Molecular Engines, Therapeutic Targets, and Challenges in Pediatric Brain Tumors: A Special Emphasis on Hydrogen Sulfide and RNA-Based Nano-Delivery.

Pediatric primary brain tumors represent a real challenge in the oncology arena. Besides the psychosocial burden, brain tumors are considered one of the most difficult-to-treat malignancies due to their sophisticated cellular and molecular pathophysiology. Notwithstanding the advances in research and the substantial efforts to develop a suitable therapy, a full understanding of the molecular pathways involved in primary brain tumors is still demanded. On the other hand, the physiological nature of the blood-brain barrier (BBB) limits the efficiency of many available treatments, including molecular therapeutic approaches. Hydrogen Sulfide (H2S), as a member of the gasotransmitters family, and its synthesizing machinery have represented promising molecular targets for plentiful cancer types. However, its role in primary brain tumors, generally, and pediatric types, particularly, is barely investigated. In this review, the authors shed the light on the novel role of hydrogen sulfide (H2S) as a prominent player in pediatric brain tumor pathophysiology and its potential as a therapeutic avenue for brain tumors. In addition, the review also focuses on the challenges and opportunities of several molecular targeting approaches and proposes promising brain-delivery strategies for the sake of achieving better therapeutic results for brain tumor patients.

Decoding Insulin-Like Growth Factor Signaling Pathway From a Non-coding RNAs Perspective: A Step Towards Precision Oncology in Breast Cancer.

Breast cancer (BC) is a highly complex and heterogenous disease. Several oncogenic signaling pathways drive BC oncogenic activity, thus hindering scientists to unravel the exact molecular pathogenesis of such multifaceted disease. This highlights the urgent need to find a key regulator that tunes up such intertwined oncogenic drivers to trim the malignant transformation process within the breast tissue. The Insulin-like growth factor (IGF) signaling pathway is a tenacious axis that is heavily intertwined with BC where it modulates the amplitude and activity of vital downstream oncogenic signaling pathways. Yet, the complexity of the pathway and the interactions driven by its different members seem to aggravate its oncogenicity and hinder its target-ability. In this review, the authors shed the light on the stubbornness of the IGF signaling pathway and its potential regulation by non-coding RNAs in different BC subtypes. Nonetheless, this review also spots light on the possible transport systems available for efficient delivery of non-coding RNAs to their respective targets to reach a personalized treatment code for BC patients.

Hepatoprotective effect of kaempferol glycosides isolated from Cedrela odorata L. leaves in albino mice: involvement of Raf/MAPK pathway.

BACKGROUND AND PURPOSE: Paracetamol is the most implicated xenobiotic in inducing hepatotoxicity. Our study aimed to determine the impact of some kaempferol glycosides isolated from the leaves of Cedrela odorata L. on paracetamol hepatotoxicity. EXPERIMENTAL APPROACH: The methanolic extract of dried leaves of C. odorata L. was subjected to the combination of spectroscopic methods (1H and 13CNMR). Six kaempferol glycosides were isolated: kaempferol-3-O-ß-D-glycopyranoside (astragalin), kaempferol-3-O-ß-L-rhamnopyranoside, kaempferol-3-O-ß-D-rutinoside, kaempferide-3-O-ß-D-rutinoside, kaempferide-3-O-ß-Drutinosyl-7-O-ß-D-rhamnopyranoside, and kaempferol-3-O-ß-D- rutinosyl-7-O-a-D-arabinopyranoside. Fifty-four female Swiss Albino mice were divided randomly into 9 groups including (1) control negative (1 mL/kg saline; IP), (2) control positive (paracetamol 300 mg/kg; IP), (3) silymarin 50 mg/kg (IP). Animals of groups 4-9 were injected with 6 different samples of isolated compounds at 100 mg/kg (IP). One h later, groups 3-9 were injected with paracetamol (300 mg/kg IP). Two h later, tissue samples were taken from all animals to assess nitrotyrosine, c-Jun N-terminal protein kinase (c-JNK), Raf -1kinase, and oxidative stress biomarkers viz. reduced glutathione (GSH) and malondialdehyde (MDA). FINDINGS/RESULTS: Isolated glycosides had a prominent anti-apoptotic effect via inhibition of c-JNK and Raf-1 kinase. They also exerted a powerful antioxidant effect by modulating the oxidative stress induced by paracetamol via increasing GSH, reducing MDA and nitrotyrosine concentrations compared to positive control. The glycoside (1) showed a better effect than silymarin (standard) in ameliorating the formation of nitrotyrosine, Raf-1 kinase, c-JNK, and GSH. CONCLUSION AND IMPLICATION: Kaempferol glycosides isolated for the first time from C. odorata L. leaves exerted antioxidant and antiapoptotic effects via amelioration of oxidative stress and inhibition of Raf/MAPK pathway.

Assessment of Diabetic Retinopathy Vascular Density Maps.

PURPOSE: Optical coherence tomography (OCT) and OCTA were used for qualitative and quantitative assessment of retinal vascular density in superficial capillary plexus, deep capillary plexus, foveal avascular zone, and choroidal vascular density map. PATIENTS AND METHODS: This study included 64 eyes. Diabetics and control groups were recruited from an internal medicine clinic at Misr University for Science and Technology Hospital and asked to participate in this study. This study was designed as an observational and cross-sectional study in the period from 8/2018 to 8/2019. RESULTS: There was a decrease in choroidal vascular density in diabetic patients. There was a decrease in retinal thickness in diabetic patients and there were no significant differences in the retinal thickness between control subjects and patients with non-diabetic retinopathy (NDR). CONCLUSION: Our study suggests that OCTA can identify preclinical DR before the manifestation of clinically apparent retinopathy. Our findings also highlight the potential role of OCTA in monitoring and quantifying retinal vascular alterations in diabetics.

Multi-Omics and Targeted Approaches to Determine the Role of Cellular Proteases in Streptomyces Protein Secretion.

Gram-positive Streptomyces bacteria are profuse secretors of polypeptides using complex, yet unknown mechanisms. Many of their secretory proteins are proteases that play important roles in the acquisition of amino acids from the environment. Other proteases regulate cellular proteostasis. To begin dissecting the possible role of proteases in Streptomyces secretion, we applied a multi-omics approach. We probed the role of the 190 proteases of Streptomyces lividans strain TK24 in protein secretion in defined media at different stages of growth. Transcriptomics analysis revealed transcripts for 93% of these proteases and identified that 41 of them showed high abundance. Proteomics analysis identified 57 membrane-embedded or secreted proteases with variations in their abundance. We focused on 17 of these proteases and putative inhibitors and generated strains deleted of their genes. These were characterized in terms of their fitness, transcriptome and secretome changes. In addition, we performed a targeted analysis in deletion strains that also carried a secretion competent mRFP. One strain, carrying a deletion of the gene for the regulatory protease FtsH, showed significant global changes in overall transcription and enhanced secretome and secreted mRFP levels. These data provide a first multi-omics effort to characterize the complex regulatory mechanisms of protein secretion in Streptomyces lividans and lay the foundations for future rational manipulation of this process.

EFFECT OF SMOKING ON MACULAR FUNCTION AND STRUCTURE IN ACTIVE SMOKERS VERSUS PASSIVE SMOKERS.

PURPOSE: The aim is to study the effects of cigarette smoking on the structural and functional alterations of the macula in eyes of healthy young smokers. METHODS: Cross-sectional clinical study included 100 active smokers (Group 1) and 100 age- and sex-matched healthy passive smokers (Group 2). All participants underwent a complete ophthalmologic assessment, axial length measurement, central corneal thickness measurement, spectral domain optical coherence tomography, and multifocal electroretinogram. Urine samples were collected to measure urinary levels of cotinine and creatinine with subsequent calculation of the cotinine creatinine ratio. RESULTS: Central foveal thickness (255.62 ± 17.23 and 264.75 ± 17.35 µm, respectively, with P = 0.0003) and subfoveal choroidal thickness (377.48 ± 30.32 and 385.08 ± 21.10 µm, respectively, with P = 0.04) were significantly lower in active smokers than those of passive smokers. Retinal response density of ring 1 (31.08 ± 2.29 and 33.46 ± 3.83 nV/deg, respectively, with P < 0.001) and Ring 1 (R1) P1 amplitude (0.81 ± 0.07 and 0.95 ± 0.16 µV, respectively, with P < 0.001) were significantly lower, whereas R1 P1 latency (43.02 ± 0.97 and 40.39 ± 2.08 milliseconds, respectively, with P < 0.001) was significantly longer in active smokers than those of passive smokers. The mf-ERG ring ratios were significantly lower in the active smokers than those of passive smokers. CONCLUSION: In the absence of clinically apparent foveal toxicity, CFT, SFCT together with ring amplitude ratio could be used as good predictors of subclinical nicotine induced foveal changes.

Pattern Visual Evoked Potential, Pattern Electroretinogram, and Retinal Nerve Fiber Layer Thickness in Patients with Migraine during and after Aura.

PURPOSE: To study pattern visual evoked potential (PVEP), pattern electroretinogram (PERG), and retinal nerve fiber layer (RNFL) thickness in patients with migraine during and after aura. MATERIALS AND METHODS: We included 60 eyes of 60 patients with migraine (Group 1) and 30 healthy volunteers (30 eyes) as controls (Group 2). Group 1 was studied twice, during a visual aura (1-a) and in between attacks (1-b). All participants underwent full ophthalmological examination, PVEP, PERG, and optical coherence tomographyOCT imaging of the RNFL thickness for each patient. RESULTS: RNFL thickness was found to be thinner in patients during the aura compared to controls. It increased significantly post-aura but remained lower than the controls. Prolonged P100 latency and decreased amplitude were found in patients during aura compared to controls with significant change in between attacks to values comparable to the controls. We found prolonged N95 latency and decreased amplitude in patients during aura compared to controls with significant change post-aura to values comparable to the controls. There was positive correlation between average RNFL thicknesses and VA and spherical equivalent; but it showed negative correlation with duration of migraine, attack duration, and aura duration. Multiple regression analysis showed that the most important determinants of average RNFL thickness in patients of migraine were attack and aura duration (beta = -0.21 and -0.26 and p = 0.03 and 0.04, respectively). CONCLUSION: Migraine attacks impose both functional and structural retinal changes. The functional changes are fully reversible after the aura but not the structural ones. So, vigorous prevention of migraine attacks would be protective for retina.

Effect of Active and Passive Smoking on Retinal Nerve Fibre Layer and Ganglion Cell Complex.

Aim. To evaluate the possible structural and functional changes in the retinal nerve fibre layer (RNFL) and the ganglion cell complex (GCC) of chronic smokers and compare them with those of passive healthy smokers using spectral domain optical coherence tomography (SD-OCT) and pattern electroretinogram (PERG). Materials and Methods. We include 80 active chronic smokers and 80 age- and sex-matched healthy passive smokers. After a full ophthalmological examination, SD-OCT and PERG were tested for all participants. Urinary levels of cotinine and creatinine with subsequent calculation of the cotinine creatinine ratio (CCR). Results. Inferior and superior quadrants of RNFL were thinner in group I, but nasal and temporal quadrants did not show significant difference between the groups. There were no significant differences of GCC values between the two groups. There was no significant difference of PERG-P50 amplitude and latency; however, PERG-N95 showed significant difference between the two groups. Multiple regression analyses demonstrated that the number of cigarettes/day, urinary cotinine, and PERG-N95 amplitude are the most important determinants for both superior and inferior RNFL thicknesses. Conclusion. RNFL thickness decreases in chronic, healthy, heavy cigarette smokers, and this thinning is related to the number of cigarettes/day, urinary cotinine, and PERG-N95 latency and amplitude.

Relationship between functional and structural retinal changes in myopic eyes.

BACKGROUND: The aim of this study was to investigate the retinal structure in different grades of myopia and correlate it with the functional changes detected with multifocal electroretinogram (mf-ERG) and try to show the most important determining factors. METHODS: The study included 80 participants divided into four groups according to their spherical equivalent refractive error, namely, emmetropia (within ± 0.50 D), mild myopia group (greater than -0.50 to -3.00 D), moderate myopia group (more than -3.00 to -6.00 D) and high myopia group (greater than -6.00 D). Full ophthalmologic examination was performed for all participants, including visual acuity (VA), slitlamp examination, Goldmann applanation tonometry, indirect ophthalmoscopy, axial length (AL) measurement, retinal nerve fibre layer thickness assessment and mf-ERG stimulation. RESULTS: Axial length was significantly higher in myopes than emmetropes; also it was higher the greater the degree of myopia. There was a reduction in the amplitude and prolongation of implicit times of mf-ERG in myopia. Also P1 implicit time of the mf-ERG response was prolonged the greater the degree of myopia. The retinal nerve fibre layer was significantly thinner in myopic groups than the emmetropic group. The thinning of the retinal nerve fibre layer increased the more the degree of myopia. Multiple regression analysis of myopic patients showed that AL is the most important determinant of most of the mf-ERG five-rings retinal response density (RRD), mf-ERG four-quadrant (Q) RRD, most of the five-rings P1 amplitude and all five-rings latencies. The most important determinant factors of mean Q RRD were VA, AL and retinal nerve fibre layer thickness. CONCLUSION: The retina of the myope is subject to both structural and functional alterations compared to that of the emmetrope. Significant correlations exist between the functional and structural changes and can be explained on bases of longer AL and increasing myopic refraction.