cavin4 in remodeling the T-tubule membrane early in development by recycling caveolar components from the T-tubule to the sarcolemma. This generates a stable T-tubule domain lacking caveolae that is essential for T-tubule function.