Flavonoids (or bioflavonoids) are naturally occurring compounds, ubiquitous in all vascular plants. These compounds have been considered to possess anti-inflammatory properties, both in vitro and in ...vivo. Although not fully understood, these health-promoting effects have been mainly related to their interactions with several key enzymes, signaling cascades involving cytokines and regulatory transcription factors, and antioxidant systems. The biological effects of flavonoids will depend not only on these pharmacodynamic features but also on their pharmacokinetics, which are dependent on their chemical structure, administered dose schedule and route of administration. Thus, the therapeutic outcome mediated by flavonoids will result from a complex and interactive network of effects, whose prediction require a deep and integrated knowledge of those pharmacokinetic and pharmacodynamic factors. The aim of the present review is thus to provide an integrated update on the bioavailability and biotransformation of flavonoids and the mechanisms of activity at the molecular, cellular, organ and organism levels that may contribute to their anti-inflammatory effects.
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•Quercetin targets insulin resistant HepG2 cells effectively.•Incorporating quercetin into liposomes enhanced its efficacy.•Quercetin liposomes positively improved Akt and NF-κB ...pathways.•Quercetin liposomes lowered reactive species and prostaglandin E2 levels.•Quercetin liposomes offer an innovative strategy for diabetes management.
In type 2 diabetes mellitus, hepatic insulin resistance is intricately associated with oxidative stress and inflammation. Nonetheless, the lack of therapeutic interventions directly targeting hepatic dysfunction represents a notable gap in current treatment options. Flavonoids have been explored due to their potential antidiabetic effects. However, these compounds are associated with low bioavailability and high metabolization. In the present study, four flavonoids, kaempferol, quercetin, kaempferol-7-O-glucoside and quercetin-7-O-glucoside, were studied in a cellular model of hepatic insulin resistance using HepG2 cells. Quercetin was selected as the most promising flavonoid and incorporated into liposomes to enhance its therapeutic effect. Quercetin liposomes had a mean size of 0.12 µm, with an incorporation efficiency of 93 %. Quercetin liposomes exhibited increased efficacy in modulating insulin resistance. This was achieved through the modulation of Akt expression and the attenuation of inflammation, particularly via the NF-κB pathway, as well as the regulation of PGE2 and COX-2 expression. Furthermore, quercetin liposomes displayed a significant advantage over free quercetin in attenuating the production of reactive pro-oxidant species. These findings open new avenues for developing innovative therapeutic strategies to manage diabetes, emphasizing the potential of quercetin liposomes as a promising approach for targeting both hepatic insulin resistance and associated inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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One of the main challenges when developing a spray dried formulation of an inhalable enzyme is the generation of a safe and effective aerosol, able to reach the lungs, while ...preserving protein function and structural levels of the biologic. Hence, an appropriate excipient selection based on enzyme stabilization, inhalation precedence and spray drying (SD) process development is required to meet this balance. Herein, an integrated methodology is presented to expedite the selection of the best dry powder inhaler excipient system to formulate three model enzymes of increasing molecular mass and structural complexity belonging to the oxidoreductase class and often implicated in oxidative stress: superoxide dismutase, glucose oxidase and catalase. Three non-reducing sugars and four amino acids were screened using High Throughput Isothermal Denaturation Fluorimetry (HT-ITDF) for a stabilizing effect on the enzymes quaternary structure. For each tested enzyme, the sugar and amino acid showcasing a stabilizing effect, were spray dried together at fixed process conditions for three different ratios, to assess which formulation would then display the best aerodynamic performance. After SD, using the selected conditions, all powders displayed 65–85% of fine particle fraction (FPF) whilst each enzyme kept the oligomeric state. The present integrated methodology proved to be successful, allowing to narrow down 36 potential formulations (three sugars × four amino acids × three ratios) to only one for each enzyme, within few hours, while requiring a μg range of sample amount.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Diabetes mellitus is one of the biggest health emergencies of the 21st century worldwide, characterized by deficiency in insulin secretion and/or action, leading to hyperglycemia. Despite the ...currently available antidiabetic therapeutic options, 4.2 million people died in 2019 due to diabetes. Thus, new effective interventions are required. Polyphenols are plant secondary metabolites and have been recognized for their vast number of biological activities, including potential antidiabetic effects. However, the poor bioavailability and high metabolization of polyphenols restrict their biological effects in vivo. Nanotechnology is a promising area of research to improve the therapeutic effect of several compounds. Therefore, this review provides an overview of the literature about the utility of nano-based drug delivery systems as vehicles of polyphenols in diabetes treatment. It was possible to conclude that, in general, nano-based drug delivery systems can potentiate the beneficial antidiabetic properties of polyphenols, when compared with the free compounds, opening a new field of research in diabetology.
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•Diabetes mellitus is a chronic multifactorial disorder of the 21st century.•Polyphenols have been recognized for their potential antidiabetic activities.•Poor bioavailability of polyphenols restricts their antidiabetic clinical efficacy.•Nanotechnology can potentiate the beneficial antidiabetic effects of polyphenols.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite the advantages of targeting the pulmonary route through Dry Powder Inhalers (DPIs), the efficient delivery of biologics to the lungs still presents a considerable challenge: the generation of ...a powder with adequate aerodynamic properties while preserving the integrity of the biologic. Hence, the particle engineering technology employed to meet this balance plays a pivotal role.
The present work describes a proof-of-concept study to investigate the effect of spray drying (SD) outlet temperature (Tout), atomization flow rate (Rotatom) and feed flow rate (Ffeed) on powder properties such as particle morphology and aerodynamic performance but also on the enzyme activity and protein conformational stability of a trehalose:leucine spray-dried powder featuring Cu,Zn-superoxide dismutase (Cu,Zn-SOD). This enzyme, often implicated in a broad spectrum of oxidative stress related diseases, from cystic fibrosis to rheumatoid arthritis, was used as a model Active Pharmaceutical Ingredient (API).
Morphology and aerodynamic performance of the SD powders were determined by scanning electron microscopy (SEM), focused ion beam – SEM, laser diffraction and Andersen Cascade Impaction. For each SD run, enzyme activity retention (EAR) was measured by spectrophotometry and the protein melting temperature by differential scanning fluorimetry. To further understand the interaction between input and output variables, a statistical analysis was performed using SIMCA v13.0.3.0 software.
Cu,Zn-SOD:trehalose:leucine spray dried powders were successfully generated upon different processing conditions, displaying fine particle fractions of ≈60% and EAR ranging from 50–80% with no loss of protein conformational stability. This technology thus proved to be suitable to prepare Cu,Zn-SOD based DPI powders within the considered working ranges.
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•Spray Drying allowed the production of an enzyme inhalable powder.•The higher the atomization flowrate, the higher the aerodynamic performance.•The higher the atomization and feed flowrates, the higher the enzymatic activity.•The higher the outlet temperature, the higher the enzyme conformational stability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, ...thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.
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•Pyrazoles effectively inhibited PGE2, COX and leukocytes' oxidative burst.•4-(Chlorostyryl) group favored inhibition of COX-2 and leukocytes' oxidative burst.•Triazole 18 inhibits leukocytes' burst and COX, with potential COX-2 selectivity.•Pyrazole 26 reduced PGE2 levels through selective COX-1 inhibition.•Pyrazole 8 downregulated COX-2 expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•A glass-capillary microfluidic device is used for enzyme encapsulation in liposomes.•The enzyme (SOD) retains its enzymatic activity after encapsulation.•SOD-loaded liposomes ...(SOD@Lip) present an effective anti-inflammatory property.•The usefulness of systemic SOD to treat local inflammation was confirmed.
The biopharmaceuticals market is constantly growing. Despite their advantages over the conventional drugs, biopharmaceuticals have short biological half-lifes, which can be increased using liposomes. However, the common bulk methods to produce biopharmaceuticals-loaded liposomes result in lost of encapsulation efficiency (E.E.), resulting in an expensive process. Herein, the encapsulation of a therapeutic enzyme in liposomes is proposed, using a glass-capillary microfluidic technique. Cu,Zn- Superoxide dismutase (SOD) is successfully encapsulated into liposomes (SOD@Liposomes). SOD@Liposomes with a mean size of 135 ± 41 nm, a polydispersity index of 0.13 ± 0.01, an E.E. of 59 ± 6 % and an enzyme activity of 82 ± 3 % are obtained. in vivo experiments show, through an ear edema model, that SOD@Liposomes administered by the intravenous route enable an edema inhibition of 65 % ± 8 %, over the 20 % ± 13 % of SOD in its free form. The histopathological analyses show a higher inflammatory cell accumulation on the ear treated with SOD in its free form, than treated with SOD@Liposomes. Overall, this work highlights the potential of microfluidics for the production of enzyme-loaded liposomes with high encapsulation efficiency, with the intrinsic advantages of the low time-consuming and easily upscaling microfluidic assembly method.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Enzyme-based inhalable therapeutics for lung inflammation are gaining interest as an alternative to long-term corticosteroids treatments. However, enzymes have poor pharmacokinetics. Encapsulating ...enzymes in liposomes can increase their half-live and modify their biodistribution. But both liposomes and enzymes are susceptible to destabilization during storage. This drawback can be surpassed, by converting liposomal suspension into solid dosage forms for different administration routes, including inhalation. In this study, Cu, Zn- superoxide dismutase (SOD) was encapsulated in liposomes, then dried using supercritical CO2-assisted spray-drying to make SOD-loaded liposomal dry powder formulations (SOD_Lip-DPFs). Upon resuspension in water, liposomes maintained structural integrity, with 99% SOD encapsulation efficiency and preserved enzymatic activity. Stability studies showed that SOD_Lip-DPFs maintained liposomal and enzyme stability for 50 days at 40% relative humidity. This offers a stable and efficient delivery system for enzyme-based inhalable therapeutics.
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•An inhalable enzyme formulation was produced using scCO2-assisted spray drying.•Trehalose proved to be effective and fundamental in liposome stability upon drying.•Dried liposomes retained the enzyme structure, stability, and encapsulation efficiency.•Dry powder formulations were stable for 50 days at 40% relative humidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway and a potential therapeutic target in the management of type 2 diabetes. It catalyzes a reversible reaction: the release of ...the terminal glucosyl residue from glycogen as glucose 1-phosphate; or the transfer of glucose from glucose 1-phosphate to glycogen. A colorimetric method to follow in vitro the activity of GP with usefulness in structure-activity relationship studies and high-throughput screening capability is herein described. The obtained results allowed the choice of the optimal concentration of enzyme of 0.38 U/mL, 0.25 mM glucose 1-phosphate, 0.25 mg/mL glycogen, and temperature of 37 °C. Three known GP inhibitors, CP-91149, a synthetic inhibitor, caffeine, an alkaloid, and ellagic acid, a polyphenol, were used to validate the method, CP-91149 being the most active inhibitor. The effect of glucose on the IC50 value of CP-91149 was also investigated, which decreased when the concentration of glucose increased. The assay parameters for a high-throughput screening method for discovery of new potential GP inhibitors were optimized and standardized, which is desirable for the reproducibility and comparison of results in the literature. The optimized method can be applied to the study of a panel of synthetic and/or natural compounds, such as polyphenols.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed ...resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound Zn(DION)2Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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