Chitosan-coated nanostructured lipid carriers for effective brain delivery of Tanshinone IIA in Parkinson's disease: interplay between nuclear factor-kappa ß and cathepsin B.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder associated with increased oxidative stress, the underlying vital process contributing to cell death. Tanshinone IIA (TAN) is a phytomedicine with a documented activity in treating many CNS disorders, particularly PD owing to its unique anti-inflammatory and antioxidant effect. However, its clinical utility is limited by its poor aqueous solubility, short half-life, and hence low concentration reaching targeted cells. This work aimed to develop a biocompatible chitosan-coated nanostructured lipid carriers (CS-NLCs) for effective brain delivery of TAN for PD management. The proposed nanosystem was successfully prepared using a simple melt-emulsification ultra-sonication method, optimized and characterized both in vitro and in vivo in a rotenone-induced PD rat model. The developed TAN-loaded CS-NLCs (CS-TAN-NLCs) showed good colloidal properties (size ≤ 200 nm, PDI ≤ 0.2, and ζ-potential + 20 mV) and high drug entrapment efficiency (> 97%) with sustained release profile for 24 h. Following intranasal administration, CS-TAN-NLCs succeeded to achieve a remarkable antiparkinsonian and antidepressant effect in diseased animals compared to both the uncoated TAN-NLCs and free TAN suspension as evidenced by the conducted behavioral tests and improved histopathological findings. Furthermore, biochemical evaluation of oxidative stress along with inflammatory markers, nuclear factor-kabba ß (NF-Kß) and cathepsin B further confirmed the potential of the CS-TAN-NLCs in enhancing brain delivery and hence the therapeutic effect of TAN of treatment of PD. Accordingly, CS-TAN-NLCs could be addressed as a promising nano-platform for the effective management of PD.

Targeted Fisetin-Encapsulated ß-Cyclodextrin Nanosponges for Breast Cancer.

Fisetin (FS) is considered a safer phytomedicine alternative to conventional chemotherapeutics for breast cancer treatment. Despite its surpassing therapeutic potential, its clinical utility is hampered by its low systemic bioavailability. Accordingly, as far as we are aware, this is the first study to develop lactoferrin-coated FS-loaded ß-cyclodextrin nanosponges (LF-FS-NS) for targeted FS delivery to breast cancer. NS formation through cross-linking of ß-cyclodextrin by diphenyl carbonate was confirmed by FTIR and XRD. The selected LF-FS-NS showed good colloidal properties (size 52.7 ± 7.2 nm, PDI < 0.3, and ζ-potential 24 mV), high loading efficiency (96 ± 0.3%), and sustained drug release of 26 % after 24 h. Morphological examination using SEM revealed the mesoporous spherical structure of the prepared nanosponges with a pore diameter of ~30 nm, which was further confirmed by surface area measurement. Additionally, LF-FS-NS enhanced FS oral and IP bioavailability (2.5- and 3.2-fold, respectively) compared to FS suspension in rats. Antitumor efficacy evaluation in vitro on MDA-MB-231 cells and in vivo on an Ehrlich ascites mouse model demonstrated significantly higher activity and targetability of LF-FS-NS (30 mg/kg) compared to the free drug and uncoated formulation. Consequently, LF-FS-NS could be addressed as a promising formulation for the effective management of breast cancer.

Luteolin-loaded exosomes derived from bone marrow mesenchymal stem cells: a promising therapy for liver fibrosis.

Liver fibrosis is a global life-threatening disorder with no approved treatment. It leads to serious hepatic complications when progressive, such as cirrhosis and carcinoma. Luteolin (LUT) is a plant flavonoid possessing a promising therapeutic potential in various liver diseases particularly, liver fibrosis. It was reported to have potent anti-inflammatory and antioxidant properties. It also suppresses the proliferation of activated hepatic stellate cells (HSC) and induces their apoptosis. However, its poor aqueous solubility and exposure to metabolism hinder its clinical use. Mesenchymal stem cells (MSCs)-derived exosomes, nano-sized extracellular vesicles, have recently emerged as natural biocompatible drug delivery vehicles permitting efficient drug delivery. Accordingly, the present study aimed for the first time to investigate the potential of bone marrow MSCs-derived exosomes to improve LUTs antifibrotic effectiveness. LUT-loaded exosomes (LUT-Ex) were successfully developed, optimized and subjected to both in vitro and in vivo characterization. The elaborated LUT-Ex presented good colloidal properties (size; 150 nm, PDI; 0.3 and ζ-potential; -28 mV), typical vesicular shape, reasonable drug entrapment efficiency (40%) with sustained drug release over 72 h. Additionally, the cellular uptake study of coumarin-6-loaded exosomes in HEP-G2 revealed a significant enhancement in their uptake by 78.4% versus free coumarin-6 solution (p ≤ 0.001). Following a single intraperitoneal injection, LUT-Ex revealed a superior antifibrotic activity compared with either LUT-suspension or blank exosomes as evidenced by the results of biochemical and histopathological evaluation. In conclusion, the elaborated LUT-Ex could be addressed as a promising nanocarrier for effective treatment of liver fibrosis.

Impact of Platform Switched Implants on Marginal Bone Level in Mandibular Overdentures: A Six-Year Follow-Up Longitudinal Study.

Purpose: To evaluate the impact of the platform-switched implant on marginal bone loss (MBL) and the probing pocket depth (PPD) in patients wearing mandibular overdenture. Patients and Methods: This longitudinal study included 40 completely edentulous patients aged 51-64 years. All patients received complete dentures and were distributed into two groups randomly; 20 patients each. The first group GI received two platform switched implants; however, the 2nd group GII received two platform matched implants (3.6 × 11.5 mm) in the canine region of the mandible. The radiographic evaluations were carried out every year for six years, whereas probing pocket depth was evaluated every six months for 72 months for both groups. The data were analyzed by repeated ANOVA, Friedman's, and Student's t-test. Results: This study included 36 patients; 56 ± 3.6 years was the mean age; 17 females (47%) and 19 males (53%) completed the study. Statistically significant differences were observed in MBL and PPD in each of GI and GII after 6 years, p ≤ 0.05. Between GI and GII after 6 years, a statistically insignificant difference was detected in MBL or PPD, p ≥ 0.05, except in PPD at loading, 2 and 6 years, p ≤ 0.05. Conclusion: Time positively affected MBL and PPD in platform switched and matched implants retained mandibular overdentures. Platform switching influences probing pocket depth in implants retained mandibular overdentures.

Tanshinone IIA loaded bioactive nanoemulsion for alleviation of lipopolysaccharide induced acute lung injury via inhibition of endothelial glycocalyx shedding.

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI âˆ¼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.

Assessment of Quality of Life and Supporting Structures in Implant Retained Mandibular Overdenture: A 5-Year Cohort Study.

Aim: To assess oral health-related quality of life (OHRQoL), marginal bone loss (MBL), and changes in soft tissue including probing pocket depth and implant stability in 2 implants retained mandibular overdentures during 5 years follow-up periods. Methods: Forty completely edentulous patients with age 51-64 years were recruited for that longitudinal cohort study. Complete dentures were performed for all participants. Two implants (3.6 × 11.5 mm) were installed in the canine areas of the mandible. OHRQoL and MBL measures were performed every 1 year for 5 years, while clinical measures were made every 6 months for 60 months. Data were examined using repeated ANOVA and Friedman test. Results: Thirty-seven patients had 74 implants; with mean age 56 ± 3.6 years; 43% females (n = 16) and 57% males (n = 21) accomplished the study. There were statistically significant differences in OHRQoL, MBL, and changes in soft tissue, including probing pocket depth and implant stability in 2 implants retained mandibular overdentures during 5 years follow-up periods, p ≤ 0.05. Conclusion: Mandibular overdentures retained by 2 implants provide a positive long-term effect on OHRQoL, MBL, probing pocket depth, and implant stability.

Modified Lipid Nanocapsules for Targeted Tanshinone IIA Delivery in Liver Fibrosis.

INTRODUCTION: Liver fibrosis represents a serious global disease with no approved treatment. Tanshinone IIA (TSIIA) is a phytomedicine with documented activity in treating many hepatic disorders. TSIIA has been reported to have potent anti-inflammatory and antioxidant properties. It can also induce apoptosis for activated hepatic stellate cells, and is thereby considered as a promising herbal remedy for treating fibrotic liver. However, its poor aqueous solubility, short half-life, exposure to the first-pass effect, and low concentration reaching targeted cells constitute the major barriers hindering its effective therapeutic potential. Therefore, this work aimed at enhancing TSIIA systemic bioavailability together with achieving active targeting potential to fibrotic liver via its incorporation into novel modified lipid nanocapsules (LNCs). METHODS: Blank and TSIIA-loaded LNCs modified with either hyaluronate sodium or phosphatidyl serine were successfully prepared, optimized, and characterized both in vitro and in vivo. RESULTS: The developed LNCs showed good colloidal properties (size ≤100 nm and PDI ≤0.2), high drug-entrapment efficiency (>97%) with sustained-release profile for 24 hours, high storage stability up to 6 months, and good in vitro serum stability. After a single intraperitoneal injection, the administered LNCs exhibited a 2.4-fold significant increase in AUC0-∞ compared with the TSIIA suspension (p≤0.01). Biodistribution-study results proved the liver-targeting ability of the prepared modified LNCs, with a significant ~1.5-fold increase in hepatic accumulation compared with the unmodified formulation (p≤0.05). Moreover, the modified formulations had an improved antifibrotic effect compared with both unmodified LNCs and TSIIA suspension, as evidenced by the results of biochemical and histopathological evaluation. CONCLUSION: The modified TSIIA-LNCs could be regarded as promising novel targeted nanomedicines for effective management of liver fibrosis.

Enhanced oral bioavailability of Tanshinone IIA using lipid nanocapsules: Formulation, in-vitro appraisal and pharmacokinetics.

Tanshinone IIA (TSIIA) is a promising phytomedicine that has been extensively studied due to its numerous biological activities, especially as an anticancer drug. However, it suffers from poor oral bioavailability owing to low aqueous solubility, poor permeability and exposure to first-pass metabolism. This study endeavored to improve TSIIA oral bioavailability by encapsulation into lipid nanocapsules (LNCs) for the first time. A previously reported phase-inversion method was used to prepare Tanshinone II A loaded LNCs (TSIIA-LNCs) with slight modifications based on a constructed phase diagram. They were then in-vitro characterized and their oral pharmacokinetics were studied in rats. TSIIA-LNCs showed excellent colloidal properties (size; 70 nm, PDI < 0.2 and zeta-potential; -13.5 mV), a high percent entrapment efficiency (98%) and a good drug payload (2.6 mg/g). Furthermore, the in-vivo pharmacokinetic study revealed a significant enhancement in both the rate and extent of absorption of TSIIA-LNCs compared with TSIIA suspension with about 3.6-fold increase in AUC 0-inf value (p ≤ 0.01). Additionally, a significant increase in both half-life and mean residence time was exhibited by TSIIA-LNCs (p ≤ 0.01), confirming their long circulating properties. Therefore, the elaborated LNCs could be addressed as a promising nanoplatform permitting higher TSIIA oral bioavailability.

Green synthesis of silver nanoparticles using cranberry powder aqueous extract: characterization and antimicrobial properties.

BACKGROUND: The growing threat of microbial resistance against traditional antibiotics has prompted the development of several antimicrobial nanoparticles (NPs), including silver NPs (AgNPs). In this article, a simple and eco-friendly method for the synthesis of AgNPs using the cranberry powder aqueous extract is reported. MATERIALS AND METHODS: Cranberry powder aqueous extracts (0.2%, 0.5%, and 0.8% w/v) were allowed to interact for 24 hours with a silver nitrate solution (10 mM) at 30°C at a ratio of 1:10. The formation of AgNPs was confirmed by ultraviolet-visible spectroscopy and their concentrations were determined using atomic absorption spectroscopy. The prepared NPs were evaluated by transmission electron microscopy, measurement of ζ-potential, and Fourier-transform infrared spectroscopy. The in vitro antimicrobial properties of AgNPs were then investigated against several microbial strains. Finally, in vivo appraisal of both wound-healing and antimicrobial properties of either plain AgNPs (prepared using 0.2% extract) or AgNP-Pluronic F-127 gel was conducted in a rat model after induction of a Staphylococcus aureus ATCC 6538P wound infection. RESULTS: The formation of AgNPs was confirmed by ultraviolet-visible spectroscopy, where a surface-plasmon resonance absorption peak was observed between 432 and 438 nm. Both size and concentration of the formed AgNPs increased with increasing concentration of the extracts. The developed NPs were stable, almost spherical, and polydisperse, with a size range of 1.4-8.6 nm. The negative ζ-potential values, as well as Fourier-transform infrared spectroscopy analysis, indicated the presence of a capping agent adsorbed onto the surface of the particles. In vitro antimicrobial evaluation revealed a size-dependent activity of the AgNPs against the tested organisms. Finally, AgNPs prepared using 0.2% extract exhibited a substantial in vivo healing potential for full-thickness excision wounds in rats. CONCLUSION: AgNPs were successfully synthesized from a silver nitrate solution through a simple green route, using cranberry powder aqueous extract as a reducing as well as capping agent.