Biliary pancreatic diversion and laparoscopic adjustable gastric banding in morbid obesity: their long-term effects on metabolic syndrome and on cardiovascular parameters

<p>Abstract</p> <p>Background</p> <p>Bariatric surgery is able to improve glucose and lipid metabolism, and cardiovascular function in morbid obesity. Aim of this study was to compare the long-term effects of malabsorptive (biliary pancreatic diversion, BPD), and restrictive (laparoscopic gastric banding, LAGB) procedures on metabolic and cardiovascular parameters, as well as on metabolic syndrome in morbidly obese patients.</p> <p>Methods</p> <p>170 patients studied between 1989 and 2001 were called back after a mean period of 65 months. 138 patients undergoing BPD (n = 23) or LAGB (n = 78), and control patients (refusing surgery and treated with diet, n = 37) were analysed for body mass index (BMI), blood glucose, cholesterol, and triglycerides, blood pressure, heart rate, and ECG indexes (QTc, Cornell voltage-duration product, and rate-pressure-product).</p> <p>Results</p> <p>After a mean 65 months period, surgery was more effective than diet on all items under evaluation; diabetes, hypertension, and metabolic syndrome disappeared more in surgery than in control patients, and new cases appeared only in controls. BPD was more effective than LAGB on BMI, on almost all cardiovascular parameters, and on cholesterol, not on triglyceride and blood glucose. Disappearance of diabetes, hypertension, and metabolic syndrome was similar with BPD and with LAGB, and no new cases were observed.</p> <p>Conclusion</p> <p>These data indicate that BPD, likely due to a greater BMI decrease, is more effective than LAGB in improving cardiovascular parameters, and similar to LAGB on metabolic parameters, in obese patients. The greater effect on cholesterol levels is probably due to the different mechanism of action.</p

TSPO-ligands prevent oxidative damage and inflammatory response in C6 glioma cells by neurosteroid synthesis

Translocator protein 18 kDa (TSPO) is predominantly located in the mitochondrial outer membrane, playing an important role in steroidogenesis, inflammation, cell survival and proliferation. Its expression in central nervous system, mainly in glial cells, has been found to be upregulated in neuropathology, and brain injury. In this study, we investigated the anti-oxidative and anti-inflammatory effects of a group of TSPO ligands from the N,N-dialkyl-2-phenylindol-3-ylglyoxylamide class (PIGAs), highlighting the involvement of neurosteroids in their pharmacological effects. To this aim we used a well-known in vitro model of neurosteroidogenesis: the astrocytic C6 glioma cell line, where TSPO expression and localization, as well as cell response to TSPO ligand treatment, have been established. All PIGAs reduced l-buthionine-(S,R)-sulfoximine (BSO)-driven cell cytotoxicity and lipid peroxidation. Moreover, an anti-inflammatory effect was observed due to the reduction of inducible nitric oxide synthase and cyclooxygenase-2 induction in LPS/IFNγ challenged cells. Both effects were blunted by aminoglutethimide (AMG), an inhibitor of pregnenolone synthesis, suggesting neurosteroids' involvement in PIGA protective mechanism. Finally, pregnenolone evaluation in PIGA exposed cells revealed an increase in its synthesis, which was prevented by AMG pre-treatment. These findings indicate that these TSPO ligands reduce oxidative stress and pro-inflammatory enzymes in glial cells through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of inflammatory-based neuropathologies with beneficial effects possibly comparable to steroids, but potentially avoiding the negative side effects of long-term therapies with steroid hormones

Enhancing the Anticancer Activity of Sorafenib through Its Combination with a Nitric Oxide Photodelivering β-Cyclodextrin Polymer

In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL(−1)) up to a concentration of 18 μg mL(−1). The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC(50) and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO

On the photobehaviour of curcumin in biocompatible hosts: The role of H-abstraction in the photodegradation and photosensitization

: Curcumin (CUR) is a naturally occurring pigment extensively studied due to its therapeutic activity and delivered by suitable nanocarriers to overcome poor solubility in aqueous media. The significant absorption of CUR in the visible blue region has prompted its use as a potential phototherapeutic agent in treating infectious and cancer diseases, although the mechanism underlying the phototoxic effects is still not fully understood. This contribution investigates the photobehaviour of CUR within polymeric micelles, microemulsions, and zein nanoparticles, chosen as biocompatible nanocarriers, and human serum albumin as a representative biomolecule. Spectroscopic studies indicate that in all host systems, the enolic tautomeric form of CUR is converted in a significant amount of the diketo form because of the perturbation of the intramolecular hydrogen bond. This leads to intermolecular H-abstraction from the host components by the lowest excited triplet state of CUR with the formation of the corresponding ketyl radical, detected by nanosecond laser flash photolysis. This radical is oxidized by molecular oxygen, likely generating peroxyl and hydroperoxyl radical species, unless in Zein, reasonably due to the poor availability of oxygen in the closely packed structure of this nanocarrier. In contrast, no detectable formation of singlet oxygen was revealed in all the systems. Overall these results highlight the key role of the H-abstraction process over singlet oxygen sensitization as a primary photochemical pathway strictly dictated by the specific features of the microenvironment, providing new insights into the photoreactivity of CUR in biocompatible hosts that can also be useful for a better understanding of its phototoxicity mechanism

Mixed β-γ-Cyclodextrin Branched Polymer with Multiple Photo-Chemotherapeutic Cargos

The achievement of biocompatible platforms for multimodal therapies is one of the major challenges in the burgeoning field of nanomedicine. Here, we report on a mixed beta-and gamma-cyclodextrin-based branched polymeric material (beta.CDNOPD) covalently integrating a nitric oxide (NO) photodonor (NOPD) within its macromolecular scaffold, and its supra-molecular ensemble with a singlet oxygen (O-1(2)) photosensitizer (PS) Zn(II) phthalocyanine ( ZnPc) and the chemodrug Lenvatinib (LVB). This polymer is highly water-soluble and generates NO under visible blue light stimuli with an efficiency of more than 1 order of magnitude higher than that of the single NOPD. The PS, which in an aqueous solution is aggregated and non-photoresponsive, can be entangled in the polymeric network as a photoresponsive monomeric species. In addition, the poorly water-soluble LVB can be co-encapsulated within the polymeric host, which increases the drug solubility by more than 30-fold compared to the free drug and more than 2-fold compared with a similar branched polymer containing only beta CD units. The supramolecular nanoensemble, ca. 15 nm in diameter, retains well the photochemical properties of both the NOPD and PS, which can operate in parallel under light stimuli of different energies. Irradiation with blue and red light results in the photogeneration of NO and O-1(2) associated with red fluorescence emission, without inducing any photodegradation of LVB. This result is not trivial and is due to the absence of significant, mutual interactions between the NOPD, the PS and LVB both in the ground and excited states, despite these components are confined in the same host. The proposed polymeric nanoplatform may represent a potential trimodal nanomedicine for biomedical research studies, since it combines the double photodynamic action of NO and O-1(2), two species that do not suffer multidrug resistance, with the therapeutic activity of a conventional chemodrug

β-Defensins in the Fight against Helicobacter pylori

Antimicrobial peptides (AMPs) play a pivotal role in the innate immune responses to Helicobacter pylori (Hp) in humans. β-Defensins, a class of cationic arginine-rich AMPs, are small peptides secreted by immune cells and epithelial cells that exert antimicrobial activity against a broad spectrum of microorganisms, including Gram-positive and Gram-negative bacteria and fungi. During Hp infections, AMP expression is able to eradicate the bacteria, thereby preventing Hp infections in gastrointestinal tract. It is likely that gastric β-defensins expression is increased during Hp infection. The aim of this review is to focus on increased knowledge of the role of β-defensins in response to Hp infection. We also briefly discuss the potential use of AMPs, either alone or in combination with conventional antibiotics, for the treatment of Hp infection

Green Synthesis of Near-Infrared Plasmonic Gold Nanostructures by Pomegranate Extract and Their Supramolecular Assembling with Chemo- and Photo-Therapeutics

Au nanostructures exhibiting a localized surface plasmon resonance in the near-infrared spectral window are obtained in a single, green step at room temperature by pomegranate extract in the presence of a highly biocompatible β-cyclodextrin branched polymer, without the need of preformed seeds, external reducing and sacrificial agents, and conventional surfactants. The polymeric component makes the Au nanostructures dispersible in water, stable for weeks and permits their supramolecular assembling with the chemotherapeutic sorafenib and a nitric oxide (NO) photodonor (NOPD), chosen as representative for chemo- and photo-therapeutics. Irradiation of the plasmonic Au nanostructures in the therapeutic window with 808 nm laser light results in a good photothermal response, which (i) is not affected by the presence of either the chemo- or the phototherapeutic guests and (ii) does not lead to their photoinduced decomposition. Besides, irradiation of the hybrid Au nanoassembly with the highly biocompatible green light results in the NO release from the NOPD with efficiency similar to that observed for the free guest. Preliminary biological experiments against Hep-G2 hepatocarcinoma cell lines are also reported

A Supramolecular Nanoassembly of Lenvatinib and a Green Light-Activatable NO Releaser for Combined Chemo-Phototherapy

The chemotherapeutic Lenvatinib (LVB) and a nitric oxide (NO) photodonor based on a rhodamine antenna (RD-NO) activatable by the highly compatible green light are supramolecularly assembled by a β-cyclodextrin branched polymer (PolyCD). The poorly water-soluble LVB and RD-NO solubilize very well within the polymeric host leading to a ternary supramolecular nanoassembly with a diameter of ~55 nm. The efficiency of the NO photorelease and the typical red fluorescence of RD-NO significantly enhance within the polymer due to its active role in the photochemical and photophysical deactivation pathways. The co-presence of LVB within the same host does not affect either the nature or the efficiency of the photoinduced processes of RD-NO. Besides, irradiation of RD-NO does not lead to the decomposition of LVB, ruling out any intermolecular photoinduced process between the two guests despite sharing the same host. Ad-hoc devised Förster Resonance Energy Transfer experiments demonstrate this to be the result of the not close proximity of the two guests, which are confined in different compartments of the same polymeric host. The supramolecular complex is stable in a culture medium, and its biological activity has been evaluated against HEP-G2 hepatocarcinoma cell lines in the dark and under irradiation with visible green light, using LVB at a concentration well below the IC50. Comparative experiments performed using the polymeric host encapsulating the individual LVB and RD-NO components under the same experimental conditions show that the moderate cell mortality induced by the ternary complex in the dark increases significantly upon irradiation with visible green light, more likely as the result of synergism between the NO photogenerated and the chemotherapeutic