Benefits of a prolonged-release amino acid mixture in four pregnant women with phenylketonuria.

Background: Maternal phenylketonuria (mPKU) is a pathologic condition occurring in the fetus of a mother with PKU that is caused by prolonged elevated intrauterine blood phenylalanine (Phe) levels, which can lead to congenital abnormalities and mental retardation of newborns. Management of PKU during pregnancy can be challenging as protein substitutes may exacerbate nausea, vomiting, and gastrointestinal symptoms. Aim: To report the successful management of four PKU pregnant women. Methods: The patients were administered with prolonged-release amino acid supplementation and were recommended to follow a strict diet. Blood Phe concentration, adherence to diet, and occurrence of adverse events were monitored. Results: All patients achieved safe levels of blood Phe concentration (120-360 µmol/L) since preconception and during pregnancy (mean Phe concentration values of 143.34 ± 137.59, 226.48 ± 194.57, 186.68 ± 133.67, and 187.47 ± 42.59 µmol/L). During the first trimester of pregnancy, all patients manifested gastrointestinal symptoms such as nausea, gastrointestinal reflux, and abdominal bloating, which were managed by either changing protein substitute or extending the time window between different meals and amino acid mixtures administration. The four women continued their pregnancies without experiencing further complications and delivered neonates with normal growth parameters and no malformations. Conclusion: Findings of this case series suggest that the intake of a prolonged-release amino acid mixture in granules is well tolerated by pregnant PKU patients, eventually leading to good metabolic control and fetal growth within normal ranges.

Nutraceuticals and Pain Disorders of the Gut-Brain Interaction in Infants and Children: A Narrative Review and Practical Insights.

Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through a search of the literature in Pubmed and Medline updated to October 2023 focused on the effect of nutraceuticals in infantile colic, functional abdominal pain, and irritable bowel syndrome in children and adolescents. Significant reductions in colic episodes and crying time were reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to a placebo, in children with functional abdominal pain or irritable bowel syndrome, a significant reduction in pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, and in one study on corn fiber cookies, partial hydrolyzed guar gum, a specific multiple herbal extract (STW-5), or vitamin D supplementation. To date, there is moderate-certainty evidence with a weak grade of recommendation on Lactobacillus reuteri DSM 17938 (108 CFU/day) in reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 × 109 CFU twice daily) in reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove the efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.

c.376A>G, (p.Ser126Gly) Alpha-Galactosidase A mutation induces ER stress, unfolded protein response and reduced enzyme trafficking to lysosome: Possible relevance in the pathogenesis of late-onset forms of Fabry Disease.

Fabry Disease (FD) (OMIM 301500) is a metabolic X-linked inherited lysosomal storage disorder that results from the deficient activity of Alpha-Galactosidase A (Alpha-Gal), a lysosomal hydrolase that cleaves neutral glycosphingolipids with terminal N-linked galactosyl moieties, mainly globotriaosylceramides (Gb3). The enzyme, encoded by a 12-kb gene mapping on the long arm (Xq22.1 region) of the X chromosome, is constituted by a glycosylated subunit of approximately 55 kD, synthesized as an inactive precursor that undergoes maturation in endoplasmic reticulum (ER) and Golgi apparatus before being delivered to the lysosome to form a functional dimer. The gene is comprised of seven exons and, so far, >1000 different mutations have been described as associated to FD (www.dbfgp.org/dbFgp/fabry/FabryGP.htm). Clinical phenotypes are divided in two main classes, classic or non-classic, based on clinical and biochemical findings. Non-classic FD, usually recognized as late-onset forms with oligosymptomatic phenotype, presents with symptoms restricted solely to cardiocytes, kidneys or brain associated to missense misfolding mutations. In the group of the non-classic FD, special attention should be given to patients carrying the c.376A > G (p.Ser126Gly) mutation. The lack of clear experimental evidences on its pathogenetic role, despite the clinical pictures of the patients with severe ischaemic lesions, renal involvement and acroparesthesias, led many authors to classify this mutation as inconsistent, non-pathogenetic, and consequently not eligible to the current pharmacological treatments for FD. To shed light on the cellular processes affected by this mutation and to assess if the biochemical pathways involved with, could really have a significant pathogenetic impact, we studied the mutation in silico and in COS-7 and HEK 293 cell models. We found p.Ser126Gly, even retaining both high degree of synthesis and residual activity, is mostly stacked into the ER inducing unfolded protein response (UPR) with reduced trafficking to the lysosome. These data strongly suggest that p.Ser126Gly could trigger a pathogenetic mechanism different from the classic and well assessed increased turnover with loss of biological activity described for other missense mutations. This mechanism seems mainly related to a negative gain of function, with ER retention and UPR activation and could lead, via inflammation and/or apoptosis, to irreversible cell damage.

7p22.2 Microduplication: A Pathogenic CNV?

Partial duplication of the short arm of chromosome 7 is a rare chromosome rearrangement. The phenotype spectrum associated with this rearrangement is extremely variable even if in the last decade the use of high-resolution microarray technology for the investigation of patients carrying this rearrangement allowed for the identification of the 7p22.1 sub-band causative of this phenotype and to recognize the corresponding 7p22.1 microduplication syndrome. We report two unrelated patients that carry a microduplication involving the 7.22.2 sub-band. Unlike 7p22.1 microduplication carriers, both patients only show a neurodevelopmental disorder without malformations. We better characterized the clinical pictures of these two patients providing insight into the clinical phenotype associated with the microduplication of the 7p22.2 sub-band and support for a possible role of this sub-band in the 7p22 microduplication syndrome.

Prevalence of Non-erosive Esophageal Phenotypes in Children: A European Multicenter Study.

Background/Aims: Since available data on pediatric non-erosive esophageal phenotypes (NEEPs) are scant, we investigated their prevalence and the phenotype-dependent treatment response in these children. Methods: Over a 5-year period, children with negative upper endoscopy, who underwent esophageal pH-impedance (off-therapy) for persisting symptoms not responsive to proton pump inhibitor (PPI)-treatment, were recruited. Based on the results of acid reflux index (RI) and symptom association probability (SAP), patients were categorized into: (1) abnormal RI (non-erosive reflux disease [NERD]), (2) normal RI and abnormal SAP (reflux hypersensitivity [RH]), (3) normal RI and normal SAP (functional heartburn [FH]), and (4) normal RI and not-reliable SAP (normal-RI-not otherwise-specified [normal-RI-NOS]). For each subgroup, treatment response was evaluated. Results: Out of 2333 children who underwent esophageal pH-impedance, 68 cases, including 18 NERD, 14 RH, 26 FH, and 10 normal-RI-NOS were identified as fulfilling the inclusion criteria and were analyzed. Considering symptoms before endoscopy, chest pain was more reported in NERD than in other cases (6/18 vs 5/50, P = 0.031). At long-term follow-up of 23 patients (8 NERD, 8 FH, 2 RH, and 5 normal-RI-NOS): 17 were on PPIs and 2 combined alginate, 1 (FH) was on benzodiazepine + anticholinergic, 1 (normal-RI-NOS) on citalopram, and 3 had no therapy. A complete symptom-resolution was observed in 5/8 NERD, in 2/8 FH, and in 2/5 normal-RI-NOS. Conclusions: FH may be the most common pediatric NEEP. At long-term follow-up, there was a trend toward a more frequent complete symptom resolution with PPI-therapy in NERD patients while other groups did not benefit from extended acid-suppressive-treatment.

Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives.

Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 µM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.

Role of inflammation in pediatric irritable bowel syndrome.

BACKGROUND: IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE: The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.

Multi-Target Mechanisms of Phytochemicals in Alzheimer's Disease: Effects on Oxidative Stress, Neuroinflammation and Protein Aggregation.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a tangle-shaped accumulation of beta-amyloid peptide fragments and Tau protein in brain neurons. The pathophysiological mechanism involves the presence of Aß-amyloid peptide, Tau protein, oxidative stress, and an exacerbated neuro-inflammatory response. This review aims to offer an updated compendium of the most recent and promising advances in AD treatment through the administration of phytochemicals. The literature survey was carried out by electronic search in the following specialized databases PubMed/Medline, Embase, TRIP database, Google Scholar, Wiley, and Web of Science regarding published works that included molecular mechanisms and signaling pathways targeted by phytochemicals in various experimental models of Alzheimer's disease in vitro and in vivo. The results of the studies showed that the use of phytochemicals against AD has gained relevance due to their antioxidant, anti-neuroinflammatory, anti-amyloid, and anti-hyperphosphorylation properties of Tau protein. Some bioactive compounds from plants have been shown to have the ability to prevent and stop the progression of Alzheimer's.

Antibiotics and Carbohydrate-Containing Drugs Targeting Bacterial Cell Envelopes: An Overview.

Certain bacteria constitute a threat to humans due to their ability to escape host defenses as they easily develop drug resistance. Bacteria are classified into gram-positive and gram-negative according to the composition of the cell membrane structure. Gram-negative bacteria have an additional outer membrane (OM) that is not present in their gram-positive counterpart; the latter instead hold a thicker peptidoglycan (PG) layer. This review covers the main structural and functional properties of cell wall polysaccharides (CWPs) and PG. Drugs targeting CWPs are discussed, both noncarbohydrate-related (ß-lactams, fosfomycin, and lipopeptides) and carbohydrate-related (glycopeptides and lipoglycopeptides). Bacterial resistance to these drugs continues to evolve, which calls for novel antibacterial approaches to be developed. The use of carbohydrate-based vaccines as a valid strategy to prevent bacterial infections is also addressed.

Design, synthesis, and biological screening of a series of 4'-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs).

Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents.Results: A novel series of 4'-fluoro-substituted ligands (5-13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability.Discussion: The 4'-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration.

Design, Synthesis, and In Vitro Evaluation of Novel 8-Amino-Quinoline Combined with Natural Antioxidant Acids.

Overproduction of reactive oxygen species (ROS) and alterations in metallostasis are common and related hallmarks in several neurodegenerative diseases (NDDs). Nature-based derivatives always represent an attractive tool in MTDL drug design, especially against ROS in NDDs. On this notion, we designed a new series of 8-quinoline-N-substituted derivatives with a natural antioxidant portion (i.e., lipoic, caffeic, and ferulic acids). These compounds were shown to chelate copper, a metal involved in ROS-induced degeneration, and scavenger oxygen radicals in DPPH assay. Then, selected compounds 4 and 5 were evaluated in an in vitro model of oxidative stress and shown to possess cytoprotective effects in 661W photoreceptor-like cells. The obtained results may represent a starting point for the application of the proposed class of compounds in retinal neurodegenerative diseases such as retinitis pigmentosa (RP), comprising a group of hereditary rod-cone dystrophies that represent a major cause of blindness in patients of working age, where the progression of the disease is a multifactorial event, with oxidative stress contributing predominantly.

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3ε induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3ε significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3ε is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.

Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study.

BACKGROUND: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage. RESULTS: Our findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype. CONCLUSIONS: In conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.

Cows' Milk Allergy-Associated Constipation: When to Look for It? A Narrative Review.

Constipation is a very common disorder, mostly functional in nature, that may persist for years in up to 35-52% of children. Food allergy prevalence, severity and persistence are increasing over time, and cows' milk protein is the commonest food allergen recognised to affect gastrointestinal motility in children. There is mounting evidence of the role of cows' milk (CM) allergy (CMA) in children with constipation. With this narrative review, we aim to provide clinicians with an updated and critical overview of food allergy-associated constipation. We searched Embase, Medline and the Cochrane Library, using keywords related to the topic. Only reviews and studies including children aged 0-17 years that were published in English were considered. Constipation has been reported in 4.6% of infants with CMA; the prevalence of food allergy underlying chronic constipation in children resistant to conventional treatment and presenting to tertiary clinics ranges between 28% and 78%. The identification of predisposing risk factors and of a specific phenotype of food allergy-induced constipation remains elusive. No allergic tests, radiological or motility investigations achieve sufficient sensitivity and specificity to screen children for CMA-related constipation. A 4-week cows' milk protein (CMP) elimination diet may be considered for children with chronic constipation resistant to conventional treatment and who lack alarm sign/symptoms of organic diseases. In subjects with ameliorated symptoms on CMP elimination, the diagnosis of CMA should be confirmed by a food challenge to avoid an unnecessary protracted diet.

Beneficial Effects of Slow-Release Large Neutral Amino Acids after a Phenylalanine Oral Load in Patients with Phenylketonuria.

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.

Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile.

We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.

Paving Luteolin Therapeutic Potentialities and Agro-Food-Pharma Applications: Emphasis on In Vivo Pharmacological Effects and Bioavailability Traits.

Luteolin is a naturally occurring secondary metabolite belonging to the class of flavones. As many other natural flavonoids, it is often found in combination with glycosides in many fruits, vegetables, and plants, contributing to their biological and pharmacological value. Many preclinical studies report that luteolin present excellent antioxidant, anticancer, antimicrobial, neuroprotective, cardioprotective, antiviral, and anti-inflammatory effects, and as a consequence, various clinical trials have been designed to investigate the therapeutic potential of luteolin in humans. However, luteolin has a very limited bioavailability, which consequently affects its biological properties and efficacy. Several drug delivery strategies have been developed to raise its bioavailability, with nanoformulations and lipid carriers, such as liposomes, being the most intensively explored. Pharmacological potential of luteolin in various disorders has also been underlined, but to some of them, the exact mechanism is still poorly understood. Given the great potential of this natural antioxidant in health, this review is aimed at providing an extensive overview on the in vivo pharmacological action of luteolin and at stressing the main features related to its bioavailability, absorption, and metabolism, while essential steps determine its absolute health benefits and safety profiles. In addition, despite the scarcity of studies on luteolin bioavailability, the different drug delivery formulations developed to increase its bioavailability are also listed here.

A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs).

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 µM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 µM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, ß-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.

Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment.

The study describes the current state of knowledge on nanotechnology and its utilization in medicine. The focus in this manuscript was on the properties, usage safety, and potentially valuable applications of chitosan-based nanomaterials. Chitosan nanoparticles have high importance in nanomedicine, biomedical engineering, discovery and development of new drugs. The manuscript reviewed the new studies regarding the use of chitosan-based nanoparticles for creating new release systems with improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of drugs. Nowadays, effective cancer treatment is a global problem, and recent advances in nanomedicine are of great importance. Special attention was put on the application of chitosan nanoparticles in developing new system for anticancer drug delivery. Pre-clinical and clinical studies support the use of chitosan-based nanoparticles in nanomedicine. This manuscript overviews the last progresses regarding the utilization, stability, and bioavailability of drug nanoencapsulation with chitosan and their safety.

Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study.

Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood-brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.