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Resveratrol is a polyphenolic compound showing anti-inflammatory activity by inhibition of high mobility group box 1 cytokine responsible for the activation of nuclear factor-κB pathway in atopic dermatitis. To evaluate the efficacy of resveratrol through topical route we have developed resveratrol-loaded nanoemulgel for the effective management of atopic dermatitis in mice model. The resveratrol-loaded nanoemulsion (0.5%, 0.75% and 1% w/w) was optimized by spontaneous nano-emulsification. The optimized resveratrol-loaded nanoemulsions showed average globule size in the 180–230 nm range and found to be monodispersed. The resveratrol nanoemulgel was prepared with a SEPINEO™ P 600 gel base and propylene glycol. Ex vivo permeation and retention study resulted in significantly higher skin retention of resveratrol from resveratrol-loaded nanoemulgel than free resveratrol-loaded gel. Preclinical efficacy of resveratrol nanoemulgel displayed promising therapeutic outcomes where, western blotting of skin tissues disclosed a significant reduction in the relative expression of high mobility group box 1, the receptor for advanced glycation end products, toll-like receptor-4 and phosphorylated nuclear factor-κB. Further, real-time polymerase chain reaction also disclosed a significant reduction in pro-inflammatory cytokines such as thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-31, tumor necrosis factor-α and interleukin-6. The histopathological examination of skin sections showed improvement in the skin condition. Collectively, the findings from our study showcased the significant improvement in the atopic dermatitis skin condition in mice model after topical application of resveratrol loaded nanoemulgel. [ABSTRACT FROM AUTHOR]

In this work, we tested the efficacy of yttrium oxide nanoparticles (NY), a promising antioxidant and anti-inflammatory agent, in L-arginine (L-Arg) induced chronic pancreatitis (CP) model. The nanoparticles were characterized using multiple techniques including transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (pXRD), and Energy dispersive X-ray analysis (EDX). The rats were divided into three groups: normal control, L-Arg control, L-Arg + NY (1 mg/kg). We probed the mechanistic effects of the NY by ELISA, multiplex analysis of TGF-β pathway and inflammatory cytokines and immunoblotting. NY treatment significantly reduced pancreatic oxidative-nitrosative stress. In addition, NY intervention also reduced inflammatory cytokines and chemokines resulting in the inhibition of fibrosis signaling. Further, NY treatment suppressed the TGF-β signaling and epithelial-mesenchymal transition (EMT). We conclude that NY shows potential antioxidant, anti-inflammatory, and anti-fibrotic effects against CP and associated fibrosis. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a hallmark feature of chronic kidney diseases (CKDs). However, despite the increased prevalence of renal fibrosis, there is no approved antifibrotic drug for the management of renal fibrosis. Cerium oxide nanoparticles (CONPs) have been demonstrated to possess a number of properties including antioxidant, anti-inflammatory and nephroprotective activity. As the kidneys are rich in lactoferrin (Lf) receptors, we synthesised the lactoferrin-CONP (Lf-CONP) system to be used for active targeting of the kidneys and provide antifibrotic effects of CONPs to the kidneys. We used the unilateral ureteral obstruction (UUO)–induced renal fibrosis model and treated the animals with Lf-CONP to observe the antifibrotic effects of Lf-CONP. Lf-CONP was found to inhibit the progression of renal fibrosis in a superior manner when compared to CONPs alone. [ABSTRACT FROM AUTHOR]

Essential oils consist of oxygenated structures of secondary metabolites of aromatic plants with anti-psoriatic activities. Tea tree oil (TTO) is an essential oil with good anti-microbial and anti-inflammatory properties, exhibiting reduced levels of IL-1, IL-8, and PGE 2. Thymoquinone (TMQ) is popular herb in traditional medicine with known therapeutic benefits in several diseases and ailments. The ternary phase diagram was prepared with the weight ratio of Smix (Tween® 80:Labrasol®): oil:water ratio for o/w emulsion preparation. The globule size was 16.54 ± 0.13 nm, and PDI around 0.22 ± 0.01 of the TTO-TMQ emulsion and found thermodynamically stable. The percentage drug content was found in the range of 98.97 ± 0.62 to 99.45 ± 0.17% with uniformity of the ThymoGel using Carbopol®. The extensive physicochemical properties were studied using different analytical techniques, and in vitro drug release was performed using Franz-diffusion apparatus. Anti-psoriatic activity of the formulations was studied using Imiquimod-induced psoriasis-like inflammation model in male Balb/c mice and parameters like PASI score, ear thickness, and spleen to body weight index were determined as well as histological staining, ELISA, skin compliance, and safety evaluation of TTO were performed. The combination of essential oils with TMQ shows synergistic activity and efficiently reduces the psoriasis disease condition. [ABSTRACT FROM AUTHOR]

Purpose: Cancer is one of the most common and fatal disease, chemotherapy is the major treatment against many cancer types. The anti-apoptotic BCL-2 protein's expression was increased in many cancer types and Venetoclax (VLX; BCL-2 inhibitor) is a small molecule, which selectively inhibits this specified protein. In order to increase the clinical performance of this promising inhibitor as a repurposed drug, polymeric mixed micelles formulations approach was explored. Methods: The Venetoclax loaded polymeric mixed micelles (VPMM) were prepared by using Pluronic® F-127 and alpha tocopherol polyethylene glycol 1000 succinate (TPGS) as excipients by thin film hydration method and characteristics. The percentage drug loading capacity, entrapment efficiency and in-vitro drug release studies were performed using HPLC method. The cytotoxicity assay, cell uptake and anticancer activities were evaluated in two different cancer cells i.e. MCF-7 (breast cancer) and A-549 (lung cancer). Results: Particle size, polydispersity index and zeta potential of the VPMM was found to be 72.88 ± 0.09 nm, 0.078 ± 0.009 and -4.29 ± 0.24 mV, respectively. The entrapment efficiency and %drug loading were found to be 80.12 ± 0.23% and 2.13% ± 0.14%, respectively. The IC50 of VLX was found to be 4.78, 1.30, 0.94 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 1.24, 0.68, and 0.314 µg/ml at 24, 48, and 72 h, respectively in A549 cells. Whereas, IC50 of VPMM was found to be 0.42, 0.29, 0.09 µg/ml at 24, 48 and 72 h, respectively in MCF-7 cells and 0.85, 0.13, 0.008 µg/ml at 24, 48 and 72 h in A549 cells, respectively, indicating VPMM showing better anti-cancer activity compared to VLX. The VPMM showed better cytotoxicity which was further proven by other assays and explained the anti-cancer activity is shown through the generation of ROS, nuclear damage,apoptotic cell death and expression of caspase-3,7, and 9 activities in apoptotic cells. Conclusion: The current investigation revealed that the Venetoclax loaded polymeric mixed micelles (VPMM) revealed the enhanced therapeutic efficacy against breast and lung cancer in vitro models. [ABSTRACT FROM AUTHOR]

Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis. In the present study, we have investigated the role of DDR1 and DDR2 in CP. The induced expression of DDR1 and DDR2 was observed in primary pancreatic stellate cells (PSCs) and cerulein-induced CP. Subsequently, the protective effects of DDR1/DDR2 inhibitor, imatinib (IMT) were investigated. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, IMT treatment reduced pancreatic injury, inflammation, extracellular matrix deposition and PSCs activation along with inhibition of TGF-β1/Smad signaling pathway. Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP. [ABSTRACT FROM AUTHOR]

Delivering drugs through inhalation for systemic and local applications has been in practice since several decades to treat various diseases. In recent times, inhalation drug delivery is becoming one of the highly focused areas of research in the pharmaceutical industry. It is being considered as one of the major portals for delivering drugs because of its wide range of advantages like requirement of low concentrations of drug to reach therapeutic efficacy, surpassing first pass metabolism and a very low incidence of side effects as compared to conventional delivery of drugs. Owing to these favorable characteristics of pulmonary drug delivery, diverse pharmaceutical formulations like liposomes, nanoparticles, and microparticles are developed through consistent efforts for delivery drugs to lungs in suitable form. However, drug-loaded microparticles have displayed various advantages over the other pharmaceutical dosage forms which give a cutting edge over other inhalational drug delivery systems. Assuring results with respect to sustained release through inhalational delivery of drug-loaded microparticles from pre-clinical studies are anticipative of similar benefits in the clinical settings. This review centralizes partly on the advantages of inhalational microparticles over other inhalational dosage forms and largely on the therapeutic applications and future perspectives of inhalable microparticle drug delivery systems. [ABSTRACT FROM AUTHOR]

Cisplatin (CP) is one of the most important anticancer compounds with its therapeutic usefulness in diverse types of solid cancer. However, its use is limited due to nephrotoxicity induced by it. Oxidative stress is an effective participant which contributes actively to pathogenesis of CP-induced nephrotoxicity. Nanoparticle form of a rare earth metal cerium, also known as nanoceria (NC), has come up as a potential antioxidant and anti-inflammatory agent. In the present study, administration of CP in Swiss mice resulted in reduction of body weight, increased oxidative stress and pro-inflammatory cytokine levels including IL-6 and TNF-α along with alteration in normal histological architecture of kidney. On the contrary, NC (0.2 and 2 mg/kg i.p.) ameliorated nephrotoxicity of CP which was evident by reduction in levels of renal injury markers in plasma, i.e., creatinine and blood urea nitrogen. NC ameliorated oxidative stress by showing a reduction in levels of malondialdehyde and increased levels of endogenous antioxidants reduced glutathione and catalase. Further, NC treatment also reduced the levels of pro-inflammatory cytokines. Furthermore, protective effect of NC was also corroborated by histopathological studies wherein, kidneys from CP group showed altered tissue structure after acute as well as chronic exposure of CP while the tissues from treated groups showed absence of alterations in kidney histology. The results from present study suggested that oxidative stress and pro-inflammatory cytokines play a central role in pathogenesis of CP-induced nephrotoxicity and NC provides protection from CP-induced nephrotoxicity due to its antioxidant and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: Clinical manifestations of skin fibrosis are very variable and ambiguous, making its management quite critical and challenging. The lack of appropriate established pharmacological interventions make its treatment even more complicated. Intricate details of the underlying pathogenesis are thus imperative to further explore different treatment possibilities. Of note, the TGF-β/Smad signaling axis and epithelial to mesenchymal transition (EMT) are the principal offenders in this fibrotic disorder. Objective: Our current study is aimed at demonstrating the antifibrotic and anti-inflammatory potential of nimbolide, a triterpene derived from Indian traditional plant neem, in a murine model of Bleomycin-induced scleroderma. Methods: Male C57BL/6 mice were administered with Bleomycin injections subcutaneously, daily for 28 days, at a constant site on the dorsum of the mice. Treatment with nimbolide lasted from day 1 to day 28. At the time of study termination, the injected sites were collected and stored suitably to conduct further molecular experiments and protein expression studies. Results and conclusion: The results of our study show that nimbolide can significantly intervene in the TGF-β/Smad signaling axis and the consequent EMT process, thus attenuating deposition of extracellular matrix. Nimbolide also profoundly caused the regression of established inflammation-driven fibrosis, thus demonstrating both antifibrotic and anti-inflammatory activities. Another commendable finding of this study is that nimbolide was able to decrease the levels of LOXL2, a collagen cross-linker, which is aberrantly expressed in scleroderma. Although further mechanistic studies are required, our study displays nimbolide for the first time as a potent antifibrotic agent which can be used as a pharmacological intervention for the treatment of scleroderma. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp), a well known efflux transporter in the blood brain barrier inhibits the uptake of substrate drugs into brain. The main aim of this study is to evaluate the effect of natural product based P-gp inhibitors on brain penetration of various CNS drugs which are P-gp substrates. In this study, we have evaluated the inhibitory effects of natural bioflavonoids (quercetin and silymarin) on P-gp by using digoxin and quinidine as model P-gp model substrate drugs. In vitro inhibitory effects were evaluated in Caco-2 cell lines using digoxin as a model drug and in vivo P-gp inhibiting effect was evaluated in mice model using quinidine as model drug. The accumulation and bidirectional transport of digoxin in Caco-2 cells was determined in presence and absence of quercetin and silymarin. Elacridar was used as standard P-gp inhibitor and used to compare the inhibitory effects of test compounds. The apical to basolateral transport of digoxin was increased where as basolateral to apical transport of digoxin was decreased in concentration dependent manner in the presence of elacridar, quercetin and silymarin. After intravenous administration of P-gp inhibitors, brain levels of quinidine were estimated using LC-MS method. Increased brain uptake was observed with quercetin (2.5-fold) and silymarin (3.5-fold). Though the brain penetration potential of P-gp substrates was lower than that observed in elacridar, both quercetin and silymarin improved plasma quinidine levels. Caco-2 permeability studies and brain uptake indicate that both quercetin and silymarin can inhibit P-gp mediated efflux of drug into brain. Our results suggest that both silymarin and quercetin could potentially increase the brain distribution of co-administered drugs that are P-gp substrates. [ABSTRACT FROM AUTHOR]

Purpose: Oral administration of anticancer agents presents a series of advantages for patients. However, most of the anticancer drugs have poor water solubility leading to low bioavailability. Methods: Controlled released spray dried matrix system of Gefitinib with hydroxypropyl β-cyclodextrin, chitosan, hydroxy propyl methyl cellulose, vitamin E TPGS, succinic acid were used for the design of formulations to improve the oral absorption of Gefitinib. Spray drying with a customized spray gun which allows simultaneous/pulsatile flow of two different liquid systems through single nozzle was used to prepare Gefitinib spray dried formulations (Gef-SD). Formulation was characterized by in vitro drug release and Caco-2 permeability studies. Pharmacokinetic studies were performed in Sprague Dawley rats. Efficacy of Gef-SD was carried out in A431 xenografts models in nude mice. Results: In Gef-SD group 9.14-fold increase in the AUC was observed compared to free Gef. Improved pharmacokinetic profile of Gef-SD translated into increase (1.75 fold compared to Gef free drug) in anticancer effects. Animal survival was significantly increased in Gef formulation treated groups, with superior reduction in the tumor size (1.48-fold) and volumes (1.75-fold) and also increase in the anticancer effects (TUNEL positive apoptotic cells) was observed in Gef-SD treated groups. Further, western blot, immunohistochemical and proteomics analysis demonstrated the increased pharmacodynamic effects of Gef-SD formulations in A431 xenograft tumor models. Conclusion: Our studies suggested that Gefitinib can be successfully incorporated into control release microparticles based oral formulation with enhanced pharmacokinetic and pharmacodynamic activity. This study demonstrates the novel application of Gef in A431 tumor models. [ABSTRACT FROM AUTHOR]

Purpose: In an effort to prepare an oral dosage form for poorly bioavailable anti-cancer agents, we have incorporated spray drying using a customized spray gun generating enteric coated Self-emulsifying drug delivery systems. The objective of this study was to design and evaluate pharmacokinetics and pharmacodynamic characteristics of Spray BIO-Max DIM-P (SB DIM-P). Methods: SB DIM-P was prepared and optimized based on physico-chemical characteristics using design of experiment (DOE-Vr 8.0) software. Pharmacokinetic parameters in dogs and rats were evaluated and analyzed using Winonlin. Anti-tumor activity was carried out in orthotopic and metastatic lung tumor models using size M capsules in mice. Results: Based on the optimization using DOE analysis of SB DIM-P characteristics, formulations were selected for further investigation. Pharmacokinetic studies showed a 30% increase in oral bioavailability in rats and ~2.9 times more bioavailability of SB DIM-P compare to solution in dogs. SB DIM-P showed ~20-25% more tumor volume/weight reduction in H1650 metastatic tumor model and ~25-30% tumor volume/weight reduction in A549 orthotopic tumor model compared to DIM-P solution. Conclusions: Our studies demonstrate the potential application of spray dried enteric coated self-emulsifying delivery system (SB DIM-P) to enhances oral absorption and efficacy of DIM-P in lung tumor models. [ABSTRACT FROM AUTHOR]