55 research outputs found
Is it Possible to Improve the Success Rate of Cellular Therapy Based on Mesenchymal Stem Cells?
Non-clonal stromal cultures, containing a variable amount of Mesenchymal
Stem Cells (MSCs), can be easily isolated from a small aspirate of bone marrow
and expanded in vitro. As such, these cultures are currently used as a source of
putative MSCs for therapeutic purposes.
Nowadays, dozens of clinical trials aim to treat a number of diseases,
primarily immune system-related diseases, with MSCs. Moreover, several
private companies are setting up clinical trials to exploit the immunomodulation
and tissue repair properties of MSCs. Nevertheless, besides some successes,
specifically in the treatment of immunological diseases, MSC therapies have
experienced many failures. There are some issues to be analyses that may
improve the success rate of MSC therapy. This editorial will briefly address
some concerns associated with MSC transplants
The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From StructureâBased Virtual Screening to In Vivo Biological Activity
A mismatch between βâoxidation and the tricarboxylic acid cycle (TCA) cycle flux in
mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted
metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to
switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty
acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation
of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a
decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3â(2,2,2â
trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking
both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2),
was reported to improve mitochondrial dysfunction in several diseases, such as Huntingtonâs
disease (HD). Here, new THPâderived carnitineâlowering agents (TCL), characterized by a high
affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their
biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds
showed promising biological activities: reducing protein aggregates in HD cells, ameliorating
motility defects, and increasing the lifespan of HD Drosophila melanogaster
tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1.
Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of b-oxidation flux by labeled palmitate demonstrates that tBid inhibits b-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but
dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on b-oxidation. The unexpected role of tBid in the regulation of lipid b-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway
Anxiolytic, Antidepressant-Like Proprieties and Impact on the Memory of the Hydro-Ethanolic Extract of Origanum majorana L. on Mice
Marjoram (Origanum majorana L.) infusion has been used as folk medicine against depression and anxiety. However, no studies have been carried out yet to prove those activities scientifically. In this study, the anxiolytic, antidepressant-like effects, and memory impact of the hydro-ethanolic extracts of marjoram were evaluated in mice. The hydro-ethanolic extracts (250 and 500 mg/kg) were evaluated for their central nervous effect using six different behavioral tests such as lightâdark box (LDB) and open field (OF) for anxiety, forced swim test (FST), and tail suspension test (TST) for depression, and object recognition test (ORT), Morris water maze (MWM) for the impact on memory. The experiments were realized on days 1, 7, 14, and 21 of treatments and compared with bromazepam for anxiety (1 mg/kg) and paroxetine for depression (11.5 mg/kg). The phytochemical screening was performed by HPLC, and the acute and sub-acute toxicities were performed following OCED guidelines (N°423 and 407) with biochemical parameters evaluation and histopathological analysis. Oral administration of marjoram hydro-ethanolic extract induced significant anxiolytic and antidepressant-like effects without memory impairment, increasing the exploration and time spent in the light area in the LDB test in a similar way to that of bromazepam. In the FST and TST, the extract was as effective as paroxetine (11.5 mg/kg, p.o.) in reducing immobility. The phytochemical screening showed the presence of ferulic acid, naringin, hydroxytyrosol, geraniol, and quercetin. This study approves the traditional use of this plant and encourages further investigation on its bioactive compounds
Anxiolytic, Antidepressant-Like Proprieties and Impact on the Memory of the Hydro-Ethanolic Extract of Origanum majorana L. on Mice
Marjoram (Origanum majorana L.) infusion has been used as folk medicine against depression and anxiety. However, no studies have been carried out yet to prove those activities scientifically. In this study, the anxiolytic, antidepressant-like effects, and memory impact of the hydro-ethanolic extracts of marjoram were evaluated in mice. The hydro-ethanolic extracts (250 and 500 mg/kg) were evaluated for their central nervous effect using six different behavioral tests such as lightâdark box (LDB) and open field (OF) for anxiety, forced swim test (FST), and tail suspension test (TST) for depression, and object recognition test (ORT), Morris water maze (MWM) for the impact on memory. The experiments were realized on days 1, 7, 14, and 21 of treatments and compared with bromazepam for anxiety (1 mg/kg) and paroxetine for depression (11.5 mg/kg). The phytochemical screening was performed by HPLC, and the acute and sub-acute toxicities were performed following OCED guidelines (N°423 and 407) with biochemical parameters evaluation and histopathological analysis. Oral administration of marjoram hydro-ethanolic extract induced significant anxiolytic and antidepressant-like effects without memory impairment, increasing the exploration and time spent in the light area in the LDB test in a similar way to that of bromazepam. In the FST and TST, the extract was as effective as paroxetine (11.5 mg/kg, p.o.) in reducing immobility. The phytochemical screening showed the presence of ferulic acid, naringin, hydroxytyrosol, geraniol, and quercetin. This study approves the traditional use of this plant and encourages further investigation on its bioactive compounds
Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.
Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene
involved in the pathogenesis of lung cancer.
Objectives: The purpose of this study was to investigate the different
molecular alterations leading to the inactivation of FHIT gene
function and to validate their use as biomarkers of risk for progression
of the disease in patients belonging to the multicentric
European study for the Early detection of Lung Cancer (EUELC) who
were resected for early-stage lung tumors.
Methods: FHIT immunostaining was performed on 305 tumor samples.
Themethylation status of FHIT promoterwas assessed by nested
methylation-specific polymerase chain reaction (MSP-PCR) in 232
tumor and 225 normal lung samples ofwhich a subset of 187 patients
had available normal/tumorDNA pairs. Loss of heterozygosity (LOH)
at the FHIT locus was analyzed in 202 informative cases by D3S1300
and D3S1234 microsatellite markers.
Measurements and Main Results: Lost or reduced FHIT expression was
found in 36.7 and 75.7% of the tumor samples, respectively. Methylation
of the FHIT promoter was found in 36.7%of tumor and 32.7%
of normal lung samples, whereas LOH was detected in 61.9% of the
tumors. A strong association with complete loss of FHIT expression
was presentwhenmethylation and LOHwere analyzed together (P5
0.0064). Loss of FHIT protein expression was significantly more
frequent in squamous cell carcinoma histotype (P , 0.0001) and in
smokers (P5 0.008). FHIT methylation in normal lung was associated
with an increased risk of progressive disease (OR, 2.27; P 5 0.0415).
Conclusions:Our results indicate thatdifferentmolecularmechanisms
interplay to inactivate FHIT expression and support the proposition
that FHIT methylation in normal lung tissue could represent a prognostic
marker for progressive disease
Origanum majorana L. polyphenols: in vivo antiepileptic effect, in silico evaluation of their bioavailability, and interaction with the NMDA receptor
Introduction: Epilepsy is a chronic brain disease characterized by repeated seizures and caused by excessive glutamate receptor activation. Many plants are traditionally used in the treatment of this disease. This study aimed to evaluate the bioavailability of a polyphenolic extract obtained from Origanum majorana L. (OMP) leaves, as well as its antiepileptic activity and its potential mechanism of action.Methods: We have developed and validated a simple, rapid, and accurate stability-indicating reversed-phase liquid chromatographic method for the simultaneous determination of caffeine and quercetin in rat plasma. The OMP antiepileptic effect was evaluated with pilocarpine-induced seizures, and a docking method was used to determine the possible interaction between caffeic acid and quercetin with the N-methyl-D-aspartate (NMDA) receptor.Results and Discussion: Both compounds tested showed low bioavailability in unchanged form. However, the tested extract showed an anticonvulsant effect due to the considerably delayed onset of seizures in the pilocarpine model at a dose of 100Â mg/kg. The molecular docking proved a high-affinity interaction between the caffeic acid and quercetin with the NMDA receptor. Taken together, OLP polyphenols demonstrated good antiepileptic activity, probably due to the interaction of quercetin, caffeic acid, or their metabolites with the NMDA receptor
Functionalized Gold Nanoparticles as Biosensors for Monitoring Cellular Uptake and Localization in Normal and Tumor Prostatic Cells
In the present contribution the fabrication and characterization of functionalized gold nanospheres of uniform shape and controlled size is reported. These nano-objects are intended to be used as Surface Enhanced Raman Spectroscopy (SERS) sensors for in-vitro cellular uptake and localization. Thiophenol was used as molecular reporter and was bound to the Au surface by a chemisorption process in aqueous solution. The obtained colloidal solution was highly stable and no aggregation of the single nanospheres into larger clusters was observed. The nanoparticles were incubated in human prostatic cells with the aim of developing a robust, SERS-based method to differentiate normal and tumor cell lines. SERS imaging experiments showed that tumor cells uptake considerably larger amounts of nanoparticles in comparison to normal cells (up to 950% more); significant differences were also observed in the uptake kinetics. This largely different behaviour might be exploited in diagnostic and therapeutic applications
Food-Derived Bioactive Molecules from Mediterranean Diet: Nanotechnological Approaches and Waste Valorization as Strategies to Improve Human Wellness
The beneficial effects of the Mediterranean diet (MedDiet), the most widely followed healthy diet in the world, are principally due to the presence in the foods of secondary metabolites, mainly polyphenols, whose healthy characteristics are widely recognized. However, one of the biggest problems associated with the consumption of polyphenols as nutraceutical adjuvant concerns their bioavailability. During the last decades, different nanotechnological approaches have been developed to enhance polyphenol bioavailability, avoiding the metabolic modifications that lead to low absorption, and improving their retention time inside the organisms. This review focuses on the most recent findings regarding the encapsulation and delivery of the bioactive molecules present in the foods daily consumed in the MedDiet such as olive oil, wine, nuts, spice, and herbs. In addition, the possibility of recovering the polyphenols from food waste was also explored, taking into account the increased market demand of functional foods and the necessity to obtain valuable biomolecules at low cost and in high quantity. This circular economy strategy, therefore, represents an excellent approach to respond to both the growing demand of consumers for the maintenance of human wellness and the economic and ecological exigencies of our society
Recent Advances in Nanoparticle-Mediated Delivery of Anti-Inflammatory Phytocompounds
Phytocompounds have been used in medicine for decades owing to their potential in anti-inflammatory applications. However, major difficulties in achieving sustained delivery of phyto-based drugs are related to their low solubility and cell penetration, and high instability. To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained and enhanced delivery of phyto-derived bioactive compounds in the pharmaceutical sector. This review focuses on the recent advances in nanocarrier-mediated drug delivery of bioactive molecules of plant origin in the field of anti-inflammatory research. In particular, special attention is paid to the relationship between structure and properties of the nanocarrier and phytodrug release behavior
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