Nintedanib solid lipid nanoparticles improve oral bioavailability and ameliorate pulmonary fibrosis in vitro and in vivo models.

Nintedanib (NIN) and pirfenidone are the only approved drugs for the treatment of Idiopathic Pulmonary Fibrosis (IPF). However, NIN and pirfenidone have low oral bioavailability and limited therapeutic potential, requiring higher dosages to increase their efficacy, which causes significant liver and gastrointestinal toxicities. In this study, we aimed to develop nintedanib-loaded solid lipid nanoparticles (NIN-SLN) to improve the oral bioavailability and therapeutic potential against TGF-ß-induced differentiation in IPF fibroblasts and bleomycin (BLM)-induced lung fibrosis in rat models. NIN-SLN was prepared using a double-emulsification method and characterization studies (Particle size, zeta potential, entrapment efficiency and other parameters) were performed using various techniques. NIN-SLN treatment significantly (p < 0.001) downregulated α-SMA and COL3A1 expression in TGF-ß stimulated DHLF and LL29 cells. NIN-SLN showed a 2.87-fold increase in the bioavailability of NIN and also improved the NIN levels in lung tissues compared to NIN alone. Pharmacodynamic investigation revealed that NIN-SLN (50 mg/Kg) treatment significantly attenuated BLM-induced lung fibrosis by inhibiting epithelial-to-mesenchymal-transition (EMT), extracellular matrix remodelling, and collagen deposition compared to free NIN. Additionally, in the BLM model of fibrosis, NIN-SLN greatly improved the BLM-caused pathological changes, attenuated the NIN-induced gastrointestinal abnormalities, and significantly improved the lung functional indices compared to free NIN. Collectively, NIN-SLN could be a promising nanoformulation for the management of pulmonary fibrosis.

Toxicological evaluation of therapeutically active zinc oxide nanoflowers in pre-clinical mouse model.

Our earlier reports established that zinc oxide nanoflowers (ZONF) show significant pro-angiogenic properties, where reactive oxygen species, nitric oxide and MAPK-AKT-eNOS cell signaling axis play an essential task. Considering the significance of angiogenesis in healthcare, our research group has recently demonstrated the in vivo therapeutic application of ZONF (10 mg/kg b.w.) for treating peripheral artery disease. Moreover, based on the angio-neural crosstalk between vascular and neuronal systems, we have further demonstrated the neuritogenic and neuroprotective characteristics of pro-angiogenic nanoflowers (10 mg/kg b.w.) for the treatment of cerebral ischemia. However, it is crucial for a therapeutic material to be non-toxic for its practical clinical applications and therefore assessment of its in vivo toxicity and adverse effect is highly important. Herein, for the first time, we investigate a detailed nanotoxicology of therapeutically active ZONF in Swiss albino mice to evaluate their safety profile and comprehend their aspects for future clinical applications. The maximum tolerated dose (MTD) of ZONF was found to be 512.5 mg/kg b.w. which was employed for acute exposure (2 weeks), showing slight toxicity. However, sub-chronic (4 weeks) and long term chronic (8-12 weeks) studies of nanoflowers exhibited their non-toxic nature particularly at lower therapeutic doses (1-10 mg/kg b.w.). Additionally, in depth genotoxicity study revealed that lower therapeutic dose of ZONF (10 mg/kg b.w.) did not exhibit significant toxicity even in genetic level. Overall, the present nanotoxicology of ZONF suggests their high biocompatible nature at therapeutic dose, offering the basis of their future clinical applications in ischemic and other vascular diseases.

Anti-hyperglycemic and genotoxic studies of 1-O-methyl chrysophanol, a new anthraquinone isolated from Amycolatopsis thermoflava strain SFMA-103.

The compound 1-O-methyl chrysophanol (OMC) which belongs to a class of hydroxyanthraquinones was isolated from Amycolatopsis thermoflava strain SFMA-103 and studied for their anti-diabetic properties. OMC was evaluated as an anti-diabetic agent based on in silico studies which initially predicted the binding energy with α-amylase (-188.81 KJ mol-1) and with α-glucosidase (70.53 KJ mol-1). Further, these results were validated based on enzyme inhibition assays where OMC demonstrated enzyme inhibitory activity towards α-amylase (IC50 3.4 mg mL-1) and α-glucosidase (IC50 38.49 µg mL-1). To confirm the anti-diabetic activity, in vivo studies (oral dose in Wistar rats) revealed that OMC inhibited significantly the increase in glucose concentration at 100 mg/kg as compared to starch control (p < 0.05). Further, to understand the safety of OMC as a therapeutic agent, the genotoxic analysis was performed in both in vitro Chinese Hamster Ovary cells (250, 500, and 1000 µM/mL) and in vivo Swiss albino mice (250, 500, and 1000 mg/kg). In vitro results showed that OMC concentration of up to 250 µM/mL did not elicit significant changes in CAs, MI, and MN counts in CHO cells. Similarly, in mice experiments (i.p. injection), no significant changes in CAs, MI, and MN induction were observed till 500 mg/kg of OMC when compared with chrysophanic acid (Cy) (200 mg/kg). In addition, mice that received the lowest dose of OMC (250 mg/kg) did not show any histological changes in liver, kidney, and heart. The study concluded that five times higher therapeutic dose (100 mg/kg) of OMC can be utilized against hyperglycemia with no genotoxic effects.

Phytometabolomic analysis of boiled rhizome of Nymphaea nouchali (Burm. f.) using UPLC-Q-TOF-MSE, LC-QqQ-MS & GC-MS and evaluation of antihyperglycemic and antioxidant activities.

Phytometabolomic analysis of Nymphaea nouchali (Burm. F.) boiled rhizome was carried out utilizing UPLC-Q-TOF-MSE, LC-QqQ-MS and GC-MS techniques and evaluated for antihyperglycemic and antioxidative stress potentials. Metabolomic analysis revealed presence of multiple antidiabetic and antioxidant compounds. Boiled rhizome powder exhibited potent antihyperglycemic activity against sugar-induced postprandial hyperglycemia in rats plausibly due to the presence of intestinal α-glucosidase inhibitory and augmenting cellular glucose uptake activities. It also prevented hyperglycemia-induced hemoglobin and insulin glycation. Rhizome displayed potent reducing power, effectively scavenged various reactive oxygen species. It displayed antioxidative stress potential in assuaging H2O2 induced erythrocyte hemolysis and antioxidant activity by inhibiting membrane lipid peroxidation. Boiled rhizome was also found to preserve the loss of cellular antioxidants under H2O2 induced oxidative stress and disturbances caused to mitochondrial membrane potential. This is the first research reporting boiled N. nouchali rhizome as an ideal food material to manage the cause of hyperglycemia and resultant oxidative stress.

Anti-inflammatory effect of stevioside abates Freund's complete adjuvant (FCA)-induced adjuvant arthritis in rats.

Adjuvant arthritis is a chronic, autoimmune and inflammatory disorder of the joints. The occurrence of disorder causes a severe damage to the connective tissue eventually leading to progressive physical disability and eventual death. The recent years of evidence suggests the anti-inflammatory properties of stevioside, a diterpene glycoside. However, the effect of stevioside against adjuvant arthritis, a chronic inflammatory disorder is not known. Hence, the present study was designed to study the effect of stevioside against Freund's complete adjuvant induced arthritis model in rats. The acute anti-inflammatory effect of stevioside also studied by employing carrageenan-induced paw oedema model in rats. The biochemical markers, haematological parameters, lipid peroxidation, myeloperoxidase activity, lipoxygenase activity, the levels of PGE2 and pro-inflammatory (TNF-α, IL-6 & IL-1ß) and anti-inflammatory cytokine (IL-10) were analysed. The protein expression of NF-κB (p65) COX-2 and iNOS in paw tissues were estimated by western blotting. Stevioside treatment significantly ameliorates the adjuvant induced arthritic scoring, histological alterations, paw volume, elevation of biochemical (AST, ALT, ALP and glucose levels) and haematological (haemoglobin, differential and platelet count) parameters and restored the endogenous anti-oxidant (SOD, CAT, GSH and GST) activities. Treatment with stevioside also significantly prevented the adjuvant induced elevation of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), pro-inflammatory protein expressions (iNOS, COX-2, NF-κB (p65) and pIκB/IκB ratio), prevented the increase in myeloperoxidase activity and significantly restored the anti-inflammatory (IL-10) cytokine level in paw tissues. Collectively, our findings suggest that stevioside may serve as anti-inflammatory agent and could serve as a potential adjunct therapeutic option in treating adjuvant arthritis.

Synthesis and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates.

Cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (3a-g) and 4-chloro-2H-chromene-3-carbaldehydes (7a-h) with activated alkynes (4a-b) provided the 2-oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n) and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (8a-p). All the prepared compounds were screened for anti-inflammatory activity. In vitro anti-inflammatory activity data demonstrated that the compounds 5g, 5i, 5k-l and 8f are effective among the tested compounds against TNF-α (1.108 ± 0.002, 0.423 ± 0.022, 0.047 ± 0.001, 0.070 ± 0.002 and 0.142 ± 0.001 µM) in comparison with standard compound Prednisolone (0.033 ± 0.002 µM). Based on in vitro results, three compounds (5i, 5k and 8f) have been selected for in vivo experiments and these compounds are identified as better compounds with respect to anti-inflammatory activity in LPS induced mice model. Compound 5i was identified as potent and showed significant reduction in TNF-α and IL-6.

Anti-angiogenic vanadium pentoxide nanoparticles for the treatment of melanoma and their in vivo toxicity study.

In recent days, vanadium complexes and nanoparticles have received sustainable attention owing to their vast applications in different fields. In the present study, we report a facile approach for the synthesis of irregular dumbbell shaped vanadium pentoxide nanoparticles (V2O5 NPs: 30-60 nm) via the polyol-induced microwave irradiation process along with calcination. The as-synthesized nanoparticles were characterized using various physico-chemical techniques (e.g. XRD, TEM, FT-IR, DLS and XPS). The cell viability assay showed that V2O5 NPs could efficiently inhibit the proliferation of different cancer cells (B16F10, A549, and PANC1), depicting their anti-proliferative activity. However, V2O5 NPs did not exert significant cytotoxicity to the normal cells (CHO, HEK-293 and NRK-49F), suggesting their biocompatible nature. Interestingly, these nanoparticles inhibited the proliferation and migration of the endothelial cells (HUVECs and EA.hy926) and disrupted the blood vasculature in a chick embryo model, indicating their anti-angiogenic properties. The mechanistic study revealed that the effective internalization of V2O5 NPs generated intracellular reactive oxygen species (ROS) which in turn up-regulated p53 protein and down-regulated survivin protein in cancer cells, leading to the apoptosis process. Furthermore, the administration of V2O5 NPs to melanoma bearing C57BL6/J mice significantly increased their survivability as compared to the control untreated tumor bearing mice, exhibiting the therapeutic potential of the nanoparticles against melanoma. Additionally, the in vivo toxicity study demonstrated no toxic effect in mice upon sub-chronic exposure to V2O5 NPs. Altogether, we strongly believe that V2O5 NPs could intrinsically provide a new direction for alternative therapeutic treatment strategies for melanoma and other cancers by employing their anti-angiogenic properties in the future.

Combating Glioblastoma by Codelivering the Small-Molecule Inhibitor of STAT3 and STAT3siRNA with α5ß1 Integrin Receptor-Selective Liposomes.

Glioblastoma multiforme (GBM) is one of the most aggressive tumors with a median survival of only 15 months. Effective therapeutics need to overcome the formidable challenge of crossing the blood-brain barrier (BBB). Receptors and transporters overexpressed on BCECs are being used for designing liposomes, polymers, polymeric micelles, peptides, and dendrimer-based drug carriers for combating brain tumors. Herein, using the orthotopic mouse glioblastoma model, we show that codelivering a small-molecule inhibitor of the JAK/STAT pathway (WP1066) and STAT3siRNA with nanometric (100-150 nm) α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide holds therapeutic promise in combating glioblastoma. Rh-PE (red)-labeled liposomes of RGDK-lipopeptide were found to be internalized in GL261 cells via integrin α5ß1 receptors. Intravenously administered near-infrared (NIR)-dye-labeled α5ß1 integrin receptor-selective liposomes of RGDK-lipopeptide were found to be accumulated preferentially in the mouse brain tumor tissue. Importantly, we show that iv injection of WP1066 (a commercially sold small-molecule inhibitor of the JAK/STAT pathway) and STAT3siRNA cosolubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.

Potent and Selective Cytotoxic and Anti-inflammatory Gold(III) Compounds Containing Cyclometalated Phosphine Sulfide Ligands.

Four cycloaurated phosphine sulfide complexes, [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ][AuX2 ] [X=Cl (2), Br (3), I (4)] and [Au{κ2 -2-C6 H4 P(S)Ph2 }2 ]PF6 (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showed excellent cytotoxicity against a broad range of cancer cell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer (HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductase and induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showed that treatment with compounds 4 and 5 resulted in significant inhibition of tumor growth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexes were also evaluated for their in vitro and in vivo anti-inflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edema in rats, respectively.

An innovative in situ method of creating hybrid dendrimer nano-assembly: An efficient next generation dendritic platform for drug delivery.

Dendrimers have proven to be effective for drug delivery and their biodisposition varies with change on their surface, generation and core. In an effort to understand the role of critical nanoscale design parameters, we developed a novel hybrid dendrimer approach to harness unique features of individual dendrimers and create a nano-assembly. We report an easy in situ method of creating hybrid dendrimer nano-assembly by mixing G4.0 PAMAM (-NH2) and G3.5 PAMAM (-COONa) dendrimers with a chemotherapeutic drug docetaxel (DTX). Zeta potential, HR-TEM, 1H-NMR proved the formation of nano-assembly. In vitro dissolution, release studies revealed pH dependent dissolution and sustained drug release. Cellular uptake, cytotoxicity, and flow cytometric analysis in human/mouse glioblastoma cells indicated the effectiveness of hybrid dendrimers. The oral administration of the hybrid dendrimers showed pharmacokinetic equivalence to intravenous injection of commercially available Taxotere®. Hybrid dendrimer concept provides much needed fine-tuning to create multistage next-generation dendritic platform in nanomedicine.

Modulating the site-specific oral delivery of sorafenib using sugar-grafted nanoparticles for hepatocellular carcinoma treatment.

Globally, one in six deaths is reported due to cancer suggesting the critical need for development of advanced treatment regimens. In this study, solid lipid nanoparticles (SLN) were prepared and appended with polyethylene glycol (PEGylated) galactose and a multikinase inhibitor sorafenib (SRFB) was used as chemotherapeutic drug, for treating hepatocellular carcinoma (HCC). The nanoparticles were evaluated for in-vitro and in-vivo performances to showcase the targeting efficiency and therapeutic benefits of the sorafenib loaded ligand conjugated nanoparticles (GAL-SSLN). When compared with SRFB or Sorafenib loaded SLN, GAL-SSLN showed superior cytotoxicity and apoptosis in HepG2 (human hepatocellular carcinoma cells). In addition, in-vivo pharmacokinetics and real time biodistribution studies in BALB/c mice showed that the surface conjugation of nanoparticles with galactose resulted in better pharmacokinetic performance and targeted delivery of the nanoparticles to liver. Results indicated that GAL-SSLN showed promising attributes in terms of targeting sorafenib to liver and therapeutic efficacy.

Restoration of p53 Function in Ovarian Cancer Mediated by Gold Nanoparticle-Based EGFR Targeted Gene Delivery System.

Targeted gene delivery of wild type tumor suppressor gene p53 is a promising approach to inhibit the progression of ovarian cancer. Although several gene delivery vehicles have been reported earlier, there is paucity for targeted delivery of wild type p53 to ovarian cancer using gold nanoparticles. As it is well-known that EGFR (epidermal growth factor receptor) is overexpressed in ovarian cancer, in this study we hypothesized that the FDA approved monoclonal antibody C225 (cetuximab) that targets EGFR could be used for targeted delivery of wild type p53 gene. With this impetus, we devised an approach wherein cationic gold nanoparticles (AuNPs) were employed to generate gold nanoparticle-based drug delivery system (DDS, Au-C225-p53DNA where p53DNA is pCMVp53 plasmid) that was formulated and characterized by biochemical and biophysical methods. The nanoconjugate complexed with DNA (Au-C225-p53DNA) is serum-stable and protects the bound DNA from digestion by DNase-I. Additionally, in vitro reporter gene expression assays demonstrated efficient and specific gene transfection in EGFR overexpressing SK-OV-3 cells. Further, the intraperitoneal administration of Au-C225-p53DNA in SK-OV-3 xenograft mouse model displayed significant tumor targeting and tumor regression. Altogether, these studies indicated a promising nanoparticle-based approach for targeting ovarian cancers caused by mutated p53.

Supplementation of oat (Avena sativa L.) extract abates alcohol-induced acute liver injury in a mouse model.

Dietary supplementation of oats has been associated with reduced risk of cardiovascular disease, diabetes, and gastrointestinal disorders. The role of oat extract as prophylactic in treating acute liver injury is not thoroughly established. We, therefore, hypothesized that oat extract would exert protective effect against alcohol-induced acute liver injury in a mouse model. To test this hypothesis, male C57BL/6 mice were pretreated with phenolic-enriched ethyl acetate (EA) fraction of oats (prepared by fractionating aqueous ethanolic extract with solvents of increasing polarity) at dosages of 125 and 250 mg kg-1 d-1 for 12 consecutive days. Acute liver injury was induced by administering 5 doses of 50% ethanol intragastrically (10 g/kg body weight) to mice at an interval of 12 hours. The alcohol-induced liver injury was evaluated by measuring serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, antioxidant parameters, mitochondrial function, and histology of liver tissue. Our results demonstrated that pretreatment with EA fraction at 250 mg kg-1 d-1 significantly (P < .001 for aspartate aminotransferase, alanine aminotransferase, and thiobarbituric acid-reactive species and P < .01 for lactate dehydrogenase and nitrites) reduced the levels of liver injury markers and significantly (P < .001 for glutathione reductase and glutathione S-transferase; P < .01 for catalase, superoxide dismustase, and vitamin C; P < .05 for reduced glutathione and NAD(P)H quinone dehydrogenase 1) increased the levels of antioxidant defenses. Furthermore, EA-pretreated mice showed mechanistic inhibition of nuclear factor κB signaling pathway through decreased phosphorylation and degradation of IκBα. We conclude that phenolic-enriched EA fraction of oats has immense potential to serve as dietary intervention against alcohol-induced liver damage.

Ferulic acid protects lipopolysaccharide-induced acute kidney injury by suppressing inflammatory events and upregulating antioxidant defenses in Balb/c mice.

Sepsis-induced acute kidney injury (AKI) is responsible for 70-80% mortality in intensive care patients due to elevated levels of endotoxin, Lipopolysaccharide (LPS) caused by gram-negative infections. Ferulic acid (FA), a phenolic phytochemical is known for its renal protection on various induced models of nephrotoxicity. However, the curative effect of FA in LPS-induced AKI is not well studied. This study aimed to investigate the effect of FA on LPS-induced AKI in mice model and to understand the protective mechanisms involved, to provide evidence for FA in the treatment of AKI. Balb/c mice were treated with FA at 50 mg/kg and 100 mg/kg dosages after LPS stimulation (10 mg/kg). At the end of the intervention, we determined the concentrations of serum creatinine and blood urea nitrogen, inflammatory cytokines and histopathological changes in animals. Also, the relative protein expression level of TLR4 mediated NF-κB signaling pathway were studied in kidney tissues. FA treated animals showed upregulation of antioxidant defenses and suppression of inflammatory events by inhibiting TLR-4 mediated NFκB activation. However, LPS alone administered group, resulted in rapid renal damage with increased levels of blood urea nitrogen and modest increase in creatinine; decreased antioxidant defenses and release of inflammatory cytokines. The histopathological analysis also revealed the protective action of the FA against sepsis induced fibrosis and renal damage. Our findings demonstrated that FA exhibits marked protective effects on LPS-induced AKI in mice suggesting its chemopotential role for treating AKI in humans.

Capsaicin, the pungent principle of peppers, ameliorates alcohol-induced acute liver injury in mice via modulation of matrix metalloproteinases.

Alcohol, the most common cause for hepatic injury, may further deteriorate the hepatic tissue when left unattended. Capsaicin, the pungent principle of chilli peppers, possesses antioxidant and anti-inflammatory properties and is a proven dietary antioxidant in various ailments. However, its role in alcohol-induced hepatic injury is unclear. In this study, we investigated the effects of capsaicin on the hepatic tissue of mice treated with alcohol. Acute liver injury was induced in mice by oral gavage of 5 doses of 10 mL/kg of 50% ethyl alcohol at an interval of 12 h. The tissue antioxidant levels along with the mitochondrial functional parameters and matrix metalloproteinase levels were evaluated in the hepatic tissues of mice following alcohol challenge. The results showed that alcohol intake significantly attenuated the hepatic antioxidant levels and mitochondrial function. These changes were accompanied by enhanced serum hepatic injury markers and matrix metalloproteinases. However, capsaicin treatment (10 and 20 mg/kg, oral) throughout the experimental period caused a drastic improvement in the hepatic tissue of the alcohol-treated mice, reflected by the normalization of hepatic enzyme and protein levels along with restored histological alterations. These results indicate that capsaicin, as a dietary intervention, may prevent alcohol-induced acute liver injury.

Large Amino Acid Transporter 1 Selective Liposomes of l-DOPA Functionalized Amphiphile for Combating Glioblastoma.

Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma.

Polydatin alleviates alcohol-induced acute liver injury in mice: Relevance of matrix metalloproteinases (MMPs) and hepatic antioxidants.

BACKGROUND: Alcohol, a most commonly consumed beverage, is the foremost cause of liver injury throughout the world. Polydatin, a stilbenoid glucoside, was known to possess antioxidant and anti-inflammatory properties and is being investigated for use in various disorders. PURPOSE: The present study was intended at investigating the hepatoprotective efficacy of polydatin against acute-alcohol induced liver injury model in mice. STUDY DESIGN: C57BL/6 mice were fed with five doses of 50% ethyl alcohol (10ml/kg body weight) to induce acute liver injury. Effect of polydatin against alcohol induced hepatic injury was investigated by giving 50 or 100mg/kg polydatin, orally, for 8 days. METHODS: Serum markers of liver injury, morphology, histology and fibrosis of liver tissue, levels of enzymatic and non-enzymatic antioxidants and the mitochondrial respiratory enzyme activities in liver tissue were investigated. The activities and the protein expression of matrix metalloproteinases (MMP-2 and -9), the expression of NF-κB in the liver tissue were also studied. RESULTS: Polydatin pre-treatment significantly alleviated the alcohol induced hepatic injury by reducing the serum liver injury markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), attenuating oxidative stress and restoring antioxidant balance in the hepatic tissue. Simultaneously, polydatin pre-treatment also prevented alcohol induced mitochondrial damage and refurbished the matrix metalloproteinases levels of the hepatic tissue. CONCLUSION: The findings of the present study suggest that polydatin may have a potential benefit in preventing alcohol-induced acute hepatic injury.

Improving Efficacy, Oral Bioavailability, and Delivery of Paclitaxel Using Protein-Grafted Solid Lipid Nanoparticles.

Oral delivery of anticancer drugs remains challenging despite the most convenient route of drug administration. Hydrophobicity and nonspecific toxicities of anticancer agents are major impediments in the development of oral formulation. In this study, we developed wheat germ agglutinin (WGA)-conjugated, solid lipid nanoparticles to improve the oral delivery of the hydrophobic anticancer drug, paclitaxel (PTX). This study was focused to improve the PTX loading in biocompatible lipid matrix with high bioconjugation efficiency. WGA-conjugated, PTX-loaded solid lipid nanoparticles (LPSN) exhibited enhanced anticancer activity against A549 lung cancer cells after internalization through lectin receptors than free PTX. Biodistribution studies in rats revealed that LPSN significantly improved the oral bioavailability and lung targetability of PTX, which could be due to cumulative bioadhesive property of the nanocarrier system and the targeting ligand WGA.

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer.

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

Baicalein alleviates doxorubicin-induced cardiotoxicity via suppression of myocardial oxidative stress and apoptosis in mice.

AIMS: Doxorubicin is a widely used anthracycline derivative anticancer drug. Unfortunately, the clinical use of doxorubicin has the serious drawback of cardiotoxicity. In this study, we investigated whether baicalein, a bioflavonoid, can prevent doxorubicin-induced cardiotoxicity in vivo and we delineated the possible underlying mechanisms. MAIN METHODS: Male BALB/c mice were treated with either intraperitoneal doxorubicin (15 mg/kg divided into three equal doses for 15 days) and/or oral baicalein (25 and 50 mg/kg for 15 days). Serum markers of cardiac injury, histology of heart, parameters related to myocardial oxidative stress, apoptosis and inflammation were investigated. KEY FINDINGS: Treatment with baicalein reduced doxorubicin-induced elevation of serum creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and ameliorated the histopathological damage. Baicalein restored the doxorubicin-induced decrease in both enzymatic and non-enzymatic myocardial antioxidants and increased the myocardial expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Further studies showed that baicalein could inverse the Bax/Bcl-2 ratio, suppress doxorubicin-induced p53, cleaved caspase-3 and PARP expression and prevented doxorubicin-induced DNA damage. Baicalein treatment also interferes with doxorubicin-induced myocardial NF-κB signaling through inhibition of IκBα phosphorylation and nuclear translocation of p65 subunit. Doxorubicin elevated iNOS and nitrites levels were also significantly decreased in baicalein treated mice. However, we did not find any significant change (p>0.05) in the myocardial TNF-α and IL-6 levels in control and treated animals. SIGNIFICANCE: Our finding suggests that baicalein might be a promising molecule for the prevention of doxorubicin-induced cardiotoxicity.