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The development of targeted drug delivery systems has been a pivotal area in nanomedicine, addressing challenges like low drug loading capacity, uncontrolled release, and systemic toxicity. This study aims to develop and evaluate dual-functionalized mesoporous silica nanoparticles (MSN) for targeted delivery of celecoxib, enhancing drug loading, achieving controlled release, and reducing systemic toxicity through amine grafting and imidazolyl polyethyleneimine (PEI) gatekeepers. MSN were synthesized using the sol–gel method and functionalized with (3-aminopropyl) triethoxysilane (APTES) to create amine-grafted MSN (MSN-NH2). Celecoxib was loaded into MSN-NH2, followed by conjugation of imidazole-functionalized PEI (IP) gatekeepers synthesized via carbodiimide coupling. Characterization was conducted using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Drug loading capacity, entrapment efficiency, and in vitro drug release at pH 5.5 and 7.4 were evaluated. Cytotoxicity was assessed using the MTT assay on RAW 264.7 macrophages. The synthesized IP was confirmed by FTIR and 1H-NMR. Amine-grafted MSN demonstrated a celecoxib loading capacity of 12.91 ± 2.02%, 2.1 times higher than non-functionalized MSN. In vitro release studies showed pH-responsive behavior with significantly higher celecoxib release from MSN-NH2-celecoxib-IP at pH 5.5 compared to pH 7.4, achieving a 33% increase in release rate within 2 h. Cytotoxicity tests indicated significantly higher cell viability for IP-treated cells compared to PEI-treated cells, confirming reduced toxicity. The dual-functionalization of MSN with amine grafting and imidazolyl PEI gatekeepers enhances celecoxib loading and provides controlled pH-responsive drug release while reducing systemic toxicity. These findings highlight the potential of this advanced drug delivery system for targeted anti-inflammatory and anticancer therapies. [ABSTRACT FROM AUTHOR]

Daidzein and genistein, the main isoflavone aglycone in soybean, are significantly gaining attention due to the numerous health benefits. Devon-1 variety of soybean, found in Indonesia, has the highest total isoflavone content. However, the compound predominantly exists in glycoside form, requiring hydrolysis during tempeh fermentation to obtain bioactive aglycone. Previous investigations indicated that ethanol extract of Devon-1 soybean after 61 hours showed lower daidzein and genistein levels compared to 1 N HCl hydrolyzed soybean. Therefore, this study aimed to enhance daidzein and genistein contents through heat treatment of Devon-1 soybean tempeh after 61 hours of fermentation. The sample was heated using a dry oven at 40, 50, and 60°C for 2 hours and extracted with ultrasonic bath with ethyl acetate solvent and 100% amplitude for 10 mins. Extract was analyzed using RP-HPLC with UV/Vis detector at 265 nm, methanol, and 0.1% acetic acid (47:53) as mobile phase. The results showed a 2-3 times increase in daidzein and genistein levels after heat treatment in all temperatures, particularly at 40°C. This suggested that heat treatment was a viable means to enhance the main isoflavone in tempeh. [ABSTRACT FROM AUTHOR]

Momordica charantia has various biological activities as antihyperglycemic, anti-inflammatory, and antioxidant. Thisstudy evaluated Momordica charantia fruit extract against the LDH and CKMB serum in rats induced with isoproterenol. We also evaluated the molecular docking of bioactive compounds in Momordica charantia fruit against the SIRT1 protein. Wistar male rats were divided into four groups: negative control (Na-CMC), positive control (Na-CMC and isoproterenol), and resveratrol group at 9 mg/kg b.wt, and Momordica charantia fruit extract at 300 mg/kg b.w with isoproterenol. The interaction between ligand and receptor was evaluated and calculated with molecular docking software. The ligands were docked using the AutoDock Tools - 1.5.7. The binding affinity was calculated using the binding free energy (kcal/mol). The results showed that Momordica charantia fruit extract at 300 mg/kg b.w could attenuate the LDH (49.37%) and CKMB (44.5%) increase in serum after isoproterenol-induced myocardial infarction in rats. Molecular docking of selected compounds from Momordica charantia fruit extract presents that momordicilin has great potential as a SIRT-1 activator with a binding energy of - 11.3 kcal/mol. These findings implicate that Momordica charantia fruit extract can be developed further as a potential cardioprotective drug. [ABSTRACT FROM AUTHOR]

Rationale Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction. Objective To investigate the molecular mechanisms underlying the changes in Tie2 expression upon lipopolysaccharide (LPS) challenge. Methods and results Studies were performed in LPS and pro-inflammatory cytokine challenged mice as well as in mice subjected to hemorrhagic shock, primary endothelial cells were used for in vitro experiments in static and flow conditions. Eight hours after LPS challenge, Tie2 mRNA loss was observed in all major organs, while loss of Tie2 protein was predominantly observed in lungs and kidneys, in the capillaries. A similar loss could be induced by secondary cytokines TNF-[alpha] and IL-1[beta]. Ang2 protein administration did not affect Tie2 protein expression nor was Tie2 protein rescued in LPS-challenged Ang2-deficient mice, excluding a major role for Ang2 in Tie2 down regulation. In vitro, endothelial loss of Tie2 was observed upon lowering of shear stress, not upon LPS and TNF-[alpha] stimulation, suggesting that inflammation related haemodynamic changes play a major role in loss of Tie2 in vivo, as also hemorrhagic shock induced Tie2 mRNA loss. In vitro, this loss was partially counteracted by pre-incubation with a pharmacologically NF-кB inhibitor (BAY11-7082), an effect further substantiated in vivo by pre-treatment of mice with the NF-кB inhibitor prior to the inflammatory challenge. Conclusions Microvascular bed specific loss of Tie2 mRNA and protein in vivo upon LPS, TNF[alpha], IL-1[beta] challenge, as well as in response to hemorrhagic shock, is likely an indirect effect caused by a change in endothelial shear stress. This loss of Tie2 mRNA, but not Tie2 protein, induced by TNF[alpha] exposure was shown to be controlled by NF-кB signaling. Drugs aiming at restoring vascular integrity in sepsis could focus on preventing the Tie2 loss., Author(s): Neng F. Kurniati [sup.1] [sup.6], Rianne M. Jongman [sup.1] [sup.5], Franziska vom Hagen [sup.3], Katherine C. Spokes [sup.4], Jill Moser [sup.1] [sup.2], Erzsébet Ravasz Regan [sup.4], Guido Krenning [sup.1], [...]

Both hemorrhagic shock and endotoxemia induce a pronounced vascular activation in the kidney which coincides with albuminuria and glomerular barrier dysfunction. We hypothesized that changes in Tie2, a vascular restricted receptor tyrosine kinase shown to control microvascular integrity and endothelial inflammation, underlie this loss of glomerular barrier function. In healthy murine and human kidney, Tie2 is heterogeneously expressed in all microvascular beds, although to different extents. In mice subjected to hemorrhagic and septic shock, Tie2 mRNA and protein were rapidly, and temporarily, lost from the renal microvasculature, and normalized within 24 h after initiation of the shock insult. The loss of Tie2 protein could not be attributed to shedding as both in mice and healthy volunteers subjected to endotoxemia, sTie2 levels in the systemic circulation did not change. In an attempt to identify the molecular control of Tie2, we activated glomerular endothelial cell cultures and human kidney slices in vitro with LPS or TNF-[alpha], but did not observe a change in Tie2 mRNA levels. In parallel to the loss of Tie2 in vivo, an overt influx of neutrophils in the glomerular compartment, which coincided with proteinuria, was seen. As neutrophil-endothelial cell interactions may play a role in endothelial adaptation to shock, and these effects cannot be mimicked in vitro, we depleted neutrophils before shock induction. While this neutrophil depletion abolished proteinuria, Tie2 was not rescued, implying that Tie2 may not be a major factor controlling maintenance of the glomerular filtration barrier in this model. endothelium; hemorrhagic shock; endotoxemia; neutrophil

Polycystic ovary syndrome (PCOS), a hormonal and metabolic disorder manifested in women of reproductive age, is still being treated using drugs with side effects. As an alternative to these drugs, isoflavone, also identified as phytoestrogen, has anti-PCOS activity. Isoflavone can help relieve PCOS symptoms by lowering the level of testosterone, which causes hyperandrogenism, thereby normalizing the menstrual cycle and restoring normal ovarian morphology. Furthermore, isoflavone influences the improvement of the metabolic profile, which changes because of PCOS, as well as the reduction of inflammatory markers and oxidative stress. However, both significant and non-significant results have been generated on the activity of isoflavones in PCOS. The present review aims to discuss the existing literature on the effect of isoflavone on PCOS symptoms based on in vivo and clinical trial studies. [ABSTRACT FROM AUTHOR]