The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model.

BACKGROUND: Candida albicans is the most common fungus that causes vaginal candidiasis in immunocompetent women and catastrophic infections in immunocompromised patients. The treatment of such infections is hindered due to the increasing emergence of resistance to azoles in C. albicans. New treatment approaches are needed to combat candidiasis especially in the dwindled supply of new effective and safe antifungals. The resistance to azoles is mainly attributed to export of azoles outside the cells by means of the efflux pump that confers cross resistance to all azoles including fluconazole (FLC). OBJECTIVES: This study aimed to investigate the possible efflux pump inhibiting activity of fusidic acid (FA) in C. albicans resistant isolates and the potential use of Fusidic acid in combination with fluconazole to potentiate the antifungal activity of fluconazole to restore its activity in the resistant C. albicans isolates. METHODS: The resistance of C. albicans isolates was assessed by determination of minimum inhibitory concentration. The effect of Fusidic acid at sub-inhibitory concentration on efflux activity was assayed by rhodamine 6G efflux assay and intracellular accumulation. Mice model studies were conducted to evaluate the anti-efflux activity of Fusidic acid and its synergistic effects in combination with fluconazole. Impact of Fusidic acid on ergosterol biosynthesis was quantified. The synergy of fluconazole when combined with Fusidic acid was investigated by determination of minimum inhibitory concentration. The cytotoxicity of Fusidic acid was tested against erythrocytes. The effect of Fusidic acid on efflux pumps was tested at the molecular level by real-time PCR and in silico study. In vivo vulvovaginitis mice model was used to confirm the activity of the combination in treating vulvovaginal candidiasis. RESULTS: Fusidic acid showed efflux inhibiting activity as it increased the accumulation of rhodamine 6G, a substrate for ABC-efflux transporter, and decreased its efflux in C. albicans cells. The antifungal activity of fluconazole was synergized when combined with Fusidic acid. Fusidic acid exerted only minimal cytotoxicity on human erythrocytes indicating its safety. The FA efflux inhibitory activity could be owed to its ability to interfere with efflux protein transporters as revealed by docking studies and downregulation of the efflux-encoding genes of both ABC transporters and MFS superfamily. Moreover, in vivo mice model showed that using fluconazole-fusidic acid combination by vaginal route enhanced fluconazole antifungal activity as shown by lowered fungal burden and a negligible histopathological change in vaginal tissue. CONCLUSION: The current findings highlight FA's potential as a potential adjuvant to FLC in the treatment of vulvovaginal candidiasis.

The assessment of pharmacokinetics and neuroprotective effect of berberine hydrochloride-embedded albumin nanoparticles via various administration routes: comparative in-vivo studies in rats.

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles.

Verapamil-Loaded Cubosomes for Enhancing Intranasal Drug Delivery: Development, Characterization, Ex Vivo Permeation, and Brain Biodistribution Studies.

Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.

Development of depot PLGA-based in-situ implant of Linagliptin: Sustained release and glycemic control.

High percentage of diabetic people are diagnosed as type 2 who require daily dosing of an antidiabetic drug such as Linagliptin (Lina) to manage their blood glucose levels. This study aimed to develop injectable Lina-loaded biodegradable poly (lactic-co-glycolic acid) (PLGA) in-situ implants (ISIs) to deliver a desired burst effect of Lina followed by a sustained release over several days for controlling the blood glucose levels over prolonged time periods. The morphological, pharmacokinetic, and pharmacodynamic assessments of the Lina-loaded ISIs were performed. Scanning electron microscopy (SEM) study revealed the rapid exchange between the water miscible solvent (N-methyl-2-pyrrolidone; NMP) and water during the ISI preparation, hence enhancing the initial burst Lina release. While, triacetin of lower water affinity could lead to formation of more compact and dense ISI structure with slower drug release. By comparing various ISI formulations containing different solvents and different PLGA concentrations, the ISI containing 40 % PLGA and triacetin was selected for its sustained release of Lina (93.06 ± 1.50 %) after 21 days. The pharmacokinetic results showed prolonged half life (t1/2) and higher area under the curve (AUC) values of the selected Lina-loaded ISI when compared to those of oral Lina preparation. The single Lina-ISI injection produced a hypoglycemic control in the diabetic rats very similar to the daily oral administration of Lina after 7 and 14 days. In conclusion, PLGA-based ISIs confirmed their suitability for prolonging Lina release in patients receiving long-term antidiabetic therapy, thereby achieving more enhanced patient compliance and reduced dosing frequency.

Effect of febuxostat on biochemical parameters of hyperlipidemia induced by a high-fat diet in rabbits.

Febuxostat, a highly potent xanthine oxidase inhibitor with an antioxidant effect, inhibits elevated xanthine oxidase, leading to reduction of reactive oxygen species and oxidative stress, the main causes of vascular inflammation in hyperlipidemia. The aim of this study was to test the potential antioxidant and anti-inflammatory effects of febuxostat and (or) stopping a high-fat diet on the biochemical parameters in rabbits with hyperlipidemia induced by a high-fat diet. Male New Zealand rabbits were distributed into 3 groups: a normal control group fed standard chow for 12 weeks and 2 other groups fed a high-fat diet with 1% cholesterol for 8 weeks, and then shifted to standard chow for 4 weeks. During the last 4 weeks, one high-fat diet group received 0.5% carboxymethyl cellulose, whereas the other group was treated with febuxostat (2 mg/kg per day p.o.). Febuxostat significantly lowered low-density lipoprotein cholesterol ("bad" cholesterol) compared to the untreated group (high-fat diet group). Febuxostat also displayed a potent anti-inflammatory and antioxidant activity by decreasing serum levels of lipid peroxidation index, proinflammatory cytokines, and enhancing antioxidant enzyme activity. Stopping the hyperlipidemic diet in the high-fat diet group did not show improvement. These findings indicate the antioxidant and anti-inflammatory effects of febuxostat that may be common mechanisms of the anti-hyperlipidemic effect of this drug. Stopping a hyperlipidemic diet without treatment is not sufficient once injury has occurred.

Transdermal ethosomal gel nanocarriers; a promising strategy for enhancement of anti-hypertensive effect of carvedilol.

The current study was conducted to develop vesicular ethosomal gel (ethogel) systems for upgrading the transdermal delivery of anti-hypertensive carvedilol. Ethosomes composed of Phospholipon 100 H, cholesterol, ethanol, and Transcutol P at different ratios, were prepared by thin-film hydration method with sonication. Carvedilol-loaded ethosomes were characterized by microscopic examinations followed by other in-vitro assessments. Selected ethosomal formulation (E10) was incorporated into different concentrations of gelling agents to prepare the ethogel formulations. Ethogels were subjected to physicochemical characterization, compatibility, and in-vitro drug release studies. Ex-vivo skin permeation and retention studies were performed followed by in-vivo studies in induced hypertensive rats. The smooth ethosomes demonstrated vesicular size of 201.55-398.55 nm, entrapment efficiency of 30.00-90.66% and loading capacity of 7.64-43.04% with zeta potential range of -30.30 to -44.90 mV. The homogeneous ethogels exhibited appropriate results of pH and drug content measurements. Spreadability was observed as a function of viscosity as the latter increased, the former decreased. The ethogel formulation (G2) manifested satisfactory physical appearance, spreadability, viscosity, and in-vitro release. In comparison to pure carvedilol gel, tested formulations (E10 and G2) developed high ex-vivo permeation, steady-state flux and drug retention through skin layers. The in-vivo study of G2 formulation revealed a significant gradual decline (p < 0.01) in the mean arterial pressure of rats at the second hour of experiment (146.11 mmHg) with continuous significant decrease (p < 0.001) after 6 h (98.88 mmHg). In conclusion, ethogels as promising lipid carriers proved their potential to enhance skin permeation with extended anti-hypertensive action of carvedilol.

Upgrading of dissolution and anti-hypertensive effect of Carvedilol via two combined approaches: self-emulsification and liquisolid techniques.

OBJECTIVE: The aim of the study was to design a self-emulsifying drug delivery system (SEDDS) of the anti-hypertensive Carvedilol in liquid and liquisolid forms as a way to enhance its dissolution profile and anti-hypertensive effect. METHODS: Solubility studies of Carvedilol in various oils, surfactants and co-surfactants were conducted, followed by the construction of pseudo-ternary phase diagrams and other in vitro assessments. The selected SEDDS formulation (S1) was adsorbed onto solid powder excipients and compressed into tablets. The resulting liquisolid tablets were evaluated under British Pharmacopoeia (B.P.) specifications. Pre- and post-compression studies were performed to determine the flow properties and evaluate the liquisolid systems, followed by in vivo studies in hypertensive rats. RESULTS: Attempts of self-emulsification, droplet size, and thermodynamic stability studies showed acceptable results for the S1 formulation containing Capryol 90, Tween 20, and Transcutol HP (10:53.3:26.2%), respectively. Pre-compression studies showed adequate flowability and compatibility of liquid and solid excipients with Carvedilol. The selected liquisolid tablet (LS7) demonstrated the best disintegration and water absorption ratio in addition to satisfactory friability and hardness. A significantly (p < .05) fast dissolution rate was observed for both SEDDS and liquisolid formulations when compared to pure drug and marketed Carvepress®. The in vivo study of LS7 formulation revealed a rapid significant (p < .01) decrease in the mean arterial pressure (MAP) of the rats (112.72 mmHg) within the first 30 min followed by a further decline (107.22 mmHg) after 1 h when compared to Carvepress®. CONCLUSION: Self-emulsifying liquisolid tablets expressed rapid onset of action with enhanced anti-hypertensive effect of Carvedilol.

N-Acetylborrelidin B: a new bioactive metabolite from Streptomyces mutabilis sp. MII.

In the course of our screening program for new bioactive compounds, a naturally new 18-membered macrolide antibiotic, N-acetylborrelidin B (1) along with borrelidin (2) were obtained from the marine Streptomyces mutabilis sp. MII. The strain was isolated from a sediment sample collected in the Red Sea at the Hurghada Coast and characterized taxonomically. Additional nine diverse bioactive compounds were reported: 6-prenyl-indole-3-acetonitrile (3), sitosteryl-3ß-d-glucoside, campesterol, ferulic acid, linoleic acid methyl ester, linoleic acid, N-acetylanthranilic acid, indole 3-acetic acid methyl ester, indole 3-carboxylic acid, and adenosine. Structure 1 was confirmed by in-depth NMR studies and by mass spectra, and comparison with related literature data. The antimicrobial activity of the strain extract and compounds 1 and 2 were studied using a panel of pathogenic microorganisms. The in vitro cytotoxicity of compounds 1 and 2 as well as the crude extract were tested against the human cervix carcinoma cell line (KB-3-1).

Terretonin N: A New Meroterpenoid from Nocardiopsis sp.

Terretonin N (1), a new highly oxygenated and unique tetracyclic 6-hydroxymeroterpenoid, was isolated together with seven known compounds from the ethyl acetate extract of a solid-state fermented culture of Nocardiopsis sp. Their structures were elucidated by spectroscopic analysis. The structure and absolute configuration of 1 were unambiguously determined by X-ray crystallography. The isolation and taxonomic characterization of Nocardiopsis sp. is reported. The antimicrobial activity and cytotoxicity of the strain extract and compound 1 were studied using different microorganisms and a cervix carcinoma cell line, respectively.

Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases.

Increasing hepatic stellate cell (HSC) death is a very attractive approach for limiting liver fibrosis. Tyrosine kinase inhibitors have been shown to have anti-fibrotic properties, but the mechanisms are poorly understood. Here, we identified the mechanism of action of the second-generation tyrosine kinase inhibitor nilotinib in inducing HSC death. Human HSC line (LX-2) and rat HSCs were treated with nilotinib and its predecessor, imatinib, in the absence or presence of various blockers, known to interfere with death signaling pathways. Nilotinib, but not imatinib, induced progressive cell death of activated, but not quiescent, HSCs in a dose-dependent manner. Activated HSCs died through apoptosis, as denoted by increased DNA fragmentation and caspase activation, and through autophagy, as indicated by the accumulation of autophagic markers, light chain (LC)3A-II and LC3B-II. Although inhibition of caspases with Z-VAD-FMK suppressed nilotinib-induced HSCs' apoptosis, there was no increase in HSCs' survival, because autophagy was exacerbated. However, blocking the mitochondrial permeability transition pore (mPTP) opening with cyclosporin A completely abolished both apoptosis and autophagy due to nilotinib. Moreover, nilotinib treatment decreased the protein expression of histone deacetylases 1, 2 and 4. Interestingly, pretreament with C646, a selective p300/CBP histone acetyl transferase inhibitor, resulted in diverting nilotinib-induced apoptosis and autophagy towards necrosis. In conclusion, the identification of mPTP as a target of nilotinib in activated HSCs suggests coordination with histone deacetylases inhibition to induce apoptosis and autophagy. Thus, our study provides novel insights into the anti-fibrotic effects of nilotinib.

Tracking anti-fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: an insight.

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl4 for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti-inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α-smooth muscle actin, transforming growth factor (TGF)-ß1 antibodies and platelet-derived growth factor receptor ß (PDGFRß) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl4 -induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF-ß1 levels and tissue expression of its antibody, as well expression of PDGFRß. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)-1 and IL-6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF-ß1 levels and decreasing expression of PDGFRß.

G protein-coupled estrogen receptor selective agonist, G1, improves the molecular and biochemical markers in a cisplatin mouse model of CKD.

Multiple cycles of cisplatin result in a permanent loss of kidney function with severe and life-limited chronic kidney disease (CKD) after successful cisplatin therapy. Recently, studies have showed that the activation of G-protein coupled estrogen receptor (GPER) could protect against kidney disease. This study aimed to test the potential of the G1 compound, a GPER selective agonist, to prevent CKD development after cisplatin therapy. Male C57BL/6 mice were exposed to 2 cycles of 2.5 mg/kg cisplatin in a regimen miming clinical exposure (1 injection daily for 5 days, followed by a 16-day recovery period between cycles). G1 (50 or 100 µg/kg) was administered daily for 6 weeks. G1 dose-dependently improved kidney function biomarkers (serum creatinine, creatinine clearance, and protein excretion) and histopathological changes compared to the cisplatin-treated group. Collagen 3 expression was dose-dependently decreased in G1-treated groups that was parallel to the reduction of fibrosis in Masson's trichrome-stained sections. G1 administration also increased total antioxidant capacity (TAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) and reduced the level of malondialdehyde and the proinflammatory cytokine, tumor necrosis factor-α. In addition, G1 downregulated the expression of inflammasome NLRP3 and nuclear factor kappa B p65 (NF-κB p65) in a dose-dependent manner. In conclusion, these data suggest that G1 could be a new therapeutic tool for CKD prevention post cisplatin therapy. These effects might be mediated through the activation of Nrf2 and the inhibition of NF-κB/NLRP3 signaling.

Development of Carvedilol-Loaded Albumin-Based Nanoparticles with Factorial Design to Optimize In Vitro and In Vivo Performance.

Carvedilol, an anti-hypertensive medication commonly prescribed by healthcare providers, falls under the BCS class II category due to its low-solubility and high-permeability characteristics, resulting in limited dissolution and low absorption when taken orally. Herein, carvedilol was entrapped into bovine serum albumin (BSA)-based nanoparticles using the desolvation method to obtain a controlled release profile. Carvedilol-BSA nanoparticles were prepared and optimized using 32 factorial design. The nanoparticles were characterized for their particle size (Y1), entrapment efficiency (Y2), and time to release 50% of carvedilol (Y3). The optimized formulation was assessed for its in vitro and in vivo performance by solid-state, microscopical, and pharmacokinetic evaluations. The factorial design showed that an increment of BSA concentration demonstrated a significant positive effect on Y1 and Y2 responses with a negative effect on Y3 response. Meanwhile, the carvedilol percentage in BSA nanoparticles represented its obvious positive impact on both Y1 and Y3 responses, along with a negative impact on Y2 response. The optimized nanoformulation entailed BSA at a concentration of 0.5%, whereas the carvedilol percentage was 6%. The DSC thermograms indicated the amorphization of carvedilol inside the nanoparticles, which confirmed its entrapment into the BSA structure. The plasma concentrations of carvedilol released were observable from optimized nanoparticles up to 72 h subsequent to their injection into rats, revealing their longer in vivo circulation time compared to pure carvedilol suspension. This study offers new insight into the significance of BSA-based nanoparticles in sustaining the release of carvedilol and presents a potential value-added in the remediation of hypertension.

Tailoring Risperidone-Loaded Glycethosomal In Situ Gels Using Box-Behnken Design for Treatment of Schizophrenia-Induced Rats via Intranasal Route.

Schizophrenic patients often face challenges with adherence to oral regimens. The study aimed to highlight the potentiality of intranasal ethanol/glycerin-containing lipid-nanovesicles (glycethosomes) incorporated into in situ gels for sustaining anti-psychotic risperidone (RS) release. The Box-Behnken Design (BBD) was followed for in vitro characterization. Glycethosomal-based in situ gels were examined by physical, ex vivo, and in vivo investigations. The ethanol impact on minimizing the vesicle size (VS) and enhancing the zeta potential (ZP) and entrapment efficiency (EE%) of nanovesicles was observed. Glycerin displayed positive action on increasing VS and ZP of nanovesicles, but reduced their EE%. After incorporation into various mucoadhesive agent-enriched poloxamer 407 (P407) in situ gels, the optimized gel containing 20% P407 and 1% hydroxypropyl methyl cellulose-K4M (HPMC-K4M) at a 4:1 gel/glycethosomes ratio showed low viscosity and high spreadability with acceptable pH, gel strength, and mucoadhesive strength ranges. The ethanol/glycerin mixture demonstrated a desirable ex vivo skin permeability of RS through the nasal mucosa. By pharmacokinetic analysis, the optimized gel showed eight-fold and three-fold greater increases in RS bioavailability than the control gel and marketed tablet, respectively. Following biochemical assessments of schizophrenia-induced rats, the optimized gel boosted the neuroprotective, anti-oxidant, and anti-inflammatory action of RS in comparison to other tested preparations. Collectively, the intranasal RS-loaded glycethosomal gel offered a potential substitute to oral therapy for schizophrenic patients.

Optimization of Potential Nanoemulgels for Boosting Transdermal Glimepiride Delivery and Upgrading Its Anti-Diabetic Activity.

Transdermal drug delivery has been widely adopted as a plausible alternative to the oral route of administration, especially for drugs with poor systemic bioavailability. The objective of this study was to design and validate a nanoemulsion (NE) system for transdermal administration of the oral hypoglycemic drug glimepiride (GM). The NEs were prepared using peppermint/bergamot oils as the oil phase and tween 80/transcutol P as the surfactant/co-surfactant mixture (Smix). The formulations were characterized using various parameters such as globule size, zeta potential, surface morphology, in vitro drug release, drug-excipient compatibility studies, and thermodynamic stability. The optimized NE formulation was then incorporated into different gel bases and examined for gel strength, pH, viscosity, and spreadability. The selected drug-loaded nanoemulgel formulation was then screened for ex vivo permeation, skin irritation, and in vivo pharmacokinetics. Characterization studies revealed the spherical shape of NE droplets with an average size of ~80 nm and a zeta potential of -11.8 mV, which indicated good electrokinetic stability of NE. In vitro release studies revealed enhanced drug release from the NE formulation compared to the plain drug. GM-loaded nanoemulgel showed a 7-fold increment in drug transdermal flux compared to plain drug gel. In addition, the GM-loaded nanoemulgel formulation did not elicit any signs of inflammation and/or irritation on the applied skin, suggesting its safety. Most importantly, the in vivo pharmacokinetic study emphasized the potential of nanoemulgel formulation to potentiate the systemic bioavailability of GM, as manifested by a 10-fold rise in the relative bioavailability compared to control gel. Collectively, transdermal NE-based GM gel might represent a promising alternative to oral therapy in the management of diabetes.

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.

The Exploitation of pH-Responsive Eudragit-Coated Mesoporous Silica Nanostructures in the Repurposing of Terbinafine Hydrochloride for Targeted Colon Cancer Inhibition: Design Optimization, In Vitro Characterization, and Cytotoxicity Assessment.

Targeted drug delivery is achieving great success in cancer therapy due to its potential to deliver drugs directly to the action site. Terbinafine hydrochloride (TER) is a broad-spectrum anti-fungal drug that has been found to have some potential anti-tumor effects in the treatment of colon cancer. We aimed here to design and develop pH-sensitive Eudragit (Eud)-coated mesoporous silica nanostructures (MSNs) to control drug release in response to changes in pH. The diffusion-supported loading (DiSupLo) technique was applied for loading TER into the MSNs. The formulation was optimized by a D-optimal design, which permits the concurrent assessment of the influence of drug/MSN%, coat concentration, and MSN type on the drug entrapment efficiency (EE) and its release performance. The optimal formula displayed a high EE of 96.49%, minimizing the release in pH 1.2 to 16.15% and maximizing the release in pH 7.4 to 78.09%. The cytotoxicity of the optimal formula on the colon cancer cells HT-29 was higher than it was with TER alone by 2.8-fold. Apoptosis in cancer cells exposed to the optimum formula was boosted as compared to what it was with the plain TER by 1.2-fold and it was more efficient in arresting cells during the G0/G1 and S stages of the cell cycle. Accordingly, the repurposing of TER utilizing Eud/MSNs is a promising technique for targeted colon cancer therapy.

Investigation of Alogliptin-Loaded In Situ Gel Implants by 23 Factorial Design with Glycemic Assessment in Rats.

The aim of the study was to design injectable long-acting poly (lactide-co-glycolide) (PLGA)-based in situ gel implants (ISGI) loaded with the anti-diabetic alogliptin. Providing sustained therapeutic exposures and improving the pharmacological responses of alogliptin were targeted for achieving reduced dosing frequency and enhanced treatment outputs. In the preliminary study, physicochemical characteristics of different solvents utilized in ISGI preparation were studied to select a proper solvent possessing satisfactory solubilization capacity, viscosity, water miscibility, and affinity to PLGA. Further, an optimization technique using a 23 factorial design was followed. The blood glucose levels of diabetic rats after a single injection with the optimized formulation were compared with those who received daily oral alogliptin. N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), as highly water-miscible and low viscous solvents, demonstrated their effectiveness in successful ISGI preparation and controlling the burst alogliptin release. The impact of increasing lactide concentration and PLGA amount on reducing the burst and cumulative alogliptin release was represented. The optimized formulation comprising 312.5 mg of PLGA (65:35) and DMSO manifested a remarkable decrease in the rats' blood glucose levels throughout the study period in comparison to that of oral alogliptin solution. Meanwhile, long-acting alogliptin-loaded ISGI systems demonstrated their feasibility for treating type 2 diabetes with frequent dosage reduction and patient compliance enhancement.

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.

Electrospun Nanofibers Revisited: An Update on the Emerging Applications in Nanomedicine.

Electrospinning (ES) has become a straightforward and customizable drug delivery technique for fabricating drug-loaded nanofibers (NFs) using various biodegradable and non-biodegradable polymers. One of NF's pros is to provide a controlled drug release through managing the NF structure by changing the spinneret type and nature of the used polymer. Electrospun NFs are employed as implants in several applications including, cancer therapy, microbial infections, and regenerative medicine. These implants facilitate a unique local delivery of chemotherapy because of their high loading capability, wide surface area, and cost-effectiveness. Multi-drug combination, magnetic, thermal, and gene therapies are promising strategies for improving chemotherapeutic efficiency. In addition, implants are recognized as an effective antimicrobial drug delivery system overriding drawbacks of traditional antibiotic administration routes such as their bioavailability and dosage levels. Recently, a sophisticated strategy has emerged for wound healing by producing biomimetic nanofibrous materials with clinically relevant properties and desirable loading capability with regenerative agents. Electrospun NFs have proposed unique solutions, including pelvic organ prolapse treatment, viable alternatives to surgical operations, and dental tissue regeneration. Conventional ES setups include difficult-assembled mega-sized equipment producing bulky matrices with inadequate stability and storage. Lately, there has become an increasing need for portable ES devices using completely available off-shelf materials to yield highly-efficient NFs for dressing wounds and rapid hemostasis. This review covers recent updates on electrospun NFs in nanomedicine applications. ES of biopolymers and drugs is discussed regarding their current scope and future outlook.