Diminazene aceturate or losartan ameliorates the functional, radiological and histopathological alterations in knee osteoarthritis rodent model: repurposing of the ACE2/Ang1‐7/MasR cascade

Abstract Purpose Current therapies for osteoarthritis (OA) are limited to analgesics and anti‐inflammatory drugs. Considering the importance of oxidative stress and inflammatory mediators in OA etiology, we tested the hypothesis that targeting the renin–angiotensin–aldosterone system (RAAS) can improve OA anomalies. Diminazene (DIZE), an activator of angiotensin‐converting enzyme 2 and the angiotensin 2 type‐1 receptor blocker losartan (LOS) were used for this purpose. Methods OA was induced by a single intra‐articular injection of monosodium iodoacetate. The effects of exposure to DIZE or LOS for 21 days on OA anomalies in rats’ knees were investigated. Evaluation of motor function, nociception, and inflammatory response was done using rotarod, knee bend and knee swelling tests. Markers of knee joint inflammation, and cellular oxidation in addition to the RAAS biomarkers, were assessed in knee tissues, along with radiological and histopathological investigations. Results Elevations in inflammatory and oxidative markers in knee tissues of OA rats were mostly improved by the two therapeutic drugs. Such effect was also reflected in the rotarod, knee bend and knee swelling tests. Treatment with DIZE has shown a more prominent effect than LOS in controlling OA‐associated inflammation and cellular oxidation. Markers of RAAS have also shown better responsiveness to DIZE over LOS. Conclusions DIZE has shown a prominent increase in the angiotensin 1–7 amount, highlighting the involvement of the signaling pathway in the immunomodulatory effect. The radiological and histopathology examination came to confirm the outcome of biochemical markers, nominating diminazene aceturate as a possible therapeutic option for OA

The antidiabetic effect of superparamagnetic iron oxide nanoparticles highlights the role of WNT/AMPK/mTOR/FOXO1/mitochondrial DNA in muscle and kidney

[Aim]: To explore the antidiabetic effect of superparamagnetic iron oxide nanoparticles (SPIONs)-PEG-550 and its related metabolic pathways in muscles and kidney.[Materials & methods]: Diabetes was induced in 5-day neonatal rats; after confirming diabetes, treatment with SPIONs-PEG-550 started at different doses for 4 weeks. Routine analysis of glucose, insulin, adipocytokines, urea and creatinine was performed. The expression of several genes involved in metabolic pathways and the corresponding protein levels were examined.[Results & conclusion]: SPIONs-PEG-550 normalized the disturbed glucose homeostasis, reversed insulin resistance, adjusted the serum level of adipocytokines, and improved several disturbed downstream effectors of the insulin signaling and WNT pathway in both tissues. Histological examination of the muscle and pancreas has shown almost normal functional characteristics without remarkable adverse effects on the kidney.Peer reviewe

Propolis-loaded nanostructured lipid carriers halt breast cancer progression through miRNA-223 related pathways: an in-vitro/in-vivo experiment

Abstract The most frequent malignant tumor in women is breast cancer, and its incidence has been rising every year. Propolis has been used for its antibacterial, antifungal, and anti-inflammatory properties. The present study aimed to examine the effect of the Egyptian Propolis Extract (ProE) and its improved targeting using nanostructured lipid carriers (ProE-NLC) in Ehrlich Ascites Carcinoma (EAC) bearing mice, the common animal model for mammary tumors. EAC mice were treated either with 5-fluorouracil (5-FU), ProE, ProE-NLC, or a combination of ProE-NLC and 5-FU. Their effect on different inflammatory, angiogenic, proliferation and apoptotic markers, as well as miR-223, was examined. ProE and ProE-NLC have shown potential anti-breast cancer activity through multiple interrelated mechanisms including, the elevation of antioxidant levels, suppression of angiogenesis, inflammatory and mTOR pathways, and induction of the apoptotic pathway. All of which is a function of increased miRNA-223 expression. The efficiency of propolis was enhanced when loaded in nanostructured lipid carriers, increasing the effectiveness of the chemotherapeutic agent 5-FU. In conclusion, this study is the first to develop propolis-loaded NLC for breast cancer targeting and to recommend propolis as an antitumor agent against breast cancer or as an adjuvant treatment with chemotherapeutic agents to enhance their antitumor activity and decrease their side effects. Tumor targeting by ProE-NLC should be considered as a future therapeutic perspective in breast cancer

Morin suppresses mTORc1/IRE-1α/JNK and IP3R-VDAC-1 pathways: Crucial mechanisms in apoptosis and mitophagy inhibition in experimental Huntington's disease, supported by in silico molecular docking simulations

Aims: Endoplasmic reticulum stress (ERS) with aberrant mitochondrial-ER contact (MERC), mitophagy, and apoptosis are interconnected determinants in neurodegenerative diseases. Previously, we proved the potential of Morin hydrate (MH), a potent antioxidant flavonoid, to mitigate Huntington’s disease (HD)-3-nitropropionic acid (3-NP) model by modulating glutamate/calpain/Kidins220/BDNF trajectory. Extending our work, we aimed to evaluate its impact on combating the ERS/MERC, mitophagy, and apoptosis. Methods: Rats were subjected to 3-NP for 14 days and post-treated with MH and/or the ERS inducer WAG-4S for 7 days. Disease progression was assessed by gross inspection and striatal biochemical, histopathological, immunohistochemical, and transmission electron microscopical (TEM) examinations. A molecular docking study was attained to explore MH binding to mTOR, JNK, the kinase domain of IRE1-α, and IP3R. Key findings: MH decreased weight loss and motor dysfunction using open field and rotarod tests. It halted HD degenerative striatal neurons and nucleus/mitochondria ultra-microscopic alterations reflecting neuroprotection. Mechanistically, MH deactivated striatal mTOR/IRE1-α/XBP1s&JNK/IP3R, PINK1/Ubiquitin/Mfn2, and cytochrome c/caspase-3 signaling pathways, besides enhancing p-PGC-1α and p-VDAC1. WAG-4S was able to ameliorate all effects initiated by MH to different extents. Molecular docking simulations revealed promising binding patterns of MH and hence its potential inhibition of the studied proteins, especially mTOR, IP3R, and JNK. Significance: MH alleviated HD-associated ERS, MERC, mitophagy, and apoptosis. This is mainly achieved by combating the mTOR/IRE1-α signaling, IP3R/VDAC hub, PINK1/Ubiquitin/Mfn2, and cytochrome c/caspase 3 axis to be worsened by WAG-4S. Molecular docking simulations showed the promising binding of MH to mTOR and JNK as novel identified targets. Citation: Mohamed A. El-Emam, Eman Sheta, Hanan S. El-Abhar, Dalaal M. Abdallah, Ahmed M. El Kerdawy, Wagdy M. Eldehna, Mennatallah A. Gowayed, Morin suppresses mTORc1/IRE-1α/JNK and IP3R-VDAC-1 pathways: Crucial mechanisms in apoptosis and mitophagy inhibition in experimental Huntington's disease, supported by in silico molecular docking simulations, Life Sciences, Volume 338, 2024, 122362, ISSN 0024-3205, https://doi.org/10.1016/j.lfs.2023.122362.</p