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1.
Anticancer Agents Med Chem ; 24(1): 39-49, 2024.
Article in English | MEDLINE | ID: mdl-37957910

ABSTRACT

BACKGROUND: Glioblastoma multiforme (GBM) is probably the most malignant and aggressive brain tumor belonging to the class of astrocytomas. The considerable aggressiveness and high malignancy of GBM make it a tumor that is difficult to treat. Here, we report the synthesis and biological evaluation of eighteen novel cinnamoyl derivatives (3a-i and 4a-i) to obtain more effective antitumor agents against GBM. METHODS: The chemical structures of novel cinnamoyl derivatives (3a-i and 4a-i) were confirmed by NMR and MS analyses. The physicochemical properties and evaluation of the ADME profile of 3a-i and 4a-i were performed by the preADMETlab2.0 web program. Cinnamoyl derivatives 3a-i and 4a-i were tested in vitro for their cytotoxicity against the human healthy fibroblast (HDFa) cells using an MTT cell viability assay. Derivatives with no toxicity on HDFa cells were tested both on human glioblastoma (U87MG) and neuroblastoma (SHSY- 5Y) cells, chosen as an experimental model of brain tumors. Cell death mechanisms were analyzed by performing flow cytometry analyses. RESULTS: Cinnamoyl derivatives 3a-i and 4a-i showed good physicochemical and ADME properties suggesting that these compounds could be developed as oral drugs endowed with a high capability to cross the blood-brain barrier. Compounds (E)-1-methoxy-4-(2-(phenylsulfonyl)vinyl)benzene (2c) and (E)-N-benzyl-N-(2- (cyclohexylamino)-2-oxoethyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (3e) did not show cytotoxicity on healthy human fibroblast cells up to 100 µg/mL. The most anticarcinogenic molecule, compound 3e, emerged as the most potent anticancer candidate in this study. Flow cytometry results showed that compound 3e (25 µg/mL) application resulted in nearly 86% and 84% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. Compound 2c (25 µg/mL) resulted in 81% and 82% cytotoxicity in the U87MG and the SHSY-5Y cell lines, respectively. CONCLUSION: Cinnamoyl derivative 3e inhibits the proliferation of cultured U87MG and SHSY-5Y cells by inducing apoptosis. Further detailed research will be conducted to confirm these data in in vivo experimental animal models.


Subject(s)
Antineoplastic Agents , Glioblastoma , Neuroblastoma , Animals , Humans , Cell Line, Tumor , Apoptosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Survival , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Cell Proliferation
2.
RSC Med Chem ; 14(11): 2315-2326, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-38020070

ABSTRACT

In this study, combining the thiazole and cinnamoyl groups into the styryl-thiazole scaffold, a series of novel styryl-thiazole hybrids (6a-p) was rationally designed, synthesized, and evaluated by the multi-target-directed ligands strategy as potential candidates for the treatment of Alzheimer's disease (AD). Hybrids 6e and 6i are the most promising among the synthesized hybrids since they are able to significantly increase cell viabilities in Aß1-42-exposed-human neuroblastoma cell line (6i at the concentration of 50 µg mL-1 and 6e at the concentration of 25 µg mL-1 resulted in ∼34% and ∼30% increase in cell viabilities, respectively). Compounds 6e and 6i exhibit highly AChE inhibitory properties in the experimental AD model at 375.6 ± 18.425 mU mL-1 and 397.6 ± 32.152 mU mL-1, respectively. Moreover, these data were also confirmed by docking studies and in vitro enzyme inhibition assays. Compared to hybrid 6e and according to the results, 6i also has the highest potential against Aß1-42 aggregation with over 80% preventive activity. The in silico prediction of the physicochemical properties confirms that 6i possesses a better profile compared to 6e. Therefore, compound 6i presents a promising multi-targeted active molecular profile for treating AD considering the multifactorial nature of AD, and it is reasonable to deepen its mechanisms of action in an in vivo experimental model of AD.

3.
Int J Mol Sci ; 24(9)2023 May 03.
Article in English | MEDLINE | ID: mdl-37175903

ABSTRACT

The use of large sized materials in drug delivery raises several challenges, including in vivo stability, poor bioavailability/solubility/absorption, and issues with target-specific delivery, in addition to the side effects of the delivered drugs [...].


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Nanoparticles , Humans , Pharmaceutical Preparations , Nanotechnology , Biological Availability , Drug Delivery Systems , Solubility
4.
Pharmaceuticals (Basel) ; 16(3)2023 Feb 22.
Article in English | MEDLINE | ID: mdl-36986440

ABSTRACT

(1) Background: Obesity, a complex metabolic disease resulting from an imbalance between food consumption and energy expenditure, leads to an increase in adipocytes and chronic inflammatory conditions. The aim of this paper was to synthesize a small series of carvacrol derivatives (CD1-3) that are able to reduce both adipogenesis and the inflammatory status often associated with the progression of the obesity disease. (2) Methods: The synthesis of CD1-3 was performed using classical procedures in a solution phase. Biological studies were performed on three cell lines: 3T3-L1, WJ-MSCs, and THP-1. The anti-adipogenic properties of CD1-3 were evaluated using western blotting and densitometric analysis by assessing the expression of obesity-related proteins, such as ChREBP. The anti-inflammatory effect was estimated by measuring the reduction in TNF-α expression in CD1-3-treated THP-1 cells. (3) Results: CD1-3-obtained through a direct linkage between the carboxylic moiety of anti-inflammatory drugs (Ibuprofen, Flurbiprofen, and Naproxen) and the hydroxyl group of carvacrol-have an inhibitory effect on the accumulation of lipids in both 3T3-L1 and WJ-MSCs cell cultures and an anti-inflammatory effect by reducing TNF- α levels in THP-1 cells. (4) Conclusions: Considering the physicochemical properties, stability, and biological data, the CD3 derivative-obtained by a direct linkage between carvacrol and naproxen-resulted in the best candidate, displaying anti-obesity and anti-inflammatory effects in vitro.

5.
Cancers (Basel) ; 15(4)2023 Feb 07.
Article in English | MEDLINE | ID: mdl-36831396

ABSTRACT

Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.

6.
Int J Mol Sci ; 24(4)2023 Feb 07.
Article in English | MEDLINE | ID: mdl-36834684

ABSTRACT

Recently, there has been an increasing interest in finding new approaches to manage oral wound healing. Although resveratrol (RSV) exhibited many biological properties, such as antioxidant and anti-inflammatory activities, its use as a drug is limited by unfavorable bioavailability. This study aimed to investigate a series of RSV derivatives (1a-j) with better pharmacokinetic profiles. At first, their cytocompatibility at different concentrations was tested on gingival fibroblasts (HGFs). Among them, derivatives 1d and 1h significantly increased cell viability compared to the reference compound RSV. Thus, 1d and 1h were investigated for cytotoxicity, proliferation, and gene expression in HGFs, endothelial cells (HUVECs), and oral osteoblasts (HOBs), which are the main cells involved in oral wound healing. For HUVECs and HGFs, the morphology was also evaluated, while for HOBs ALP and mineralization were observed. The results showed that both 1d and 1h did not exert negative effects on cell viability, and at a lower concentration (5 µM) both even significantly enhanced the proliferative rate, compared to RSV. The morphology observations pointed out that the density of HUVECs and HGFs was promoted by 1d and 1h (5 µM) and mineralization was promoted in HOBs. Moreover, 1d and 1h (5 µM) induced a higher eNOS mRNA level in HUVECs, higher COL1 mRNA in HGFs, and higher OCN in HOBs, compared to RSV. The appreciable physicochemical properties and good enzymatic and chemical stability of 1d and 1h, along with their promising biological properties, provide the scientific basis for further studies leading to the development of RSV-based agents useful in oral tissue repair.


Subject(s)
Endothelial Cells , Fibroblasts , Resveratrol/pharmacology , Cells, Cultured , Fibroblasts/metabolism , Wound Healing , RNA, Messenger/metabolism
7.
Healthcare (Basel) ; 11(3)2023 Feb 03.
Article in English | MEDLINE | ID: mdl-36767022

ABSTRACT

This systematic study aims at analyzing the differences between the approach of the European healthcare systems to the pharmaceutical market and the American one. This paper highlights the opportunities and the limitations given by the application of managed entry agreements (MEAs) in European countries as opposed to the American market, which does not regulate pharmaceutical prices. Data were collected from the Organisation for Economic Co-operation and Development (OECD), the European Medicines Agency, and the national healthcare agencies of US and European countries. A literature review was undertaken in PubMed, Scopus, MEDLINE, and Google for a period ten years (2010-2019). The period 2020-2021 was considered to compare health expenditure before and after the SARS-CoV-2 pandemic. Scarce information from national agencies has been given in terms of MEAs related to the COVID-19 pandemic. The comparison between the United States approach and the European one shows the importance of a market access regulation to reduce the cost of therapies, increasing the efficiency of national healthcare systems and the advantages in terms of quality and accessibility to the final users: patients. Nevertheless, it seems that the golden age of MEAs for Europe was during the examined period. Except for Italy, countries will move to other forms of reimbursements to obtain higher benefits, reducing the costs of an inefficient implementation and outcomes in the medium term.

8.
J Toxicol ; 2022: 3775194, 2022.
Article in English | MEDLINE | ID: mdl-36444193

ABSTRACT

The tripeptide H-Gly-Pro-Glu-OH (GPE) and its analogs began to take much interest from scientists for developing effective novel molecules in the treatment of several disorders including Alzheimer's disease, Parkinson's disease, and stroke. The peptidomimetics of GPEs exerted significant biological properties involving anti-inflammatory, antiapoptotic, and anticancer properties. The assessments of their hematological toxicity potentials are critically required for their possible usage in further preclinical and clinical trials against a wide range of pathological conditions. However, there is so limited information on the safety profiling of GPE and its analogs on human blood tissue from cytotoxic, oxidative, and genotoxic perspectives. And, their embryotoxicity potentials were not investigated yet. Therefore, in this study, measurements of mitochondrial viability (using MTT assay) and lactate dehydrogenase (LDH) release as well as total antioxidant capacity (TAC) assays were performed on cultured human whole blood cells after treatment with GPE and its three novel peptidomimetics for 72 h. Sister chromatid exchange (SCE), micronucleus (MN), and 8-oxo-2-deoxyguanosine (8-OH-dG) assays were performed for determining the genotoxic damage potentials. In addition, the nuclear division index (NDI) was figured out for revealing their cytostatic potentials. Embryotoxicity assessments were performed on cultured human pluripotent NT2 embryonal carcinoma cells by MTT and LDH assays. The present results from cytotoxicity, oxidative, genotoxicity, and embryotoxicity testing clearly propounded that GPEs had good biosafety profiles and were trouble-free from the toxicological point of view. Noncytotoxic, antioxidative, nongenotoxic, noncytostatic, and nonembryotoxic features of GPE analogs are worthwhile exploring further and may exert high potentials for improving the development of novel disease-modifying agents.

9.
Eur J Med Chem ; 243: 114746, 2022 Dec 05.
Article in English | MEDLINE | ID: mdl-36099749

ABSTRACT

In our overall goal to develop anti-Parkinson drugs, we designed novel diketopiperazines (DKP1-6) aiming to both reach the blood-brain barrier and counteract the oxidative stress related to Parkinson's Disease (PD). The anti-Parkinson properties of DKP 1-6 were evaluated using neurotoxin-treated PC12 cells, as in vitro model of PD, while their cytotoxicity and genotoxicity potentials were investigated in newborn rat cerebral cortex (RCC) and primary human whole blood (PHWB) cell cultures. The response against free radicals was evaluated by the total antioxidant capacity (TAC) assay. Comet assay was used to detect DNA damage while the content of 8-hydroxyl-2'-deoxyguanosine (8-OH-dG) was determined as a marker of oxidative DNA damage. PAMPA-BBB and Caco-2 assays were employed to evaluate the capability of DKP1-6 to cross the membranes. Stability studies were conducted in simulated gastric and intestinal fluids and human plasma. Results showed that DKP5-6 attenuate the MPP + -induced cell death on a nanomolar scale, but a remarkable effect was observed for DKP6 on Nrf2 activation that leads to the expression of genes involved in oxidative stress response thus increasing glutathione biosynthesis and ROS buffering. DKP5-6 resulted in no toxicity for RCC neurons and PHWB cells exposed to 10-500 nM concentrations during 24 h as determined by MTT and LDH assays and TAC levels were not altered in both cultured cell types. No significant difference in the induction of DNA damage was observed for DKP5-6. Both DKPs resulted stable in simulated gastric fluids (t1/2 > 22h). In simulated intestinal fluids, DKP5 underwent immediate hydrolysis while DKP6 showed a half-life higher than 3 h. In human plasma, DKP6 resulted quite stable. DKP6 displayed both high BBB and Caco-2 permeability confirming that the DKP scaffold represents a useful tool to improve the crossing of drugs through the biological membranes.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Parkinson Disease , Animals , Rats , Humans , Levodopa/pharmacology , Levodopa/metabolism , Levodopa/therapeutic use , Blood-Brain Barrier/metabolism , Diketopiperazines/pharmacology , Diketopiperazines/metabolism , Caco-2 Cells , Carcinoma, Renal Cell/drug therapy , Oxidative Stress , Antioxidants/pharmacology , Parkinson Disease/drug therapy , Kidney Neoplasms/drug therapy
10.
Front Cardiovasc Med ; 9: 983003, 2022.
Article in English | MEDLINE | ID: mdl-36061555

ABSTRACT

Background: While the importance of invasive physiological assessment (IPA) to choose coronary lesions to be treated is ascertained, its role after PCI is less established. We evaluated feasibility and efficacy of Physiology-guided PCI in the everyday practice in a retrospective registry performed in a single high-volume and "physiology-believer" center. Materials and methods: The PROPHET-FFR study (NCT05056662) patients undergoing an IPA in 2015-2020 were retrospectively enrolled in three groups: Control group comprising patients for whom PCI was deferred based on a IPA; Angiography-Guided PCI group comprising patients undergoing PCI based on an IPA but without a post-PCI IPA; Physiology-guided PCI group comprising patients undergoing PCI based on an IPA and an IPA after PCI, followed by a physiology-guided optimization, if indicated. Optimal result was defined by an FFR value ≥ 0.90. Results: A total of 1,322 patients with 1,591 lesions were available for the analysis. 893 patients (67.5%) in Control Group, 249 patients (18.8%) in Angiography-guided PCI Group and 180 patients (13.6%) in Physiology-guided PCI group. In 89 patients a suboptimal functional result was achieved that was optimized in 22 cases leading to a "Final FFR" value of 0.90 ± 0.04 in Angiography-Guided PCI group. Procedural time, costs, and rate of complications were similar. At follow up the rate of MACEs for the Physiology-guided PCI group was similar to the Control Group (7.2% vs. 8.2%, p = 0.765) and significantly lower than the Angiography-guided PCI Group (14.9%, p < 0.001), mainly driven by a reduction in TVRs. Conclusion: "Physiology-guided PCI" is a feasible strategy with a favorable impact on mid-term prognosis. Prospective studies using a standardized IPA are warrant to confirm these data.

11.
Pharmaceutics ; 14(9)2022 Aug 29.
Article in English | MEDLINE | ID: mdl-36145568

ABSTRACT

The encapsulation of peptides and proteins in nanosystems has been extensively investigated for masking unfavorable biopharmaceutical properties, including short half-life and poor permeation through biological membranes. Therefore, the aim of this work was to encapsulate a small antimicrobial hydrophilic peptide (H-Ser-Pro-Trp-Thr-NH2, FS10) in PEG-PLGA (polyethylene glycol-poly lactic acid-co-glycolic acid) nanoparticles (Nps) and thereby overcome the common limitations of hydrophilic drugs, which because they facilitate water absorption suffer from rapid degradation. FS10 is structurally related to the well-known RNAIII inhibiting peptide (RIP) and inhibits S. aureus biofilm formation. Various parameters, including different method (double emulsion and nanoprecipitation), pH of the aqueous phase and polymeric composition, were investigated to load FS10 into PEG-PLGA nanoparticles. The combination of different strategies resulted in an encapsulation efficiency of around 25% for both the double emulsion and the nanoprecipitation method. It was found that the most influential parameters were the pH­which tailors the peptides charge­and the polymeric composition. FS10-PEG-PLGA nanoparticles, obtained under optimized parameters, showed size lower than 180 nm with zeta potential values ranging from −11 to −21 mV. In vitro release studies showed that the Nps had an initial burst release of 48−63%, followed by a continuous drug release up to 21 h, probably caused by the porous character of the Nps. Furthermore, transmission electron microscopy (TEM) analysis revealed particles with a spherical morphology and size of around 100 nm. Antimicrobial assay showed that the minimum inhibitory concentration (MIC) of the FS10-loaded Nps, against S. aureus strains, was lower (>128 µg/mL) than that of the free FS10 (>256 µg/mL). The main goal of this work was to develop polymeric drug delivery systems aiming at protecting the peptide from a fast degradation, thus improving its accumulation in the target site and increasing the drug-bacterial membrane interactions.

12.
Nanomaterials (Basel) ; 12(15)2022 Aug 05.
Article in English | MEDLINE | ID: mdl-35957121

ABSTRACT

Alzheimer's disease (AD) is considered as the most common neurodegenerative disease. Extracellular amyloid beta (Aß) deposition is a hallmark of AD. The options based on degradation and clearance of Aß are preferred as promising therapeutic strategies for AD. Interestingly, recent findings indicate that boron nanoparticles not only act as a carrier but also play key roles in mediating biological effects. In the present study, the aim was to investigate the effects of different concentrations (0−500 mg/L) of hexagonal boron nitride nanoparticles (hBN-NPs) against neurotoxicity by beta amyloid (Aß1-42) in differentiated human SH-SY5Y neuroblastoma cell cultures for the first time. The synthesized hBN-NPs were characterized by X-ray diffraction (XRD) measurements, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Aß1-42-induced neurotoxicity and therapeutic potential by hBN-NPs were assessed on differentiated SH-SY5Y cells using MTT and LDH release assays. Levels of total antioxidant capacity (TAC) and total oxidant status (TOS), expression levels of genes associated with AD and cellular morphologies were examined. The exposure to Aß1-42 significantly decreased the rates of viable cells which was accompanied by elevated TOS level. Aß1-42 induced both apoptotic and necrotic cell death. Aß exposure led to significant increases in expression levels of APOE, BACE 1, EGFR, NCTSN and TNF-α genes and significant decreases in expression levels of ADAM 10, APH1A, BDNF, PSEN1 and PSENEN genes (p < 0.05). All the Aß1-42-induced neurotoxic insults were inhibited by the applications with hBN-NPs. hBN-NPs also suppressed the remarkable elevation in the signal for Aß following exposure to Aß1-42 for 48 h. Our results indicated that hBN-NPs could significantly prevent the neurotoxic damages by Aß. Thus, hBN-NPs could be a novel and promising anti-AD agent for effective drug development, bio-nano imaging or drug delivery strategies.

13.
Pharmaceutics ; 14(7)2022 Jul 14.
Article in English | MEDLINE | ID: mdl-35890363

ABSTRACT

BACKGROUND: Wound healing (WH) is a complex process involving several stages, such as hemostasis, inflammation, re-epithelialization, and remodeling. Many factors can impair WH, and different pharmacological approaches were studied to date, but the increase in antibiotic resistance, invasiveness, treatment duration, and high cost, have often hampered the resolution of the wound. In this study, we investigated the possible application of water-soluble carvacrol prodrugs (WSCPs) and hyaluronic acid (HA) and their formulations (WSCPs/HA) to improve WH and regulate the inflammatory response. MATERIALS AND METHODS: Firstly, the cytotoxicity of 0.1, 1 and 10 µg/mL of HA, WSCPs and WSCPs/HA formulations were evaluated on HaCaT cells and THP-1 cell lines. The ability of WSCPs/HA formulations to modulate wound repair was evaluated in an in vitro model of WH, using HaCaT cells at 6, 18, and 24 h. The expression of WH mediators, after wound closure was determined by qRT-PCR. Following, we polarized THP-1 cells in M1/M2-like macrophages and tested the anti-inflammatory properties of WSCPs/HA formulations. After, we tested the in vitro WH model for the effects of conditioned medium (CM) from M1/M2-like cells cultured in the presence of WSCPs/HA. RESULTS: Results showed that WSCPs/HA formulations were able to significantly raise the wound closure rate, compared to the single constituents, promoting a complete wound closure after 18 h for WSCP1/HA (10 µg/mL) and after 24 h for WSCP2/HA (10 µg/mL), modulating the MMPs, TGFß, and COX-2 gene expression. The effects of CM derived from M1/M2 polarized cells cultured in the presence of WSCPs/HA determined WH regulation, with a better ability of the WSCP2/HA formulation to modulate the time-dependent expression of reparative and inflammatory mediators. CONCLUSION: Our data underline the possible application of WSCPs/HA formulations as bioactive agents for the regulation of the wound repair process by the modulation of inflammatory and remodeling phases, affecting the activity of immune cells.

14.
Int J Mol Sci ; 23(15)2022 Jul 26.
Article in English | MEDLINE | ID: mdl-35897815

ABSTRACT

The search for an innovative and effective drug delivery system that can carry and release targeted drugs with enhanced activity to treat Alzheimer's disease has received much attention in the last decade. In this study, we first designed a boron-based drug delivery system for effective treatment of AD by integrating the folic acid (FA) functional group into hexagonal boron nitride (hBN) nanoparticles (NPs) through an esterification reaction. The hBN-FA drug carrier system was assembled with a new drug candidate and a novel boron-based hybrid containing an antioxidant as BLA, to constitute a self-assembled AD nano transport system. We performed molecular characterization analyses by using UV-vis spectroscopy, Fourier transform infrared spectrophotometer (FTIR), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Zeta potential investigations. Second, we tested the anti-Alzheimer properties of the carrier system on a differentiated neuroblastoma (SHSY5-Y) cell line, which was exposed to beta-amyloid (1-42) peptides to stimulate an experimental in vitro AD model. Next, we performed cytotoxicity analyses of synthesized molecules on the human dermal fibroblast cell line (HDFa) and the experimental AD model. Cytotoxicity analyses showed that even higher concentrations of the carrier system did not enhance the toxicological outcome in HDFa cells. Drug loading analyses reported that uncoated hBN nano conjugate could not load the BLA, whereas the memantine loading capacity of hBN was 84.3%. On the other hand, memantine and the BLA loading capacity of the hBN-FA construct was found to be 95% and 97.5%, respectively. Finally, we investigated the neuroprotective properties of the nano carrier systems in the experimental AD model. According to the results, 25 µg/mL concentrations of hBN-FA+memantine (94% cell viability) and hBN-FA+BLA (99% cell viability) showed ameliorative properties against beta-amyloid (1-42) peptide toxicity (50% cell viability). These results were generated through the use of flow cytometry, acetylcholinesterase (AChE) and antioxidant assays. In conclusion, the developed drug carrier system for AD treatment showed promising potential for further investigations and enlightened neuroprotective capabilities of boron molecules to treat AD and other neurodegenerative diseases. On the other hand, enzyme activity, systematic toxicity analyses, and animal studies should be performed to understand neuroprotective properties of the designed carrier system comprehensively.


Subject(s)
Alzheimer Disease , Nanoparticles , Acetylcholinesterase , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Boron , Boron Compounds , Drug Carriers/therapeutic use , Folic Acid/therapeutic use , Humans , Memantine/therapeutic use , Nanoparticles/chemistry
15.
Pharmaceuticals (Basel) ; 15(2)2022 Feb 15.
Article in English | MEDLINE | ID: mdl-35215340

ABSTRACT

The main antimicrobial resistance (AMR) nosocomial strains (ESKAPE pathogens such as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are the most widespread bacteria in cutaneous infections. In this work we report the synthesis, in silico skin permeability prediction, antimicrobial, antibiofilm, and wound healing properties of novel cinnamic acid-based antimicrobials (DM1-11) as novel antibacterial drugs for the treatment of ESKAPE-related skin infections. Antimicrobial and wound healing scratch assays were performed to evaluate the antibacterial properties of DM1-11. In silico skin permeability capabilities of DM1-11 were evaluated using Swiss-ADME online database. Cytotoxicity assays were performed on keratinocytes and fibroblasts. DM2, bearing a catechol group on the aromatic ring of the cinnamic portion of the molecule, possesses a significant antibacterial activity against S. aureus (MIC range 16-64 mg/L) and contrasts the biofilm-mediated S. epidermidis infection at low concentrations. Wound healing assays showed that wound closure in 48 h was observed in DM2-treated keratinocytes with a better healing pattern at all the used concentrations (0.1, 1.0, and 10 µM). A potential good skin permeation for DM2, that could guarantee its effectiveness at the target site, was also observed. Cytotoxicity studies revealed that DM2 may be a safe compound for topical use. Taking together all these data confirm that DM2 could represent a safe wound-healing topical agent for the treatment of skin wound infections caused by two of main Gram-positive bacteria belonging to ESKAPE microorganisms.

16.
Braz. arch. biol. technol ; 65: e22200784, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1364455

ABSTRACT

Abstract Nanoscale biomaterials are commonly used in a wide range of biomedical applications such as bone graft substitutes, gene delivery systems, and biologically active agents. On the other hand, the cytotoxic potential of these particles hasn't yet been studied comprehensively to understand whether or not they exert any negative impact on the cellular structures. Here, we undertook the synthesis of beta-tricalcium phosphate (ß-TCP) and biphasic tricalcium phosphate (BCP) nanoparticles (NPs) and determine their concentration-dependent toxic effects in human fetal osteoblastic (hFOB 1.19) cell line. Firstly, BCP and β-TCP were synthesized using a water-based precipitation technique and characterized by X-Ray Diffraction (XRD), Raman Spectroscopy, and Transmission Electron Microscopy (TEM). The cytological effects of β-TCP and BCP at different concentrations (0-640 ppm) were evaluated by using 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The total oxidative status (TOS) parameter was used for investigating oxidative stress potentials of the NPs. In addition, the study assessed the DNA damage product 8-hydroxy-2′-deoxyguanosine (8-Oxo-dG) level in hFOB 1.19 cell cultures. The results indicated that the β-TCP (above 320 ppm) and BCP (above 80 ppm) NPs exhibited cytotoxicity effects on high concentrations. It was also observed that the oxidative stress increased relatively as the concentrations of NPs increased, aligning with the cytotoxicity results. However, the NPs concentrations of 160 ppm and above increased the level of 8-OH-dG. Consequently, there is a need for more systematic in vivo and in vitro approaches to the toxic effects of both nanoparticles.

17.
RSC Med Chem ; 12(11): 1944-1949, 2021 Nov 17.
Article in English | MEDLINE | ID: mdl-34825189

ABSTRACT

Novel boron-based compounds (BBCs) were synthesized and evaluated as potential candidates for the development of novel drugs against Alzheimer's disease (AD). The neuroprotective profile of novel BBCs was evaluated using Aß1-42-treated-SH-SY5Y cells while their antioxidant activity was evaluated by total antioxidant capacity (TAC) and total oxidative status (TOS) assays. Results showed that BLA (a novel boron-based hybrid containing an antioxidant portion) inhibited cell death induced by Aß1-42-exposure in differentiated SH-SY5Y cells, resulting in an increase in cell viability by 25-33% (MTT assay) and by 63-71% (LDH assay) in a concentration range of 25-100 µM. Antioxidant assays demonstrated a good capability of BLA to counteract the oxidative status. Moreover, BLA possessed a significant ability to inhibit acetylcholinesterase (AChE) (22.96% at 50 µM), an enzyme whose enzymatic activity is increased in AD patients. In the present work, absorption and distribution properties of boron-based hybrids were predicted using Pre-ADMET software. In vitro preliminary results suggested that boron-based hybrids could be new structural scaffolds for the development of novel drugs for the management of AD.

18.
Biomolecules ; 11(11)2021 11 05.
Article in English | MEDLINE | ID: mdl-34827638

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative age-related disorder worldwide after Alzheimer's disease [...].


Subject(s)
Alzheimer Disease , Parkinson Disease , Pharmaceutical Preparations , Alzheimer Disease/drug therapy , Humans , Parkinson Disease/drug therapy
19.
Pharmaceutics ; 13(8)2021 Jul 22.
Article in English | MEDLINE | ID: mdl-34452078

ABSTRACT

Recently, mineral healing clays have gained much attention for wound-dressing applications. Here, we selected halloysite (HAL) clay as a biocompatible, non-toxic material that is useful as a drug delivery system to enhance the healing properties of water-soluble terpenoids 1-3 (T1-3). Terpenoids-loaded HAL clay (TH1-3) was prepared and characterized by adsorption equilibrium studies, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and release studies. The results reveal that T1-3 were adsorbed at the HAL surface with good efficiency. The prevalent mechanism of drug retention is due to the adsorption via electrostatic interactions between the cationic groups of the T1-3 and the HAL's external surface. Release studies demonstrated that T3 was released in a higher percentage (>60%) compared to T1-2 (≈50%). Additionally, TH1-3 were assessed for their antimicrobial activity and capability to promote the re-epithelialization of scratched HaCat monolayers, through the time-kill test and the wound-healing assays, respectively. The results reveal that all the tested formulations were able to reduce the microbial growth after 1 h of incubation and that they ensured complete wound closure after 48 h. Furthermore, at the concentration of 1 µg/mL, TH3 exhibited 45% wound closure at 24 h, compared to TH1 (27%) and TH2 (30%), proving to be the best candidate in making the tissue-repair process easier and faster.

20.
Hemasphere ; 5(7): e593, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34131633

ABSTRACT

Mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and primary myelofibrosis patients. To address the contribution of the human CALR mutants to the pathogenesis of myeloproliferative neoplasms (MPNs) in an endogenous context, we modeled the CALRdel52 and CALRins5 mutants by induced pluripotent stem cell (iPSC) technology using CD34+ progenitors from 4 patients. We describe here the generation of several clones of iPSC carrying heterozygous CALRdel52 or CALRins5 mutations. We showed that CALRdel52 induces a stronger increase in progenitors than CALRins5 and that both CALRdel52 and CALRins5 mutants favor an expansion of the megakaryocytic lineage. Moreover, we found that both CALRdel52 and CALRins5 mutants rendered colony forming unit-megakaryocyte (CFU-MK) independent from thrombopoietin (TPO), and promoted a mild constitutive activation level of signal transducer and activator of transcription 3 in megakaryocytes. Unexpectedly, a mild increase in the sensitivity of colony forming unit-granulocyte (CFU-G) to granulocyte-colony stimulating factor was also observed in iPSC CALRdel52 and CALRins5 compared with control iPSC. Moreover, CALRdel52-induced megakaryocytic spontaneous growth is more dependent on Janus kinase 2/phosphoinositide 3-kinase/extracellular signal-regulated kinase than TPO-mediated growth and opens a therapeutic window for treatments in CALR-mutated MPN. The iPSC models described here represent an interesting platform for testing newly developed inhibitors. Altogether, this study shows that CALR-mutated iPSC recapitulate MPN phenotypes in vitro and may be used for drug screening.

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