Mitochondria‐Targeted Curcumin Delivery: Therapeutic Strategies for Mitochondrial Dysfunction‐Related Disorders

Mitochondria in neurodegenerative diseases.

Synthesis and anticancer activity evaluation of self- assembled curcumin loaded gelatin - oleic acid - carboxymethyl chitosan nanoparticles on MCF-7 cells.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

Effect of nanostructured lipid vehicles on percutaneous absorption of curcumin

A new biodegradable nano cellulose-based drug delivery system for pH-controlled delivery of curcumin

A novel curcumin (CUR) delivery system was developed using soybean whey protein (SWP)-based emulsions, enhanced by pH-adjustment and gum arabic (GA) modification. Modulating electrostatic interactions between SWP and GA at oil/water interface, pH provides favorable charging conditions for stable distribution between droplets. GA facilitated the SWP form a stable interfacial layer that significantly enhanced the emulsifying properties and CUR encapsulation efficiency of the system at pH 6.0, which were 90.15 ± 0.67%, 870.53 ± 3.22 m2/g and 2157.62 ± 115.31%, respectively. Duncan's test revealed significant improvements in thermal, UV, oxidative, and storage stabilities of CUR (P < 0.05). At pH 6.0, GA effectively protected CUR by inhibiting SWP degradation during gastric digestion and promoting the release of CUR by decreasing steric hindrance with oil droplets during intestinal digestion, achieving the highest CUR bioaccessibility (69.12% ± 0.28%) based on Duncan's test. The SWP-GA-CUR emulsion delivery system would be a novel carrier for nutrients.

Considering that the pathological changes are inconsistent with severe organ dysfunction of sepsis.It is urgent to explore the other pathogenetic mechanisms besides inflammation and immunity.A extraordinary explanation for multiple organ dysfunction is associated with mitochondrial dysfunction during sepsis.Although the exact relationship between them is not proved, and therapeutic strategy is suggested to promote the organs function by improving mitochondrial metabolism for sepsis.This article focused on mitochondrial biology, mitochondrial dysfunction, metabolic disorder and mitochondrial resuscitation in sepsis. Key words: Sepsis; Mitochondrial dysfunction; Mitochondria resuscitation

Missense mutations in the nuclear-encoded adenine nucleotide translocase 1 (Ant1) cause the protein to clog the mitochondrial protein import pathway, to severely inhibit cell growth in yeast, and to cause neurodegeneration and myopathy in mice that phenocopy ANT1-induced human disease.

Curcumin (CUM) possesses therapeutic activity against diverse skin disorders (SD); however, its clinical use faces many challenges related to physicochemical and bioavailability characteristics, that can be solve designing a new drug delivery system for CUM to treat SD. Cationic solid lipid nanoparticles (CSLN) were developed and physicochemically analyzed. The ingredients and methods adopted in this study promoted the successful preparation of CSLN with a monodispersed particle size of 218.4-238.6 nm and a polydispersity index of 0.156-0.350. A differential scanning calorimetric assay demonstrated that CUM was incorporated. The atomic force microscopy images showed uniform spherical particles, and light scattering technique confirmed the size of the particles. The zeta potential of the CSLN was +23.1 to +30.1 mV, which is important in targeting the drug to the diseased tissue that presents unregulated apoptosis. All formulations behaved as controlled drug delivery systems of CUM, as demonstrated by an in vitro drug release study, which delayed the start of drug release from formulations. At the end of the experiment, the formulations had released 14.74-21.23% of the incorporated CUM. In conclusion, the results suggest the potential of this CSLN as a controlled CUM delivery system for the treatment of SD.

Construction of quaternary ammonium chitosan-coated protein nanoparticles as novel delivery system for curcumin: Characterization, stability, antioxidant activity and bio-accessibility

Gastric environment-stable oral nanocarriers for in situ colorectal cancer therapy

Background: The current study aimed to design a novel combination of lansoprazole (LNS) and curcumin (CUR) solid oral dosage form using bioactive self-nanoemulsifying drug delivery systems (Bio-SSNEDDS). Methods: Liquid SNEDDS were prepared using the lipid-excipients: Imwitor988 (cosurfactant), Kolliphor El (surfactant), the bioactive black seed (BSO) and/or zanthoxylum rhetsa seed oils (ZRO). Liquid SNEDDS were loaded with CUR and LNS, then solidified using commercially available (uncured) and processed (cured) Neusilin® US2 (NUS2) adsorbent. A novel UHPLC method was validated to simultaneously quantify CUR and LNS in lipid-based formulations. The liquid SNEDDS were characterized in terms of self-emulsification, droplet size and zeta-potential measurements. The solidified SNEDDS were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), in vitro dissolution and stability in accelerated storage conditions. Results: Liquid SNEDDS containing BSO produced a transparent appearance and ultra-fine droplet size (14 nm) upon aqueous dilution. The solidified SNEDDS using cured and uncured NUS2 showed complete solidification with no particle agglomeration. DSC and XRD confirmed the conversion of crystalline CUR and LNS to the amorphous form in all solid SNEDDS samples. SEM images showed that CUR/LNS-SNEDDS were relatively spherical and regular in shape. The optimized solid SNEDDS showed higher percent of cumulative release as compared to the pure drugs. Curing NUS2 with 10% PVP led to significant enhancement of CUR and LNS dissolution efficiencies (up to 1.82- and 2.75-fold, respectively) compared to uncured NUS2-based solid SNEDDS. These findings could be attributed to the significant (50%) reduction in the micropore area% in cured NUS2 which reflects blocking very small pores allowing more space for the self-emulsification process to take place in the larger-size pores. Solid SNEDDS showed significant enhancement of liquid SNEDDS stability after 6 months storage in accelerated conditions. Conclusions: The developed Bio-SSNEDDS of CUR and LNS using processed NUS2 could be used as a potential combination therapy to improve the treatment of peptic ulcers.

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

Mitochondrial damage or dysfunction contribute critically to the pathogenesis of various diseases, including AKI. Upon stress, mitochondrial dynamics are disrupted and membrane integrity is compromised, resulting in the release of apoptogenic factors, mitochondrial permeability transition (MPT),

Octenyl succinate anhydride debranched starch-based nanocarriers for curcumin with improved stability and antioxidant activity