Mitochondrial targeting of potent nanoparticulated drugs in combating diseases.

Mitochondrial dysfunction, characterized by the electron transport chain (ETC) leakage and reduced adenosine tri-phosphate synthesis, occurs primarily due to free radicals -induced mutations in either the mitochondrial deoxyribonucleic acid (mtDNA) or nuclear (n) DNA caused by pathogenic infections, toxicant exposures, adverse drug-effects, or other environmental exposures, leading to secondary dysfunction affecting ischemic, diabetic, cancerous, and degenerative diseases. In these concerns, mitochondria-targeted remedies may include a significant role in the protection and treatment of mitochondrial function to enhance its activity. Coenzyme Q10 pyridinol and pyrimidinol antioxidant analogues and other potent drug-compounds for their multifunctional radical quencher and other anti-toxic activities may take a significant therapeutic effectivity for ameliorating mitochondrial dysfunction. Moreover, the encapsulation of these bioactive ligands-attached potent compounds in vesicular system may enable them a superb biological effective for the treatment of mitochondria-targeted dysfunction-related diseases with least side effects. This review depicts mainly on mitochondrial enzymatic dysfunction and their amelioration by potent drugs with the usages of nanoparticulated delivery system against mitochondria-affected diseases.

Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane.

Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remains to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α, which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment. As measured by anchorage-independent colony formation assay, cadmium induced malignant cell transformation. Inhibition of ROS by antioxidants inhibited transformation, showing that ROS were important in the mechanism of this process. The inflammatory microenvironment created by cadmium may also contribute to the mechanism of the transformation. Using tandem fluorescence protein mCherry-GFP-LC3 construct, the present study shows that cadmium-transformed cells had a property of autophagy deficiency, resulting in accumulation of autophagosomes and increased p62. This protein upregulated Nrf2, which also upregulated p62 through positive feed-back mechanism. Constitutive Nrf2 activation increased its downstream anti-apoptotic proteins, Bcl-2 and Bcl-xl, resulting in apoptosis resistance. In untransformed BEAS-2BR cells, sulforaphane, a natural compound, increased autophagy, activated Nrf2, and decreased ROS. In cadmium-transformed BEAS-2BR cells, sulforaphane restored autophagy, decreased Nrf2, and decreased apoptosis resistance. In untransformed cells, this sulforaphane induced inducible Nrf2 to decrease ROS and possibly malignant cell transformation. In cadmium-transformed cells, it decreased constitutive Nrf2 and reduced apoptosis resistance. The dual roles of sulforaphane make this natural compound a valuable agent for prevention against cadmium-induced carcinogenesis.

Vesicular melatonin efficiently downregulates sodium fluoride-induced rat hepato- and broncho-TNF-α, TGF-ß expressions, and associated oxidative injury: a comparative study of liposomal and nanoencapsulated forms.

The importance of fluoride as a natural and industrial toxicant is recognized worldwide. We evaluated the regulating role and biological effect of vesicular (liposomal and nanoencapsulated) melatonin (N-acetyl-5-methoxytryptamine) for drug delivery and controlled release on the depletion of inflammatory mediators, as well as oxidative damage in sodium fluoride (NaF)-treated lungs and liver. Hepatic and bronchial damage was induced in Swiss albino rats with a single acute ingestion of NaF (48 mg/kg body weight, oral gavage). NaF exposure caused the generation of reactive oxygen species (ROS); upregulation of TNF-α and TGF-ß; decreased activities of antioxidant systems (glutathione, glutathione-S-transferase, superoxide dismutase, catalase), succinate dehydrogenase, membrane microviscosity, and membrane potential; increased activity of lipid peroxidation and nicotinamide adenine dinucleotide hydride oxidase; and increased hepatic and nephrite toxicities (P<0.001) compared to those in normal animals. Charge (-ve/+ve)-specific single liposomal (dicetyl phosphate/stearylamine) and nanoencapsulated melatonin (4.46 mg/kg body weight, intravenous) treatments (2 hours after NaF exposure) significantly (P<0.01/0.001) and maximally (P<0.001) inhibited all alterations developed in NaF-mediated oxidative injuries in rat liver (+ve) and lungs (-ve), demonstrating their strong free radical scavenging, antioxidant and antigenotoxic properties, and vesicular efficiencies of targeting. Overall, these results suggest that nanoencapsulated melatonin might be considered as a more powerful remedial therapy in comparison to liposomes, in terms of its efficacy in regulating NaF-intoxicated oxidative injury.

Nanocapsulated quercetin downregulates rat hepatic MMP-13 and controls diethylnitrosamine-induced carcinoma.

AIMS: The aims of our work were to investigate the controlling role and the efficacy of nanocapsulated quercetin drug delivery system on the decrement of inflammatory mediators such as MMP-13 in diethyl nitrosamine (DEN)-induced hepatocarcinogenesis. MATERIALS & METHODS: Hepatocellular carcinoma was developed in the Swiss albino rats by the exposure of DEN. DEN administration caused the generation of reactive oxygen species, upregulation of TNF-α, IL-6, activation of MMP-13, severe oxidative damage, hyperplastic nodules with preneoplastic lesions and the histopathological changes in rat liver. RESULTS & CONCLUSION: Nanocapsulated quercetin treatment restricted all alterations in DEN-mediated development of hepatocarcinogenesis. Therefore, it may be concluded that nanocapsulated quercetin may be accepted as a potent therapeutic formulation in preventing DEN-mediated hepatocarcinogenesis.

Vesicular antioxidants: role in age-related cerebral oxidative injury.

Oxidative stress, due to the generation of reactive oxygen species, is a major factor in cerebral ischemic damage and changes the activities of antioxidant enzymes and substantially influences the aging process. Free chemical antioxidant is almost ineffective to treat brain ischemia as blood-brain barrier exists in between blood and brain interstitial fluid, limiting component to pass from the circulation into cerebral region. Different compounds have been tested in vivo in different vesiculated forms to prevent cerebral ischemia. Nanoparticle-encapsulated drug treatment resulted in a significant protection of the antioxidant enzymes in both young and old rats. Nanocapsulated drug treatment causes a substantial protection against cerebral ischemia-reperfusion-induced oxidative damage to all parts of brain specifically hippocampal regions of all age groups of rat brain.