Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents.

This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1-3) as potential candidates to counteract neuroinflammation processes in Alzheimer's disease. GPE 1-3 pseudotripeptides are synthetic derivatives of Gly-l-Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t1/2 > 4 h) than GPE (t1/2 = 30 min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1-3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1ß, IL-18, and TNF-α) in Aß25-35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties.

Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL4-9) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aß(25-35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1ß and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD.

Synthesis of a novel cyclic prodrug of S-allyl-glutathione able to attenuate LPS-induced ROS production through the inhibition of MAPK pathways in U937 cells.

A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.

The efficacy of the quorum sensing inhibitor FS8 and tigecycline in preventing prosthesis biofilm in an animal model of staphylococcal infection.

We investigated the efficacy of tigecycline and FS8, alone or combined, in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection. Graft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2 x 107 colony-forming units of Staphylococcus aureus, strain Smith diffuse. The study included a control group, a contaminated group that did not receive any antibiotic prophylaxis, and three contaminated groups that received: (i) intraperitoneal tigecycline, (ii) FS8-soaked graft, and (iii) tigecycline plus FS8-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro binding-study was performed to quantify the how much FS8 was coated to the surface of the prosthesis. Tigecycline, combined with FS8, against the adherent bacteria showed MICs (2.00 mg/L) and MBCs (4.00 mg/L) four-fold lower with respect to tigecycline alone in in vitro studies. The rat groups treated with tigecycline showed the lowest bacterial numbers (4.4 x 104 ± 1.2 x 104 CFU/mL). The FS8-treated group showed a good activity and significant differences compared to control group with bacterial numbers of 6.8 x 104 ± 2.0 x 104 CFU/mL. A stronger inhibition of bacterial growth was observed in rats treated with a combined FS8 and tigecycline therapy than in those that were singly treated with bacterial numbers of 101 CFU/mL graft. In conclusion, the ability to affect biofilm formation as well, its property to be an antibiotic enhancer suggests FS8 as alternative or additional agent to use in conjunction with conventional antimicrobial for prevention of staphylococcal biofilm related infection.

Anti-Obesity and Anti-Inflammatory Effects of Novel Carvacrol Derivatives on 3T3-L1 and WJ-MSCs Cells.

(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.

Synthesis of short cationic antimicrobial peptidomimetics containing arginine analogues.

Worldwide efforts are underway to develop new antimicrobial agents against bacterial resistance. To identify new compounds with a good antimicrobial profile, we designed and synthesized two series of small cationic antimicrobial peptidomimetics (1-8) containing unusual arginine mimetics (to introduce cationic charges) and several aromatic amino acids (bulky moieties to improve lipophilicity). Both series were screened for in vitro antibacterial activity against a representative panel of Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacterial strains, and Candida albicans. The biological screening showed that peptidomimetics containing tryptophan residues are endowed with the best antimicrobial activity against S. aureus and S. epidermidis in respect to the other synthesized derivatives (MIC values range 7.5-50 µg/ml). Moreover, small antimicrobial peptidomimetics derivatives 2 and 5 showed an appreciable activity against the tested Gram-negative bacteria and C. albicans. The most active compounds (1-2 and 5-6) have been tested against Gram-positive established biofilm, too. Results showed that the biofilm inhibitory concentration values of these compounds were never up to 200 µg/ml. The replacement of tryptophan with phenylalanine or tyrosine resulted in considerable loss of the antibacterial action (compounds 3-4 and 7-8) against both Gram-positive and Gram-negative bacterial strains. Furthermore, by evaluating hemolytic activity, the synthesized compounds did not reveal cytotoxic activities, except for compound 5.

Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.

So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and ß-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (Aß1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and ß-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against Aß1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by Aß1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

Carvacrol prodrugs as novel antimicrobial agents.

Carvacrol (CAR), a natural monoterpene particularly abundant in plants belonging to the Lamiaceae family, has recently attracted much attention for its many biological properties (antioxidant, anti-inflammatory, neuroprotective, antitumour, antibacterial, and several others). However, CAR has poor chemical-physical properties (low water solubility and high volatility), which hamper its potential pharmacological uses. In this paper, the synthesis and antimicrobial evaluation of 23 carvacrol derivatives (WSCP1-23) against a panel of selected gram-positive and gram-negative bacteria are reported. Using the prodrug approach, CAR hydrophilic (WSCP1-17) and lipophilic prodrugs (WSCP18-23) were prepared. Notably, CAR water solubility was increased by using polar neutral groups (such as natural amino acids) with the aim of improving oral drug delivery. On the other hand, CAR lipophilic prodrugs, obtained by prenylation of CAR hydroxyl group, were designed to promote membrane permeation and oral absorption. Our results revealed that WSCP1-3, showing the highest water solubility (>1700-fold compared to that of CAR), possessed good antibacterial activity against gram-negative bacteria with MIC values comparable to those of CAR and antifungal properties against different species of Candida. WSCP18-19 were the most promising prodrugs, showing good antibacterial profiles against gram-positive bacteria by interfering with the biofilm formation of Staphylococcus aureus and Staphylococcus epidermidis. Moreover, WSCP18-19 resulted more stable in simulated fluids and human plasma than WSCP1-3. Toxicity studies performed on human erythrocytes and HaCaT cells revealed that all WSCPs were not toxic at the tested concentrations.

(R)-α-Lipoyl-Gly-l-Pro-l-Glu dimethyl ester as dual acting agent for the treatment of Alzheimer's disease.

In this study, effects of LA-GPE (R-α-Lipoyl-Gly-l-Pro-l-Glu dimethyl ester) and GPE (Gly-L-Pro-L-Glu) on the cytotoxic action of Aß1-42 were tested with differentiated human neuroblastoma SH-SY5Y cells as cellular Alzheimer model via measurements of mitochondrial viability (MTT assay) and lactate dehydrogenase release (LDH assay). Effects of LA-GPE and GPE on acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels, and neural cell apoptosis and necrosis were also determined. In addition, biological safety of these novel formulations was evaluated in human blood cells using different cytotoxicity and genotoxicity assays. Our results indicated that both compounds could block Aß1-42 induced cell death. LA-GPE reduced Aß-induced AChE activity and oxidative stress, suggesting it as a multifunctional compound potentially valuable for the treatment of Alzheimer's disease (AD).

Synthesis and Antioxidant Properties of Novel Memantine Derivatives.

BACKGROUND: Medicinal chemistry methodologies are presently used to develop multifunctional molecules which simultaneously reduce oxidative stress, excitotoxicity, metal dyshomeostasis, and neuroinflammation that characterize neuropathological conditions, such as Alzheimer's Disease. RESULTS: Memantine (MEM) derivatives 1-6 were designed and synthesized as novel multifunctional entities with antioxidant and neuroprotective capabilities to manage neurodegenerative diseases, such as Alzheimer's Disease. In vitro neuroprotective studies were performed by using astroglial GL15 cell line to assess antioxidant capability of MEM derivatives 1-6. CONCLUSION: Our outcomes showed that compounds 1 and 5 (at the concentration of 10 µM), containing as antioxidant portion residues of N-acetyl-Cys-OH and N-acetyl-Cys(Allyl)-OH, respectively, revealed a significant neuroprotective activity against oxidative stress, as assessed by NBT assays.

Effect of MRJF4 on C6 Glioma Cells Proliferation and Migration.

BACKGROUND: MRJF4, a novel haloperidol metabolite II prodrug, was obtained through the esterification of the secondary hydroxyl group of haloperidol metabolite II with 4-phenylbutyric acid. The activities of (±)-MRJF4 and its two enantiomers [(+)-MRJF4 and (-)-MRJF4] as tumor specific inducers of pro-apoptotic genes were evaluated on malignant C6 glioma cells. In particular, changes in Nf-κB signaling pathway, activity of nitric oxide synthases (NOS), metalloproteinases (MMPs), and membrane adhesion proteins were investigated. RESULTS: IκBα reduced phosphorylation and iNOS lowered activity could be correlated with the previously demonstrated decreased proliferation and tumor progression of C6 cells upon 24 h of treatment with all the three compounds. Integrin ß1 decreased expression, at the same experimental time, seems to support lower C6 cells migrative capability and the consequent reduced invasiveness of these cells upon treatment with (±)-MRJF4 and its enantiomers. CONCLUSION: These results suggest that this multi-target prodrug and its two enantiomers might be a valuable clinical tool for the treatment of metastatic glioblastoma.

Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma.

Glioblastoma is one of the most aggressive malignant primary brain cancer in adults. To date, surgery, radiotherapy and current pharmacological treatments are not sufficient to manage this pathology that has a high mortality rate (median survival 12-15months). Recently, anticancer multi-targeted compounds have attracted much attention with the aim to obtain new drugs able to hit different biological targets that are involved in the onset and progression of the disease. Here, we report the synthesis of novel memantine-derived drugs (MP1-10) and their potential antitumor activities in human U87MG glioblastoma cell line. MP1-10 were synthetized joining memantine, which is a NMDA antagonist, to different histone deacetylase inhibitors to obtain one molecule with improved therapeutic efficacy. Biological results indicated that MP1 and MP2 possessed more potent anti-proliferative effects on U87MG cells than MP3-10 in a dose-dependent manner. MP1 and MP2 induced significant cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining. Both drugs also exhibited non-genotoxic and only mild cytotoxic effects in human whole blood cells. However, only MP1, showing good chemico-physical properties (solubility, LogP) and enzymatic stabilities in gastric and intestinal fluids, can be considered a suitable candidate for in vivo pharmacokinetic studies.

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases.

INTRODUCTION: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action. AREA COVERED: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms. EXPERT OPINION: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer's and Parkinson's diseases.

Efficacy of the Quorum Sensing Inhibitor FS10 Alone and in Combination with Tigecycline in an Animal Model of Staphylococcal Infected Wound.

In staphylococci, quorum sensing regulates both biofilm formation and toxin production, moreover it has been demonstrated to be inhibited by RNAIII inhibiting peptide (RIP). Aim our study was to evaluate the in vitro activity and its in vivo efficacy of the combined administration of FS10, a novel RIP derivative, and tigecycline in an animal model of methicillin-resistant (MR) and methicillin-sensitive (MS) Staphylococcus aureus wound infection. Using a 1.x2 cm template, one full thickness wound was established through the panniculus carnosus on the back subcutaneous tissue of each animal. Infection was determined by inoculation of 5x107 CFU/ml of bacteria, that produced an abscess within 24 h, after this, treatment was initiated. The study included, for each strain, a control group without infection, a control infected group that did not receive any treatment and a control infected group with drug-free foam dressing, and three infected groups treated, respectively, with: FS10-soaked foam dressing (containing 20 µg FS10), daily intraperitoneal tigecycline (7 mg/Kg), FS10-soaked foam dressing (containing 20 µg FS10) and daily intraperitoneal injections of tigecycline (7 mg/Kg). The main outcome measures were quantitative culture and histological examination of tissue repair. The highest inhibition of infection was achieved in the group that received FS10-soaked and parenteral tigecycline reducing the bacterial load from 107 CFU/ml to about 103 CFU/g for MSSA and to about 104 CFU/g for MRSA. The group treated with FS10-soaked foam dressing associated with parenteral tigecycline showed, histologically, better overall healing with epithelialization and collagen scores significantly higher than those of the other groups in both strains. In conclusion, the combined use of topical FS10 with i.p. tigecycline induced positive interaction in vivo, resulting in an enhanced therapeutic benefit versus staphylococcal infections in murine wound models.

Development of glycine-α-methyl-proline-containing tripeptides with neuroprotective properties.

Herein is described the synthesis of novel glycine-α-methyl-proline-containing tripeptides (GP(Me)X tripeptides namely GP(Me)R, GP(Me)K, and GP(Me)H) with the aim of obtaining derivatives highly stable in human plasma and able to counteract neuroinflammatory processes that are distinctive of neurodegenerative pathologies. The syntheses of GP(Me)R, GP(Me)K, and GP(Me)H were all achieved both by introducing the Pro(Me) residue into the Gly-Pro-Arg (GPR) sequence in place of the native Pro in P2 position and replacing the basic amino acid Arg in P3 position by Lys or His. Results showed that all novel GP(Me)X tripeptides are stable in human plasma (t1/2 > 51 h) and that GP(Me)H - generating stable intramolecular H-bond in a C11-turn by interaction of His imidazole ring and Gly carbonyl group - restored physiological levels of nitric oxide deriving from neuronal NOS (nNOS) activity, thus preventing the inflammatory response by suppression of the NF-kB activity and, consequently, the expression of inflammatory genes such as inducibile NOS (iNOS). Therefore, GP(Me)H could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes.

Solid lipid nanoparticles loaded with lipoyl-memantine codrug: preparation and characterization.

Solid lipid nanoparticles (SLNs) are considered very attractive drug-delivery systems (DDS) able to enhance the efficacy of some therapeutic agents in several pathologies difficult to treat in a conventional way. Starting from these evidences, this study describes the preparation, physicochemical characterization, release, and in vitro cytotoxicity of stealth SLNs as innovative approach to improve solubility and absorption through the gastrointestinal tract of lipoyl-memantine (LA-MEM), a potential anti-Alzheimer codrug. Physico-chemical properties of LA-MEM loaded SLNs have been intensively investigated. Differential scanning calorimetry (DSC) was used to clarify the state and crystalline structure of the formulation. The results obtained from particles size analysis, polydispersity (PDI), and zeta potential measurements allowed the identification of the optimized formulation, which was characterized by a drug-lipid ratio 1:5, an average intensity diameter of 170nm, a PDI of 0.072, a zeta potential of -33.8mV, and an entrapment efficiency of 88%. Moreover, in vitro stability and release studies in both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), and preliminary in vitro cytotoxicity studies revealed that LA-MEM loaded SLNs could represent potential candidate for an in vivo investigation as DDS for the brain since it resulted devoid of citotoxicity and able to release the free codrug.

Carvacrol codrugs: a new approach in the antimicrobial plan.

OBJECTIVE: The increasing prevalence of antibiotic-resistant bacterial infections led to identify alternative strategies for a novel therapeutic approach. In this study, we synthesized ten carvacrol codrugs - obtained linking the carvacrol hydroxyl group to the carboxyl moiety of sulphur-containing amino acids via an ester bond - to develop novel compounds with improved antimicrobial and antibiofilm activities and reduced toxicity respect to carvacrol alone. METHOD: All carvacrol codrugs were screened against a representative panel of Gram positive (S. aureus and S. epidermidis), Gram negative (E. coli and P. aeruginosa) bacterial strains and C. albicans, using broth microdilution assays. FINDINGS: Results showed that carvacrol codrug 4 possesses the most notable enhancement in the anti-bacterial activity displaying MIC and MBC values equal to 2.5 mg/mL for all bacterial strains, except for P. aeruginosa ATCC 9027 (MIC and MBC values equal to 5 mg/mL and 10 mg/mL, respectively). All carvacrol codrugs 1-10 revealed good antifungal activity against C. albicans ATCC 10231. The cytotoxicity assay showed that the novel carvacrol codrugs did not produce human blood hemolysis at their MIC values except for codrugs 8 and 9. In particular, deepened experiments performed on carvacrol codrug 4 showed an interesting antimicrobial effect on the mature biofilm produced by E. coli ATCC 8739, respect to the carvacrol alone. The antimicrobial effects of carvacrol codrug 4 were also analyzed by TEM evidencing morphological modifications in S. aureus, E. coli, and C. albicans. CONCLUSION: The current study presents an insight into the use of codrug strategy for developing carvacrol derivatives with antibacterial and antibiofilm potentials, and reduced cytotoxicity.

Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity.

Many neurological and neurodegenerative diseases are associated with oxidative stress and glial inflammation, all related to endoplasmic reticulum stress. Cyclo(His-Pro) is an endogenous cyclic dipeptide that exerts cytoprotection by interfering with the Nrf2-NF-κB systems, the former presiding the antioxidant and the latter the pro-inflammatory cellular response. Here we investigated whether the cyclic dipeptide inhibits glial inflammation thus reducing the detrimental effect of inflammatory neurotoxins on neurons. We found that systemic administration of cyclo(His-Pro) exerts in vivo anti-inflammatory effects in the central nervous system by down-regulating hepatic and cerebral TNFα expression thereby counteracting LPS-induced gliosis. Mechanistic studies indicated that the cyclic dipeptide-mediated effects are achieved through the activation of Nrf2-driven antioxidant response and the inhibition of the pro-inflammatory NF-κB pathway. Moreover, by up-regulating Bip, cyclo(His-Pro) increases the ER stress sensitivity and triggers the unfolded protein response to alleviate the ER stress. These results unveil a novel potential therapeutic use of cyclo(His-Pro) against neuroinflammatory-related diseases and we might now consider its potential anti-inflammatory role in other neuropathological conditions.

A Potent (R)-alpha-bis-lipoyl Derivative Containing 8-Hydroxyquinoline Scaffold: Synthesis and Biological Evaluation of Its Neuroprotective Capabilities in SH-SY5Y Human Neuroblastoma Cells.

A novel bis-lipoyl derivative containing 8-hydroxyquinoline scaffold (LA-HQ-LA, 5) was synthesized as a new multifunctional drug candidate with antioxidant, chelant, and neuroprotective properties for the treatment of neurodegenerative diseases. We have investigated the potential effectiveness of LA-HQ-LA against the cytotoxicity induced by 6-OHDA and H2O2 on human neuroblastoma SH-SY5Y cell line. Our outcomes showed that LA-HQ-LA resulted in significant neuroprotective and antioxidant effects against H2O2- and 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cells, as assessed by MTT assay. In particular, it showed potent neuroprotective effects against 6-OHDA in RA/PMA differentiated cells at all the tested concentrations.