Developmentally-regulated localization and possible functions of HRP-3 in the murine nervous tissue

HRP-3 is presented here as a hepatoma-derived growth factor family member that exhibits a unique expression pattern. Its expression is shown here to be restricted to the nervous system from the very early stages in the embryonic life until the adulthood. Interestingly, HRP-3 is restricted to neurons and shows a developmental stage-dependent expression pattern in cortical and sensory neurons both in vivo and in primary culture models prepared from both cell types in vitro. HRP-3 is expressed in the extranuclear compartment in embryonic nervous tissue and almost restricted to the nuclear compartment in the adult mouse nervous tissue. The second part of this work focused on the possible intracellular and extracellular roles of HRP-3. It was possible to prove that the intracellular level of HRP-3 plays an important role in promoting neurite outgrowth and neuronal cell sprouting. Reducing the intracellular level of HRP-3 in one of the primary cell culture models using synthetic siRNAs against HRP-3 resulted in negative effects on neuronal cell differentiation. This effect was reversed by over-expressing HRP-3 within an inducible neuronal cell model. The nuclear localising signal located in the carboxy terminus (NLS2) of HRP-3 is the one responsible for its nuclear localisation while the nuclear localising signal located in its amino terminus (NLS1) is the one responsible for its neurite outgrowth promoting effect. These effects of HRP-3 are mediated through its interaction with microtubules as shown in studies based partially on this work. The results also show that extracellular HRP-3 has a positive effect on the differentiation of primary cortical neurons. It is also released by cortical neurons themselves to promote their own survival and differentiation and can protect primary cortical neurons cultured in stressful, supplement-free conditions. Together, the results point to interesting roles of HRP-3 during the development of the nervous system. This work can be the basis for further interesting studies that may include an explanation of the molecular mechanisms through which it exerts its roles, like detecting the receptor through which HRP-3 signals and the signalling transduction pathways that result in these effects.Die vorgestellte Arbeit befasst sich mit HRP-3 einem Mitglied der Hepatomaderived growth factor Proteinfamilie (HDGF, LEDGF und HRP1-4). Im ersten Teil wird die differentielle Regulation der HRP-3-Expression in der Maus als Modellorganismus näher beschrieben. Dabei zeigt sich, dass die HRP-3-Expression weitestgehend auf Neurone beschränkt ist. Dabei sind interessanterweise bestimmte Neuronenpopulationen – Körnerzellen des Kleinhirns und Hypothalamus – von der Expression ausgenommen. Darüber hinaus wird in der Arbeit eine interessante Veränderung in der intrazellulären Lokalisation von HRP-3 von einer extranukleären Lokalisation im embryonalen Nervensystem zu einer nahezu vollständig nukleären in der adulten Maus beschrieben. In zwei Zellkulturmodellen von primären Neuronen kann diese Veränderung der HRP-3-Lokalisation in Vitro nachvollzogen werden. Der zweite Teil der Arbeit ist auf mögliche Funktionen von HRP-3 fokussiert. Da die Mitglieder der HDGF-Proteinfamilie auch sezerniert werden, wird dabei zunächst zwischen Funktionen von intrazellulärem und extrazellulärem HRP-3 unterschieden. Durch die Reduktion der HRP-3-Menge mit Hilfe von kleinen synthetischen RNAs konnte in einem der primären Neuronenmodelle eine Beteiligung von HRP-3 an der Differenzierung der Nervenzellen in Kultur nachgewiesen werden. Eine Überexpression in einem induzierbaren neuronalen Differenzierungsmodell bestätigte diese Beobachtung. In Studien, die teilweise über diese Arbeit hinausgehen, konnte gezeigt werden, dass die Interaktion von HRP-3 mit Komponenten des Zytoskeletts wichtig für diese Funktion von intrazellulärem HRP-3 ist. Weiterhin zeigen die Ergebnisse dieser Arbeit, dass extrazelluläres HRP-3 ebenfalls einen positiven Einfluss auf die Differenzierung von Neuronen hat. Darüber hinaus hat das Protein eine starke protektive Wirkung auf diese Zellen unter Kulturbedingungen die suboptimal sind und daher eine Art neuronale Stressbedingung darstellen. Insgesamt deuten die Ergebnisse dieser Arbeit auf eine interessante Rolle von HRP-3 während der Entwicklung des Nervensystems hin und bilden die Grundlage für weitere Studien, die die Aufklärung der genauen Mechanismen dieser Wirkungen, wie zum Beispiel mögliche HRP-3-Rezeptoren und Signaltransduktionswege, zum Ziel haben werden

Diagnostic utility of leptin and insulin-like growth factor binding protein-2 in hepatocellular carcinoma of diabetic and non-diabetic Egyptian patients

Purpose: To elucidate the possible diagnostic utility of adipokines and insulin growth factor binding proteins in hepatocellular carcinoma (HCC) diabetic subjects.Methods: Seventy five patients were divided equally into 3 groups as follows: healthy normal control (NC), non-diabetic hepatocellular carcinoma (HCC) and diabetic hepatocellular carcinoma (HCC-DM). Serum levels of leptin, insulin growth factor binding protein-2 (IGFBP-2) and alpha fetoprotein (AFP) were measured. Correlation and receiver operating characteristics (ROC) analysis was carried out.Results: HCC and HCC-DM groups showed changes in body mass index (BMI, p > 0.05 and p < 0.001 respectively), glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), liver function tests and AFP (p < 0.001). Leptin levels increased significantly in both HCC and HCC-DM (p < 0.001). Furthermore, IGFBP-2 showed significant increase in both groups (p < 0.001). Both leptin and insulin-like growth factor binding protein-2 (IGFBP-2) displayed significant positive correlation with AFP (p < 0.001). ROC analysis indicate different diagnostic accuracies for the tested markers for the various groups.Conclusion: Leptin and IGFBP-2 demonstrate significant potentials as diagnostic tools for HCC patients, especially diabetic cases, with IGFBP-2 displaying the highest diagnostic accuracy for HCC and HCC-DM groups.Keywords: Hepatocellular carcinoma, Diabetes mellitus, Leptin, Insulin-like growth factor-binding proteins-2, Adipokine

Comparative Analysis of Intralesional Immunotherapy and Conventional Treatments for Non-Genital Warts: A Systematic Review and Network Meta-Analysis

Introduction: Warts, benign skin growths caused by various human papillomavirus strains, are categorized as genital and non-genital. Non-genital warts often lack noticeable symptoms but can lead to psychological distress due to factors like embarrassment. Traditional treatments, including physical and chemical methods, show limitations, prompting the exploration of novel approaches like intralesional immunotherapy. The clinical challenge lies in selecting the most effective modality. Objective: In our study, we used the network meta-analysis (NMA) as a statistical tool to explore the most effective intralesional immunotherapy interventions. Methods: Comprehensive searches of Web of Science, PubMed, Cochrane, and Scopus databases were conducted until December 2023. Eligible studies were analyzed for outcomes presented as risk ratios (RRs) with 95% confidence intervals (CI). Treatments were ranked using the P-score in an NMA performed with R software. Results: We included 68 RCTs in our study. For complete response, needling showed a significant difference compared to Candida albicans antigen (RR= 0.13, 95% CI [0.02; 0.99]) and Mw (RR= 0.12, 95% CI [0.02; 0.94]). In overall response, both bleomycin and furosemide with digoxin were significant compared to autoimplantation (RR= 0.46, 95% CI [0.24; 0.88]) and (RR= 0.40, 95% CI [0.18; 0.91]) respectively. Similarly, both were significant compared to cryotherapy (RR= 0.45, 95% CI [0.27; 0.76]) and (RR= 0.40, 95% CI [0.19; 0.82]) respectively. Conclusion: This NMA indicates needling, furosemide with digoxin, and PBP antigen stimulants as effective for non-genital warts, surpassing traditional treatments in complete and overall response. Direct comparisons in future research are warranted to confirm their superiority

Improvement of solubility, dissolution, and bioavailability of phenytoin intercalated in Mg-Al layered double hydroxide

Layered double hydroxides (LDHs) are highly effective drug delivery systems, owing to their capacity to intercalate or adsorb biomaterials, flexible structure, swelling property, high stability, good biocompatibility, and ease of synthesis. Phenytoin (PHT) is an antiseizure BCS (Biopharmaceutics Classification System) class II drug, presenting low aqueous solubility. Therefore, the current study aimed at increasing its solubility, dissolution, and bioavailability. PHT was intercalated to the MgAl-LDH formed in situ and successful intercalation to form MgAl-PHT-LDH was confirmed by FTIR, PXRD, DSC, and TGA. Examination of particle size and morphology (by photon correlation spectroscopy and electron microscopy, respectively) confirmed the formation and intercalation of nanostructured LDH. Intercalation enhanced the saturation solubility of PHT at 25°C in 0.1N HCl and phosphate buffer (pH 6.8) by 6.57 and 10.5 times respectively. The selected drug excipient powder blend for the formulation of MgAl-PHT-LDH tablets exhibited satisfactory properties in both pre-compression parameters (angle of repose, bulk density, tapped density, Carr’s index, and Hausner ratio) and tablet characteristics (weight variation, thickness, hardness, friability, content uniformity, and disintegration time). MgAl-PHT-LDH tablets showed better dissolution of PHT compared to unprocessed PHT tablets at all time points. Oral bioavailability of MgAl-PHT-LDH tablets and unprocessed PHT tablets was tested in two groups of Sprague Dawley rats based on analysis of serum levels of both forms of PHT by UPLC-ESI-MS/MS serum. MgAl-PHT-LDH tablets demonstrated a relative bioavailability of 130.15% compared to unprocessed PHT tablets, confirming a significantly higher oral bioavailability of MgAl-PHT-LDH. In conclusion, MgAl-PHT-LDH could provide a strategy for enhancing solubility, dissolution, and thereby bioavailability of PHT, enabling the evaluation of theclinical efficacy of MgAl-PHT-LDH tablets for the treatment of seizures at lower PHT doses

Evaluating the Safety and Efficacy of Malaria Preventive Measures in Pregnant Women with a Focus on HIV Status: A Systematic Review and Network Meta-Analysis

Background and Objectives: Malaria poses significant threats to pregnant women, particularly in endemic regions. Preventive measures against it include insecticide-treated bed nets, intermittent preventive treatment, and various supplements. We aimed to assess and compare the safety and effectiveness of malaria preventive measures in pregnant women, considering their HIV status. Methods: We conducted a systematic search of PubMed, the Cochrane Library, Scopus, Embase, and Web of Science through January 2024. A network meta-analysis was performed using R 4.3.3 software on 35 studies (50,103 participants). Results: In HIV-positive pregnant women, Co-trimoxazole with dihydroartemisinin significantly reduced malaria incidence compared to Co-trimoxazole alone (RR = 0.45, 95% CI [0.30; 0.68]) and sulfadoxine–pyrimethamine (SP) (RR = 0.14, 95% CI [0.04; 0.48]). Mefloquine was also effective compared to controls and SP. In HIV-negative women, azithromycin–piperaquine significantly reduced infections compared to SP, bed nets, and controls (RR = 0.03, 95% CI [0.00; 0.83]; RR = 0.03, 95% CI [0.00; 0.86]; and RR = 0.03, 95% CI [0.00; 0.77], respectively). Conclusion: Different combinations of preventive measures show varying effectiveness based on HIV status. Co-trimoxazole with dihydroartemisinin and mefloquine are effective for HIV-infected pregnant women, while azithromycin–piperaquine and mefloquine work well for those without HIV. Customized prevention strategies considering HIV status are crucial for optimal protection