Exploring the molecular mechanisms of MSC-derived exosomes in Alzheimer's disease: Autophagy, insulin and the PI3K/Akt/mTOR signaling pathway.

Alzheimer's disease (AD) is a devastating neurological condition characterized by cognitive decline, motor coordination impairment, and amyloid plaque accumulation. The underlying molecular mechanisms involve oxidative stress, inflammation, and neuronal degeneration. This study aimed to investigate the therapeutic effects of mesenchymal stem cell-derived exosomes (MSC-exos) on AD and explore the molecular pathways involved, including the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation. To assess the potential of MSC-exos for the treatment of AD, rats were treated with AlCl3 (17 mg/kg/once/day) for 8 weeks, followed by the administration of an autophagy activator (rapamycin), or MSC-exos with or without an autophagy inhibitor (3-methyladenin; 3-MA+ chloroquine) for 4 weeks. Memory impairment was tested, and brain tissues were collected for gene expression analyses, western blotting, histological studies, immunohistochemistry, and transmission electron microscopy. Remarkably, the administration of MSC-exos improved memory performance in AD rats and reduced the accumulation of amyloid-beta (Aß) plaques and tau phosphorylation. Furthermore, MSC-exos promoted neurogenesis, enhanced synaptic function, and mitigated astrogliosis in AD brain tissues. These beneficial effects were associated with the modulation of autophagy and the PI3K/Akt/mTOR signalling pathway, as well as the inhibition of neuroinflammation. Additionally, MSC-exos were found to regulate specific microRNAs, including miRNA-21, miRNA-155, miRNA-17-5p, and miRNA-126-3p, further supporting their therapeutic potential. Histopathological and bioinformatic analyses confirmed these findings. This study provides compelling evidence that MSC-exos hold promise as a potential therapeutic approach for AD. By modulating the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation, MSC-exos have the potential to improve memory, reduce Aß accumulation, enhance neurogenesis, and mitigate astrogliosis. These findings shed light on the therapeutic potential of MSC-exos and highlight their role in combating AD.

Bio-study: Modeling of natural nanomolecules as a nanocarrier surface for antioxidant and glucose biosensor.

The nature of nano molecules as a self-assembled nanocomposite surface depends on the nanoparticles of sodium butyrate, cellulose, and pycnogenol; the synthesis is achieved via precipitation and grinding methods. The excellent functionalized surface of nanocomposite (NCP) enables the loading of the selected drugs, where the efficiency of the NCP surface arrived at 92.2 %. The electrochemical behavior emphasized the success of a functionalized NCP surface for incorporation with drugs for the drug delivery system, the results of cytotoxicity detect the effect of NCP on the mouse normal liver (BNL) cells, where the high and low concentrations on the BNL cells have a safe dose. Cell viability with BNL cells was reported at 101.8 % with10 µL and 100.12 % with 100 µL, the interaction between the NCP and the human serum albumin (HSA) at room temperature. The low interaction rate with the glutamate and increased binding with the oxidized glutathione disulfide (GSSG) and reduced glutathione (SGH) reflect the antioxidant activity of NCP. The strong binding of NCP with biomolecules such as glucose is referred to as the biosensor property. The results recommend that NCP is an excellent nanocarrier for drug delivery and glucose biosensors for diabetes.

Preparation and Characterization of Novel Polyelectrolyte Liposomes Using Chitosan Succinate Layered over Chitosomes: A Potential Strategy for Colon Cancer Treatment.

Chitosan succinate is distinguished by its ability to shield the loaded drug from the acidic environment, localize and keep the drug at the colon site, and release the drug over an extended time at basic pH. The current study attempts to develop polyelectrolyte liposomes (PEL), using chitosan and chitosan succinate (CSSC), as a carrier for liposomal-assisted colon target delivery of 5 fluorouracil (5FU). The central composite design was used to obtain an optimized formulation of 5FU-chitosomes. The chitosan-coated liposomes (chitosomes) were prepared by thin lipid film hydration technique. After that, the optimized formulation was coated with CSSC, which has several carboxylic (COOH) groups that produce an anionic charge that interacts with the cation NH2 in chitosan. The prepared 5FU-chitosomes formulations were evaluated for entrapment efficiency % (EE%), particle size, and in vitro drug release. The optimized 5FU-chitosomes formulation was examined for particle size, zeta potential, in vitro release, and mucoadhesive properties in comparison with the equivalent 5FU-liposomes and 5FU-PEL. The prepared 5FU-chitosomes exhibited high EE%, small particle size, low polydispersity index, and prolonged drug release. PEL significantly limited the drug release at acidic pH due to the deprotonation of carboxylate ions in CSSC, which resulted in strong repulsive forces, significant swelling, and prolonged drug release. According to a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, PEL treatment significantly decreased the viability of HT-29 cells. When compared to 5FU-liposome and 5FU-chitosome, the in vivo pharmacokinetics characteristics of 5FU-PEL significantly (p < 0.05) improved. The findings show that PEL enhances 5FU permeability, which permits high drug concentrations to enter cells and inhibits the growth of colon cancer cells. Based on the current research, PEL may be used as a liposomal-assisted colon-specific delivery.

Case Report of Renal Calculi in a Child Receiving Imatinib for Acute Lymphoblastic Leukemia.

Rationale: Imatinib is used in the treatment of Philadelphia chromosome positive (Ph+) leukemias and has been reported to have a direct effect on bone physiology. Presentation: To report on a child with Ph+ acute lymphoblastic leukemia who presented with bilateral flank pain and gross hematuria. Diagnosis: She was diagnosed with obstructive kidney stones 101 days after commencing daily oral imatinib. Stone analysis revealed the presence of calcium phosphate. Interventions and outcome: The patient passed the stones spontaneously with medical therapy that included the use of thiazide, allopurinol, and potassium citrate, but she required temporary insertion of a double-J stent to relieve an obstruction. Novel findings: Imatinib inhibits receptor tyrosine kinases and stimulates the flux of calcium from the extracellular fluid into bone, resulting in hypocalcemia with a compensatory rise in parathyroid hormone that may result in phosphaturia and the formation of calcium phosphate stones. Given that kidney stones are rare events in children, we believe that monitoring for kidney stone formation needs to be performed in children receiving imatinib.

Justification: L'imatinib est utilisé dans le traitement des leucémies à chromosome Philadelphie (Ph+) et a été décrit comme ayant un effet direct sur la physiologie osseuse. Présentation du cas: Une enfant atteinte d'une leucémie lymphoblastique aiguë à Ph+ présentant des douleurs lombaires bilatérales et une hématurie macroscopique. Diagnostic: La patiente a reçu un diagnostic de calculs rénaux obstructifs 101 jours après avoir commencé la prise quotidienne d'imatinib par voie orale. L'analyse des calculs a révélé la présence de phosphate de calcium. Interventions et résultats: La patiente a éliminé spontanément ses calculs grâce à un traitement médical qui comprenait un diurétique thiazidique, de l'allopurinol et du citrate de potassium, mais on a dû lui insérer temporairement une endoprothèse double J pour traiter une obstruction. Nouveaux enseignements: L'imatinib inhibe les récepteurs de la tyrosine kinase et favorise le flux du calcium du liquide extracellulaire vers les os, ce qui entraîne une hypocalcémie avec élévation secondaire de l'hormone parathyroïdienne pouvant provoquer une phosphaturie et la formation de calculs de phosphate de calcium. Puisque la formation de calculs rénaux est rare chez les enfants, nous pensons qu'elle devrait faire l'objet d'une surveillance chez les enfants qui reçoivent de l'imatinib.

Ginger Oil Nanoemulsion Formulation Augments Its Antiproliferative Effect in Ehrlich Solid Tumor Model.

Cancer is a disease that is characterized by uncontrolled cell proliferation. Breast cancer is the most prevalent cancer among women. Ginger oil is a natural cancer fighter and anti-oxidant. However, the minimal absorption of ginger oil from the gastrointestinal tract accounts for its limited medicinal efficacy. The present study was designed to evaluate the efficacy of a nanoemulsion preparation of ginger oil on its oral bioavailability and in vivo anti-cancer efficacy. Ginger oil nanoemulsion was prepared by a high-pressure homogenization technique using different surfactants (Tween 20, 40, and 80). The prepared formulations were evaluated for droplet size, polydispersity index (PDI), zeta potential (ZP), pH, viscosity, and stability by calculating the creaming index percentage. The best formulation was evaluated for shape by TEM. The antitumor activity of the best nano-formulation was determined in comparison with the free oil using the in vivo Ehrlich solid tumor (EST) model. The prepared ginger oil nanoemulsion formulations exhibited acceptable droplet size in the range from 56.67 ± 3.10 nm to 357.17 ± 3.62 nm. A PDI of less than 0.5 indicates the homogeneity of size distribution. The oil globules possessed a negative charge ranging from -12.33 ± 1.01 to -39.33 ± 0.96 mV. The pH and viscosity were in the acceptable range. The TEM image of the best formulation appeared to be spherical with a small size. The ginger oil nanoemulsion reduced in vivo tumor volume and weight, extended animals' life span, and ameliorated liver and kidney function in EST-bearing mice. These effects were superior to using free ginger oil. Collectively, the present study demonstrated that the ginger oil nanoemulsion improved oral absorption with a subsequent enhancement of its anti-proliferative efficacy in vivo, suggesting a nano-formulation of ginger oil for better therapeutic outcomes in breast cancer patients.

Interleukin-37 has A Promising Cardioprotective Effect on Isoproterenol-Induced Myocardial Infarction / La Interleucina-37 tiene un Efecto Cardioprotector Prometedor sobre el Infarto de Miocardio Inducido por Isoproterenol

SUMMARY: The main cause of mortality and disability globally is myocardial infarction (MI). Isoproterenol (ISO), a β-adrenoceptor agonist, has been used to induce rat myocardial necrosis. Whereas interleukin-37 (IL-37) has anti-inflammatory and cytoprotective properties. The study aimed to investigate the potential protective effects of IL-37 administration on cardiac architecture, oxidative stress, and inflammatory markers during ISO-induced MI in rats. Three groups of adult male rats were used in this study, the normal control group (n=8), ISO-induced MI group (n=8) that received isoproterenol hydrochloride (ISO) (100 mg/kg/day, SC, for the first 2 consecutive days), and IL-37-treated group (ISO+IL-37) (n=8) that received recombinant human IL-37 (40 µg/kg /day, intraperitoneally, for 2 weeks during and after ISO injections. Heart rate (HR.) and ECG changes were monitored. Some oxidative stress markers such as superoxide dismutase (SOD), nitric oxide (NOx), malondialdehyde (MDA), and glutathione (GSH) tissue levels in the tissue homogenate were assayed. Interleukin- 6 (IL-6), tumor necrosis factor- α (TNF-α), caspase-8, P53, and C- reactive protein (CRP) were among the inflammatory markers examined. In addition, serum levels of creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) were analyzed to evaluate the myocardial injury. For histological analysis, tissues were sectioned, fixed in paraffin, and stained with hematoxylin and eosin (H&E), Masson Trichrome and, immunohistochemical against NF-kB, TNF-α, and Caspase-9. IL-37 improved ECG changes, cardiac enzyme markers, and some inflammatory markers of oxidative stress in ISO-induced MI. It also improved the histopathological and immunohistochemical changes in MI. In conclusion: IL-37 might be a promising therapeutic modality in myocardial infarction.

La principal causa de mortalidad y discapacidad a nivel mundial es el infarto de miocardio (IM). El isoproterenol (ISO), un agonista de los receptores adrenérgicos β, se ha utilizado para inducir necrosis miocárdica en ratas. Mientras que la interleucina-37 (IL-37) tiene propiedades antiinflamatorias y citoprotectoras. El estudio tuvo como objetivo investigar los posibles efectos protectores de la administración de IL-37 en la arquitectura cardíaca, el estrés oxidativo y los marcadores inflamatorios durante el infarto de miocardio inducido por ISO en ratas. En este estudio se utilizaron tres grupos de ratas macho adultas, el grupo control normal (n=8), el grupo con IM inducido por ISO (n=8) que recibió clorhidrato de isoproterenol (ISO) (100 mg/kg/día, SC, durante los primeros 2 días consecutivos) y el grupo tratado con IL-37 (ISO+IL- 37) (n=8) que recibió IL-37 humana recombinante (40 µg/kg/día, por vía intraperitoneal, durante 2 semanas durante y después de las inyecciones de ISO. Se monitorearon la frecuencia cardíaca (FC) y los cambios en el ECG. Se analizaron algunos marcadores de estrés oxidativo como la superóxido dismutasa (SOD), el óxido nítrico (NOx), el malondialdehído (MDA) y los niveles tisulares de glutatión (GSH) en el homogeneizado de tejido. La interleucina-6 (IL-6), el factor de necrosis tumoral-α (TNF-α), la caspasa-8, la P53 y la proteína C reactiva (CRP) se encontraban entre los marcadores inflamatorios examinados. Se analizaron los niveles de creatinoquinasa (CK-MB) y lactato deshidrogenasa (LDH) para evaluar la lesión miocárdica; para el análisis histológico se seccionaron los tejidos, se fijaron en parafina y se tiñeron con hematoxilina y eosina (H&E), Tricromo de Masson e inmunohistoquímica contra NF-kB, TNF-α y Caspasa-9. IL-37 mejoró los cambios de ECG, los marcadores de enzimas cardíacas y algunos marcadores inflamatorios de estrés oxidativo en el IM inducido por ISO. Además mejoró los cambios histopatológicos e inmunohistoquímicos en MI. En conclusión: la IL-37 podría ser una modalidad terapéutica prometedora en el infarto de miocardio.

Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson's Disease.

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 µM, followed by IHC2 (IC50 = 16.934 µM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 µM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 µM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND: Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells' (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities. OBJECTIVES: This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/ß-catenin pathway that causes fibrotic liver. MATERIALS AND METHODS: BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 106 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out. RESULTS: In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group (p < 0.05). Moreover, the expression of inflammatory markers (TGFß1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (ß-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone (p < 0.05). CONCLUSION: Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.

Targeted Drug Administration onto Cancer Cells Using Hyaluronic Acid-Quercetin-Conjugated Silver Nanoparticles.

Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.

Curcumin and vitamin C improve immunity of kidney via gene expression against diethyl nitrosamine induced nephrotoxicity in rats:In vivo and molecular docking studies.

Kidney has a crucial role in immunity, so any toxicity occurs for the kidney will result in reduced immunity. The aim of this study is to improve the immune response of insufficient kidneys through immune-related genes. Diethyl Nitrosamine has been used to cause kidney damage in animal models, vitamin C and curcumin have been used to treat impaired kidney. Renal function (urea, uric acid and creatinine) and oxidative stress parameters (superoxide dismutase, malondialdehyde and glutathione peroxidase) will be evaluated in this research work. Molecular docking also will be performed to investigate the role of vitamin C and curcumin in targeting immune response proteins. Also, Complementary component 3, Lipocalin-2, Toll-like receptor 2,Toll-like receptor 4, Kidney injury molecule-1, Interleukin 6, Interleukin-10, Tumor necrosis factor and p38 mitogen-activated protein kinases will be investigated. The obtained results showed that vitamin C and curcumin have good effects in the treatment of impaired kidneys, this was also observed in renal function and oxidative stress parameters, expression levels of proteins and histopathological examinations.

Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer.

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.

The Combined Anti-Tumor Efficacy of Bioactive Hydroxyapatite Nanoparticles Loaded with Altretamine.

In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known fact that HA has great biological compatibility was confirmed through the findings of the hemolytic experiments and a maximum IC50 value seen in the MTT testing. The preparation of HA-NPs was performed using the chemical precipitation process. An in vitro release investigation was conducted, and the results demonstrated the sustained drug release of the altretamine-loaded hydroxyapatite nanoparticles (ALT-HA-NPs). Studies using the JURKAT E6.1 cell lines MTT assay, and cell uptake, as well as in vivo pharmacokinetic tests using Wistar rats demonstrated that the ALT-HA-NPs were easily absorbed by the cells. A putative synergism between the action of the Ca2+ ions and the anticancer drug obtained from the carrier was indicated by the fact that the ALT-HA-NPs displayed cytotoxicity comparable to the free ALT at 1/10th of the ALT concentration. It has been suggested that a rise in intracellular Ca2+ ions causes cells to undergo apoptosis. Ehrlich's ascites model in Balb/c mice showed comparable synergistic efficacy in a tumor regression trial. While the ALT-HA-NPs were able to shrink the tumor size by six times, the free ALT was only able to reduce the tumor volume by half.

Oil-in-Water Nanoemulsion Can Modulate the Fermentation, Fatty Acid Accumulation, and the Microbial Population in Rumen Batch Cultures.

In this study, three oil-in-water nanoemulsions were tested in two stages: In the first stage, three levels (on the substrate dry matter (DM)), namely 3%, 6%, and 9%, of three different oils, olive oil (OO), corn oil (CO), and linseed oil (LO), in raw and nanoemulsified (N) forms were used separately in three consecutive rumen batch cultures trials. The second stage, which was based on the first stage's results, consisted of a batch culture trial that compared the raw and nanoemulsified (N) forms of all three oils together, provided at 3% of the DM. In the first stage, NOO, NCO, and NLO preserved higher unsaturated fatty acid (UFA) and less saturated fatty acid (SFA) compared to OO, CO, and LO, respectively; noticeably, NCO had UFA:SFA = 1.01, 1.16, and 1.34 compared to CO, which had UFA:SFA = 0.66, 0.69, and 0.72 when supplemented at 3%, 6%, 9% of DM, respectively. In the second stage, UFA:SFA = 1.04, 1.12, and 1.07 for NOO, NCO, NLO, as compared to UFA:SFA = 0.69, 0.68, and 0.72 for OO, CO, and LO supplemented at 3% of DM. In conclusion, oil-in-water nanoemulsions showed an ability to decrease the transformation of UFA to SFA in the biohydrogenation environment without affecting the rumen microorganisms.

Nifuroxazide mitigates doxorubicin-induced cardiovascular injury: Insight into oxidative/NLRP3/GSDMD-mediated pyroptotic signaling modulation.

Doxorubicin (DOX) is a widely used powerful anthracycline for treatment of many varieties of malignancies; however its cumulative and dose-dependent cardio-toxicity has been limited its clinical use. In the current study, in vivo and in vitro (neonatal rat's cardiomyocytes) experiments were conducted to identify the impact of nifuroxazide (NIFU) on DOX-induced cardiomyopathy, vascular injury, and hemato-toxcity and plot the underlying regulatory mechanisms. Cardiovascular injury was induced in vivo by I.P. injection of an overall dose of DOX (21 mg/kg) administered (3.5 mg/kg) twice weekly for 21 days. NIFU (10 and 30 mg/kg) was administered orally once daily for 21 days, 1 week after DOX injection initiation. In vivo experiments confirmed NIFU to restore blood cells counts and hemoglobin concentration. Moreover, NIFU normalized the myocardial functional status as confirmed by ECG examination and myocardial injury markers; CK-MB, LDH, and AST. NIFU restored the balance between TAC and both of ROS and MDA and down-regulated the protein expression of TLR4, NF-kB, TXNIP, NLR-family pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, and GSDMD-N terminal, with inhibition of the up-stream of NLRP3 and the down-stream DOX-induced pyroptosis. The in vitro assay confirmed well preserved cardiomyocytes' architecture, amelioration of NLRP3/IL-1 ß-mediated cell pyroptosis, enhanced cell viability, and improved spontaneous beating. Moreover, NIFU normalized the disturbed aortic oxidant-antioxidant balance; enhanced eNOS- mediated endothelial relaxation, and down regulated IL-1ß expression. Thus, NIFU may be proposed to serve as a cardioprotective agent to attenuate DOX-induced cardio-toxicity and vascular injury.

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain.

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1ß) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.

Feeding Corn Oil in a Nanoemulsified Form Alters the Unsaturated Fatty Acids in the Milk of Zaraibi Dairy Goats.

Oil in water nanoemulsion represents a new and unstudied form of oil supplementation to the ruminant diet; that is why the aim was to evaluate the potential of nanoemulsified corn oil in dairy goats' diets on milk productivity and fatty acid proportion. Twenty-four lactating Zaraibi goats in early lactation were randomly allocated to the following treatments: control-a basal diet without any supplementation, CO-the control diet + corn oil supplied at 3% on a dry matter basis (DM), NCO-the control diet + nanoemulsified corn oil provided at 3% on a DM basis. A completely randomized design that lasted 30 days (25 days of adaptation + 5 days of sampling) was used with eight goats in each treatment. The control diet consisted of 50% concentrate and 50% Egyptian berseem clover. The NCO increased the milk production, fat percentage, and yield compared to the CO and the control. The proportions of oleic, linoleic, and linolenic acids were higher in the NCO compared to the control and CO. The NCO had less effect on the biohydrogenation intermediates' profile than the CO; noticeably, higher proportions of unsaturated fatty acid (UFA) were associated with the NCO. In conclusion, the NCO increased milk production and decreased the transformation rate of UFA to saturated fatty acids in the biohydrogenation environment.

Canagliflozin interrupts mTOR-mediated inflammatory signaling and attenuates DMBA-induced mammary cell carcinoma in rats.

BACKGROUND: Breast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study was designed to investigate the anti-cancer effect of Canagliflozin (CNG) in an experimental model of DMBA-induced mammary carcinoma in female rats. METHODS: 18 female rats were divided into three experimental groups: Normal control, DMBA control, DMBA+ CNG treated group. DMBA (7.5 mg/kg) was injected subcutaneously in the mammary cells twice weekly for 4 weeks and CNG (10 mg/kg) was orally administered daily for an additional 3 weeks while DMBA control rats only received the vehicle for 3 weeks. Tumors' weight and volume were measured, BRCA-1 and TAC were quantified in serum samples, mTOR, caspase-1, NFκB, IL-1ß, NLRP3, GSDMD and MDA were quantified in tumors' homogenates. RESULTS: CNG treatment increased the BRCA-1 expression, suppressed mTOR inflammatory pathway, attenuated tumor inflammatory mediators; NLRP3, GSDMD, NFκB, IL-1ß, suppressed the oxidative stress and inhibited tumor expression of the proliferation biomarker; Ki67. CONCLUSION: CNG modulated mTOR-mediated signaling pathway and attenuated pyroptotic, inflammatory pathways, suppressed oxidative stress and eventually inhibited DMBA-induced mammary carcinoma proliferation.

Astrocytes profiling in acute hepatic encephalopathy: Possible enrolling of glial fibrillary acidic protein, tumor necrosis factor-alpha, inwardly rectifying potassium channel (Kir 4.1) and aquaporin-4 in rat cerebral cortex.

Hepatic encephalopathy (HE) is a neurological disarray manifested as a sequel to chronic and acute liver failure (ALF). A potentially fatal consequence of ALF is brain edema with concomitant astrocyte enlargement. This study aims to outline the role of astrocytes in acute HE and shed light on the most critical mechanisms driving this role. Rats were allocated into two groups. Group 1, the control group, received the vehicle. Group 2, the TAA group, received TAA (300 mg/kg) for 3 days. Serum AST, ALT, and ammonia were determined. Liver and cerebral cortical sections were processed for hematoxylin and eosin staining. Additionally, mRNA expression and immunohistochemical staining of cortical GFAP, TNFα, Kir4.1, and AQP4 were performed. Cortical sections from the TAA group demonstrated neuropil vacuolation and astrocytes enlargement with focal gliosis. GFAP, TNFα, and AQP4 revealed increased mRNA expression, positive immunoreactivity, and a positive correlation to brain water content. In contrast, Kir 4.1 showed decreased mRNA expression and immunoreactivity and a negative correlation to brain water content. In conclusion, our findings revealed altered levels of TNFα, Kir 4.1, GFAP, and AQP4 in HE-associated brain edema. A more significant dysregulation of Kir 4.1 and TNFα was observed compared to AQP4 and GFAP.

Discovery of Some Heterocyclic Molecules as Bone Morphogenetic Protein 2 (BMP-2)-Inducible Kinase Inhibitors: Virtual Screening, ADME Properties, and Molecular Docking Simulations.

Bone morphogenetic proteins (BMPs) are growth factors that have a vital role in the production of bone, cartilage, ligaments, and tendons. Tumors' upregulation of bone morphogenetic proteins (BMPs) and their receptors are key features of cancer progression. Regulation of the BMP kinase system is a new promising strategy for the development of anti-cancer drugs. In this work, based on a careful literature study, a library of benzothiophene and benzofuran derivatives was subjected to different computational techniques to study the effect of chemical structure changes on the ability of these two scaffolds to target BMP-2 inducible kinase, and to reach promising candidates with proposed activity against BMP-2 inducible kinase. The results of screening against Lipinski's and Veber's Rules produced twenty-one outside eighty-four compounds having drug-like molecular nature. Computational ADMET studies favored ten compounds (11, 26, 27, 29, 30, 31, 34, 35, 65, and 72) with good pharmacokinetic profile. Computational toxicity studies excluded compound 34 to elect nine compounds for molecular docking studies which displayed eight compounds (26, 27, 29, 30, 31, 35, 65, and 72) as promising BMP-2 inducible kinase inhibitors. The nine fascinating compounds will be subjected to extensive screening against serine/threonine kinases to explore their potential against these critical proteins. These promising candidates based on benzothiophene and benzofuran scaffolds deserve further clinical investigation as BMP-2 kinase inhibitors for the treatment of cancer.

Gasdermin D: A potential mediator and prognostic marker of bladder cancer.

Background: Bladder cancer is considered one of the commonest widespread cancers, its presentation ranges from non-muscle invasive form to being muscle-invasive. The gasdermin family of proteins consists of six proteins. Members of gasdermin family are involved in pyroptosis; which is considered as type of inflammatory apoptosis via participation of gasdermin D and inflammatory caspases. Purpose: The goal of this research was to look into the potential involvement of gasdermin D in pathogenesis of bladder cancer, In addition, to investigate its potential role as a prognostic marker of bladder cancer. Methods: Gasdermin D gene and protein expression was examined in fresh frozen 80 bladder cancer specimens (30 NMIBC, and 50 MIBC) and the matching 80 control tissue samples utilizing real-time polymerase chain reaction and western blotting. Furthermore, the immunoreactivity of gasdermin D protein was also detected by immunohistochemistry. Results: Gasdermin D gene and protein expression showed a highly significant difference between the control and the two bladder cancer groups (p < 0.001), as demonstrated by real-time PCR, western blotting and immunohistochemistry. Cox proportional hazards regression models showed that lower gasdermin D gene expression in cancer patients (≤1.58-fold), and younger age (≤53 years) were linked with a higher risk of local tumor recurrence. Moreover, higher gasdermin D gene expression (>2.18-fold), and lymph nodes' involvement were associated with an increased mortality. Conclusion: Gasdermin D is involved in the pathogenesis of bladder cancer and muscle invasion, in addition, tissue gasdermin D expression may be used as useful tool to predict local tumor recurrence.