Poor Systemic Bioavailability Research Articles

The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia

BackgroundRestenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperproliferative and migratory vascular smooth muscle cell (VSMC) accumulate excessively in the tunica intima. 6-Phosphogluconate dehydrogenase (6PGD), sometimes referred to as PGD, is one of the critical enzymes in pentose phosphate pathway (PPP). In this study, we sought to probe whether 6PGD is aberrantly regulated in IH and contributes to VSMC phenotypic switching. MethodsWe used clinical specimens of diseased human coronary arteries with IH lesions and observed robust upregulation of 6PGD at protein level in both the medial and intimal layers in comparison with healthy arterial segments. Results6PGD activity and protein expression were profoundly stimulated upon platelet-derived growth factor-induced VSMC phenotypic switching. Using gain-of-function (dCas9-mediated transcriptional activation) and loss-of-function (small interfering RNA-mediated) silencing, we were able to demonstrate the pathogenic role of 6PGD in driving VSMC hyperproliferation, migration, dedifferentiation, and inflammation. Finally, we conducted a rat model of balloon angioplasty in the common carotid artery, with Pluronic hydrogel-assisted perivascular delivery of Physcion, a selective 6PGD inhibitor with poor systemic bioavailability, and observed effective mitigation of IH. ConclusionsWe contend that aberrant 6PGD expression and activity—indicative of a metabolic shift toward pentose phosphate pathway—could serve as a new disease-driving mechanism and, hence, an actionable target for the development of effective new therapies for IH and restenosis after endovascular interventions.

Preclinical pharmacokinetics, pharmacodynamics, and toxicity of novel small-molecule GPR119 agonists to treat type-2 diabetes and obesity

The escalating global prevalence of type-2 diabetes (T2D) and obesity necessitates the development of novel oral medications. Agonism at G-protein coupled receptor-119 (GPR119) has been recognized for modulation of metabolic homeostasis in T2D, obesity, and fatty liver disease. However, off-target effects have impeded the advancement of synthetic GPR119 agonist drug candidates. Non-systemic, gut-restricted GPR119 agonism is suggested as an alternative strategy that may locally stimulate intestinal enteroendocrine cells (EEC) for incretin secretion, without the need for systemic drug availability, consequently alleviating conventional class-related side effects. Herein, we report the preclinical acute safety, efficacy, and pharmacokinetics (PK) of novel GPR119 agonist compounds ps297 and ps318 that potentially target gut EEC for incretin secretion. In a proof-of-efficacy study, both compounds demonstrated glucagon-like peptide-1 (GLP-1) secretion capability during glucose and mixed-meal tolerance tests in healthy mice. Furthermore, co-administration of sitagliptin with investigational compounds in diabetic db/db mice resulted in synergism, with GLP-1 concentrations rising by three-fold. Both ps297 and ps318 exhibited low gut permeability assessed in the in-vitro Caco-2 cell model. A single oral dose PK study conducted on healthy mice demonstrated poor systemic bioavailability of both agents. PK measures (mean ± SD) for compound ps297 (Cmax 23 ± 19 ng/mL, Tmax range 0.5 – 1 h, AUC0–24 h 19.6 ± 21 h*ng/mL) and ps318 (Cmax 75 ± 22 ng/mL, Tmax range 0.25 – 0.5 h, AUC0–24 h 35 ± 23 h*ng/mL) suggest poor oral absorption. Additionally, examinations of drug excretion patterns in mice revealed that around 25 % (ps297) and 4 % (ps318) of the drugs were excreted through faeces as an unchanged form, while negligible drug concentrations (<0.005 %) were excreted in the urine. These acute PK/PD assessments suggest the gut is a primary site of action for both agents. Toxicity assessments conducted in the zebrafish and healthy mice models confirmed the safety and tolerability of both compounds. Future chronic in-vivo studies in relevant disease models will be essential to confirm the long-term safety and efficacy of these novel compounds.

The role of tetrahydrocurcumin in disease prevention and treatment.

In recent decades, natural compounds derived from herbal medicine or dietary sources have played important roles in prevention and treatment of various diseases and have attracted more and more attention. Curcumin, extracted from the Curcumae Longae Rhizoma and widely used as food spice and coloring agent, has been proven to possess high pharmacological value. However, the pharmacological application of curcumin is limited due to its poor systemic bioavailability. As a major active metabolite of curcumin, tetrahydrocurcumin (THC) has higher bioavailability and stability than curcumin. Increasing evidence confirmed that THC had a wide range of biological activities and significant treatment effects on diseases. In this paper, we reviewed the research progress on the biological activities and therapeutic potential of THC on different diseases such as neurological disorders, metabolic syndromes, cancers, and inflammatory diseases. The extensive pharmacological effects of THC involve the modulation of various signaling transduction pathways including MAPK, JAK/STAT, NF-κB, Nrf2, PI3K/Akt/mTOR, AMPK, Wnt/β-catenin. In addition, the pharmacokinetics, drug combination and toxicology of THC were discussed, thus providing scientific basis for the safe application of THC and the development of its dietary supplements and drugs.

Integrated multi-omics profiling highlights the benefits of resveratrol hydroxypropyl-β-cyclodextrin inclusion complex for A53T transgenic mice through the microbiota-gut-brain axis.

Parkinson's disease (PD) is a neurological disorder characterized by motor and gastrointestinal dysfunctions. Resveratrol is a potent antioxidant and anti-inflammatory phytoalexin known for its health-promoting benefits. However, little is known about its potential in treating PD by modulating the microbial gut-brain axis, and its clinical application has been limited due to poor water solubility, rapid metabolism, and limited systemic bioavailability. Our study aimed to evaluate the therapeutic potential of RHSD, a resveratrol-cyclodextrin inclusion complex, in treating PD through the gut-brain axis in human SNCA-transgenic (A53T) mice PD models. Building on our previous study, we prepared RHSD and compared its efficacy with uncoated resveratrol for PD treatment. The study results demonstrated that RHSD exhibited several advantages in improving motor function, alleviating cognitive impairment, restoring intestinal barrier function, and inhibiting neuropathy. Subsequently, a series of analyses, including fecal microbiota metagenomic sequencing, non-target metabolic assays, host transcriptome sequencing, and integrative analysis were performed to reveal the potential therapeutic pathways of RHSD in A53T mice. The metagenomic sequencing results indicated a significant increase in the levels of Lactobacillus murinus, Lactobacillus reuteri, Enterorhabduscaecimuris, Lactobacillus taiwanensis, and Lactobacillus animals following RHSD administration. Furthermore, metabolomics profiling showed that the levels of gut microbiome metabolites were reversed after RHSD treatment, and differential metabolites were significantly correlated with motor function and intestinal function in PD mice. The integrated analysis of microbial metabolites and host transcriptomics suggested that abnormal amino acid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in the PD model were associated with the diffusion of abnormal metabolites. This study illustrates the profound impact of RHSD administration on rectifying gut microbiota dysbiosis and improving the A53T mouse model. Notably, we observed significant alterations in the proliferation and metabolism of multiple probiotic strains of Lactobacillus. Furthermore, our research supports the hypothesis that microbiota-related metabolites may regulate the transcription of host genes, including dopamine receptors and calcium stabilization. Consequently, our findings underscore the potential of RHSD as a promising therapeutic candidate for the treatment of PD through the modulation of several signaling pathways within the microbiota-gut-brain axis.

Optimization of Potential Nanoemulgels for Boosting Transdermal Glimepiride Delivery and Upgrading Its Anti-Diabetic Activity.

Transdermal drug delivery has been widely adopted as a plausible alternative to the oral route of administration, especially for drugs with poor systemic bioavailability. The objective of this study was to design and validate a nanoemulsion (NE) system for transdermal administration of the oral hypoglycemic drug glimepiride (GM). The NEs were prepared using peppermint/bergamot oils as the oil phase and tween 80/transcutol P as the surfactant/co-surfactant mixture (Smix). The formulations were characterized using various parameters such as globule size, zeta potential, surface morphology, in vitro drug release, drug-excipient compatibility studies, and thermodynamic stability. The optimized NE formulation was then incorporated into different gel bases and examined for gel strength, pH, viscosity, and spreadability. The selected drug-loaded nanoemulgel formulation was then screened for ex vivo permeation, skin irritation, and in vivo pharmacokinetics. Characterization studies revealed the spherical shape of NE droplets with an average size of ~80 nm and a zeta potential of -11.8 mV, which indicated good electrokinetic stability of NE. In vitro release studies revealed enhanced drug release from the NE formulation compared to the plain drug. GM-loaded nanoemulgel showed a 7-fold increment in drug transdermal flux compared to plain drug gel. In addition, the GM-loaded nanoemulgel formulation did not elicit any signs of inflammation and/or irritation on the applied skin, suggesting its safety. Most importantly, the in vivo pharmacokinetic study emphasized the potential of nanoemulgel formulation to potentiate the systemic bioavailability of GM, as manifested by a 10-fold rise in the relative bioavailability compared to control gel. Collectively, transdermal NE-based GM gel might represent a promising alternative to oral therapy in the management of diabetes.

Chemistry Characterization and Application of Nanocrystals-based Drug Delivery System: Present to Future Perspective.

With the development of new technologies, various drugs with higher efficacy have been found, but their therapeutic use is still limited owing to poor water solubility, which leads to poor systemic bioavailability. Currently, about 40% of newly discovered drugs have a solubility issue. It is a major challenge for formulation scientists to overcome this problem and make a robust and effective formulation. One such unique approach is to formulate the drug as nanocrystals which alter the physical characteristics of the drug, resulting in the development of a novel formulation strategy for poorly soluble drugs. Nanocrystals are produced by various techniques such as top-down, bottom-up, or combination methods. Nanocrystals improve the clinical application of problematic drug molecules by decreasing the particle size, enhancing the dissolution rate and reducing the dose requirement, etc. This approach is not only improving the bioavailability of the drug but also facilitates the drug targeting to specific sites due to its feasibility of surface modification and all administration routes. This article deals with the various aspects of nanocrystals including chemistry, production, stabilization, characterization, and application in the field of pharmacy.

Nanoformulations as a strategy to overcome the delivery limitations of cannabinoids.

Medical cannabis has received significant interest in recent years due to its promising benefits in the management of pain, anxiety, depression and neurological and movement disorders. Specifically, the major phytocannabinoids derived from the cannabis plant such as (-) trans-Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), have been shown to be responsible for the pharmacological and therapeutic properties. Recently, these phytocannabinoids have also attracted special attention in cancer treatment due to their well-known palliative benefits in chemotherapy-induced nausea, vomiting, pain and loss of appetite along with their anticancer activities. Despite the enormous pharmacological benefits, the low aqueous solubility, high instability (susceptibility to extensive first pass metabolism) and poor systemic bioavailability restrict their utilization at clinical perspective. Therefore, drug delivery strategies based on nanotechnology are emerging to improve pharmacokinetic profile and bioavailability of cannabinoids as well as enhance their targeted delivery. Here, we critically review the nano-formulation systems engineered for overcoming the delivery limitations of native phytocannabinoids including polymeric and lipid-based nanoparticles (lipid nano capsules (LNCs), nanostructured lipid carriers (NLCs), nanoemulsions (NE) and self-emulsifying drug delivery systems (SEDDS)), ethosomes and cyclodextrins as well as their therapeutic applications.

Tailoring of Novel Bile Salt Stabilized Vesicles for Enhanced Transdermal Delivery of Simvastatin: A New Therapeutic Approach against Inflammation.

Simvastatin (SMV), a cholesterol-lowering agent, has antioxidant and anti-inflammatory effects. Nevertheless, the oral use of SMV is linked with poor systemic bioavailability owing to its limited aqueous solubility and extensive first-pass metabolism. The aim of this study was to evaluate the feasibility of transdermal delivery of SMV using bile salt stabilized vesicles (bilosomes) for enhancing the anti-inflammatory potential of SMV. SMV-loaded bilosomes (SMV-BS) were prepared by the thin film hydration technique and optimized by 33 Box-Behnken design. The fabricated SMV-BS were assessed for vesicle size, entrapment efficiency (% EE) and cumulative drug release. The optimized formula was incorporated into HPMC gel and investigated for physical properties, ex vivo permeation, in vivo pharmacokinetic study and anti-inflammatory potential in inflamed paw edema rat model. The optimized SMV-BS showed vesicle size of 172.1 ± 8.1 nm and % EE of 89.2 ± 1.8%. In addition, encapsulating SMV within bilosomal vesicles remarkably sustained drug release over 12 h, compared to plain drug suspension. Furthermore, SMV-loaded bilosomal gel showed a three-fold enhancement in SMV transdermal flux, compared to plain drug suspension. Most importantly, the relative bioavailability of SMV-BS gel was ~2-fold and ~3-fold higher than those of oral SMV suspension and SMV gel, respectively. In carrageenan-induced paw edema model, SMV-BS gel induced a potent anti-inflammatory effect, as evidenced by a remarkable reduction in paw edema, which was comparable to that of the standard anti-inflammatory drug, indomethacin. Collectively, bilosomes might represent a plausible transdermal drug delivery system that could enhance the anti-inflammatory activity of SMV by boosting its skin permeation and its systemic bioavailability.

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3β Signaling.

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.

High-Payload Buccal Delivery System of Amorphous Curcumin-Chitosan Nanoparticle Complex in Hydroxypropyl Methylcellulose and Starch Films.

Oral delivery of curcumin (CUR) has limited effectiveness due to CUR’s poor systemic bioavailability caused by its first-pass metabolism and low solubility. Buccal delivery of CUR nanoparticles can address the poor bioavailability issue by virtue of avoidance of first-pass metabolism and solubility enhancement afforded by CUR nanoparticles. Buccal film delivery of drug nanoparticles, nevertheless, has been limited to low drug payload. Herein, we evaluated the feasibilities of three mucoadhesive polysaccharides, i.e., hydroxypropyl methylcellulose (HPMC), starch, and hydroxypropyl starch as buccal films of amorphous CUR–chitosan nanoplex at high CUR payload. Both HPMC and starch films could accommodate high CUR payload without adverse effects on the films’ characteristics. Starch films exhibited far superior CUR release profiles at high CUR payload as the faster disintegration time of starch films lowered the precipitation propensity of the highly supersaturated CUR concentration generated by the nanoplex. Compared to unmodified starch, hydroxypropyl starch films exhibited superior CUR release, with sustained release of nearly 100% of the CUR payload in 4 h. Hydroxypropyl starch films also exhibited good payload uniformity, minimal weight/thickness variations, high folding endurance, and good long-term storage stability. The present results established hydroxypropyl starch as the suitable mucoadhesive polysaccharide for high-payload buccal film applications.

Enhanced Pharmacological Efficacy of Berberine Hydrochloride Loaded Lipid Based Pellets for the Treatment of Metabolic Diseases

Numerous researchers in past have reported the diversified therapeutic effects of Berberine hydrochloride (BERH) for the management of metabolic diseases, however due to poor systemic bioavailability these effects are dose dependant and desired effects were reported at high dose levels. The objective of present investigation is to evaluate and establish the enhancement in pharmacological efficacy of the designed BERH formulation at low oral dose level for the treatment of metabolic diseases constituting metabolic syndrome (MS). In the present investigation, BERH formulation in the dose level of (25 and 50mg/kg/day) was evaluated in cafeteria diet (CD) induced MS model in male Wistar rats for 42 days and compared with available marketed preparation in similar dose level using orlistat as reference drug. Among the studied dose level of BERH formulation the 25 mg/kg/day dose was adequate to produce significant reduction in calorie intake (P &lt; 0.01), body weight, BMI, (P&lt;0.001), organ weight viz. (stomach; P&lt;0.05, liver; P&lt;0.001, heart; P&lt;0.01) and serum biochemical parameters (P&lt;0.001). A significant improvement in lipid peroxidation (P&lt;0.001), catalase (CAT), reduced glutathione (GSH) and superoxide dismutase (SOD) contents (P&lt;0.001) was observed. The histopathological examinations indicated amelioration of liver, heart and pancreas tissues. The current study indicated significant glucose-lowering, hypophagic, anti-obesity, anti-hyperlipidemic and cardio protective activity of the BERH formulation even in much low oral dose level compared to previously reported studies. The observed behavior is attributed due to the enhanced bioavailability of BERH formulation which could be effectively used for metabolic diseases treatment.

Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin.

Silymarin is an extract from the seeds (fruits) of Silybum marianum that contains flavonolignans and flavonoids. Although it is frequently used as a hepatoprotective agent, its application remains somewhat debatable, in particular, due to the low oral bioavailability of flavonolignans. Moreover, there are claims of its potential interactions with concomitantly used drugs. This review aims at a systematic summary and critical assessment of known information on the pharmacokinetics of particular silymarin flavonolignans.There are two known major reasons for poor systemic oral bioavailability of flavonolignans: (1) rapid conjugation in intestinal cells or the liver and (2) efflux of parent flavonolignans or formed conjugates back to the lumen of the gastrointestinal tract by intestinal cells and rapid excretion by the liver into the bile. The metabolism of phase I appears to play a minor role, in contrast to extensive conjugation and indeed the unconjugated flavonolignans reach low plasma levels after common doses. Only about 1%-5% of the administered dose is eliminated by the kidneys. Many in vitro studies tested the inhibitory potential of silymarin and its components toward different enzymes and transporters involved in the absorption, metabolism, and excretion of xenobiotics. In most cases, effective concentrations are too high to be relevant under real biological conditions. Most human studies showed no silymarin-drug interactions explainable by these suggested interferences. More interactions were found in animal studies, likely due to the much higher doses administered.

Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity.

Due to extremely poor systemic bioavailability, the mechanism by which curcumin increases energy expenditure remains unelucidated. Accumulating evidence suggests a strong association between the gut microbiota (GM) and energy metabolism. We investigated whether the GM mediates the effects of curcumin on improving energy homeostasis. High-fat diet (HFD)-fed wild type, uncoupling protein 1 (Ucp1) knockout and G protein-coupled membrane receptor 5 (TGR5) knockout mice were treated with curcumin (100 mg kg-1 d-1, p.o.). Curcumin-treated HFD-fed mice displayed decreased body weight gain and augmented cold tolerance due to enhanced adaptive thermogenesis as compared with that in control mice. The anti-obesity effects of curcumin were abolished by Ucp1 knockout. 16S ribosomal DNA sequencing analysis revealed that curcumin restructured the GM in HFD-fed mice. Fecal microbiota transplantation (FMT) and endogenous GM depletion indicated that the GM mediated the enhanced effect of curcumin on Ucp1-dependent thermogenesis. Curcumin altered bile acid (BA) metabolism with increased fractions of circulating deoxycholic acid (DCA) and lithocholic acid (LCA), which are the two most potent ligands for TGR5. Consistently, the enhanced effect of curcumin on Ucp1-dependent thermogenesis was eliminated by TGR5 knockout. Curcumin requires the GM and TGR5 to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in thermogenic adipose tissue. Here, we demonstrated that the GM mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and ameliorating HFD-induced obesity by influencing BA metabolism. We disclosed the potential of nutritional and pharmacologic manipulations of the GM to enhance Ucp1-dependent thermogenesis in the prevention and treatment of obesity.

A convergent approach toward fidaxomicin: Syntheses of the fully glycosylated northern and southern fragments

Efficient approaches that enable the synthesis of analogs of natural product antibiotics are needed to keep up with the emergence of multiply-resistant strains of pathogenic organisms. One promising candidate in this area is fidaxomicin, which boasts impressive in vitro anti-tubercular activity but has poor systemic bioavailability. We designed a flexible synthetic route to this target to enable the exploration of new chemical space and the future development of analogs with superior pharmacokinetics. We developed a robust approach to each of the key macrocyclic and sugar fragments, their union via stereoselective glycosylation, and a convergent late-stage macrolide formation with fully glycosylated fragments. Although we were able to demonstrate that the final Suzuki cross-coupling and ring-closing metathesis steps enabled macrocycle formation in the presence of the northern resorcylic rhamnoside and southern novioside sugars, these final steps were hampered by poor yields and the formation of the unwanted Z-macrocycle as the major stereoisomer.

Properties, Extraction Methods, and Delivery Systems for Curcumin as a Natural Source of Beneficial Health Effects.

This review discusses the impact of curcumin—an aromatic phytoextract from the turmeric (Curcuma longa) rhizome—as an effective therapeutic agent. Despite all of the beneficial health properties ensured by curcumin application, its pharmacological efficacy is compromised in vivo due to poor aqueous solubility, high metabolism, and rapid excretion that may result in poor systemic bioavailability. To overcome these problems, novel nanosystems have been proposed to enhance its bioavailability and bioactivity by reducing the particle size, the modification of surfaces, and the encapsulation efficiency of curcumin with different nanocarriers. The solutions based on nanotechnology can improve the perspective for medical patients with serious illnesses. In this review, we discuss commonly used curcumin-loaded bio-based nanoparticles that should be implemented for overcoming the innate constraints of this natural ingredient. Furthermore, the associated challenges regarding the potential applications in combination therapies are discussed as well.

The Aryl Hydrocarbon Receptor (AhR) Mediates the Counter-Regulatory Effects of Pelargonidins in Models of Inflammation and Metabolic Dysfunctions.

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC50 of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-ƴ, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction.

&lt;p&gt;Elaboration and characterization of curcumin-loaded Tri-CL-mPEG three-arm copolymeric nanoparticles by a microchannel technology&lt;/p&gt;

Purpose: Clinical applications of curcumin (Cur) have been greatly restricted due to its low solubility and poor systemic bioavailability. Three-arm amphiphilic copolymer tricarballylic acid-poly (ε-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) nanoparticles (NPs) were designed to improve the solubility and bioavailability of Cur. The present study adopted a microchannel system to precisely control the preparation of self-assembly polymeric NPs via liquid flow-focusing and gas displacing method.Methods: The amphiphilic three-arm copolymer Tri-CL-mPEG was synthesized and self-assembled into nearly spherical NPs, yielding Cur encapsulated into NP cores (Cur-NPs). The obtained NPs were evaluated for physicochemical properties, morphology, toxicity, cellular uptake by A549 cells, release in vitro, biodistribution, and pharmacokinetics in vivo.Results: Rapidly fabricated and isodispersed Cur-NPs prepared by this method had an average diameter of 116±3 nm and a polydispersity index of 0.197±0.008. The drug loading capacity and entrapment efficiency of Cur-NPs were 5.58±0.23% and 91.42±0.39%, respectively. In vitro release experiments showed sustained release of Cur, with cumulative release values of 40.1% and 66.1% at pH 7.4 and pH 5.0, respectively, after 10 days post-incubation. The results of cellular uptake, biodistribution, and in vivo pharmacokinetics experiments demonstrated that Cur-NPs exhibited better biocompatibility and bioavailability, while additionally enabling greater cellular uptake and prolonged circulation with possible spleen, lung, and kidney targeting effects when compared to the properties of free Cur.Conclusion: These results indicate that Tri-CL-mPEG NPs are promising in clinical applications as a controllable delivery system for hydrophobic drugs.

Immunoregulatory, proliferative and anti-oxidant effects of nanocurcuminoids on adipose-derived mesenchymal stem cells.

Curcuminoids are dietary complexes extracted from the seeds of Curcuma longa L. that contain curcumin, bisdemethoxycurcumin and desmethoxycurcumin. Curcuminoids are popular for their pleiotropic therapeutic functions, such as their anti-inflammatory and anti-oxidant effects. Nonetheless, their clinical use is associated with poor systemic bioavailability and insolubility. The nano-formulation of curcuminoids eliminates these shortcomings. In the present study, we explored immunoregulatory, proliferative and anti-oxidant effects of nanocurcuminoids on adipose-derived mesenchymal stem cells (AT-MSCs). Flow cytometry analysis and MTT assay were employed to explore the effects of nanocurcuminoids on the apoptosis and proliferation of adipose-derived MSCs (AT-MSCs). The anti-oxidant effect of nanocurcuminoids on AT-MSCs also was examined. The immune regulatory effect of nanocurcuminoids was evaluated by the flow cytometric measurement of the T regulatory (Treg) population. The expression of inflammatory and anti-inflammatory cytokines was quantified using real-time PCR. Our findings demonstrate that low concentrations of nanocurcuminoids are beneficial for MSC proliferation, protection of MSCs from apoptosis, reducing inflammatory cytokines and SOD activity. A high concentration of nanocurcuminoids increases the population of Tregs and elevates the expression of TGFβ and FOXP3 genes. The beneficial effects of nanocurcuminoids on AT-MSCs were mainly observed at low doses of nanocurcuminoids.

Curcumin and Heme Oxygenase: Neuroprotection and Beyond.

Curcumin is a natural polyphenol component of Curcuma longa Linn, which is currently considered one of the most effective nutritional antioxidants for counteracting free radical-related diseases. Several experimental data have highlighted the pleiotropic neuroprotective effects of curcumin, due to its activity in multiple antioxidant and anti-inflammatory pathways involved in neurodegeneration. Although its poor systemic bioavailability after oral administration and low plasma concentrations represent restrictive factors for curcumin therapeutic efficacy, innovative delivery formulations have been developed in order to overwhelm these limitations. This review provides a summary of the main findings involving the heme oxygenase/biliverdin reductase system as a valid target in mediating the potential neuroprotective properties of curcumin. Furthermore, pharmacokinetic properties and concerns about curcumin’s safety profile have been addressed.

Gut Microbiota as a Prospective Therapeutic Target for Curcumin: A Review of Mutual Influence.

Background Turmeric is a spice that has recently received much interest and has been widely used in Ayurvedic medicine. Turmeric products are diarylheptanoids and have been characterized as safe. They are termed as curcuminoids that consists essentially of three major compounds: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Curcumin is a lipophilic polyphenol that has poor systemic bioavailability and suffers from biotransformation by human intestinal microflora to yield different metabolites that are easily conjugated to glucuronides and sulfate O-conjugated derivatives. Recently, an increasing number of studies have indicated that dysbiosis is linked with many metabolic diseases, though gut microbiota could be a novel potential therapeutic target. Scope and Approach Thus, it is suspected that curcumin and its derivatives exert direct regulative effects on the gut microbiota which could explain the paradox between curcumin's poor systemic bioavailability and its widely reported pharmacological activities. Key Findings and Conclusions This article summarizes a range of studies that highlight the interaction between curcumin and gut microbiota and considers opportunities for microbiome-targeting therapies using turmeric extract.