Search

Background: Nowadays, infectious diseases caused by bacteria are one of the major risks for the human population worldwide. Antimicrobial resistance determined the necessity to develop both, new drugs and therapeutic approaches as alternatives to antibiotics and novel methods to detect bacteria.Aptamers have revealed their potential in combating antimicrobial infections. Aptamers are small single-stranded DNA or RNA oligonucleotides obtained through an in vitro process able to bind several targets with high affinity and specificity. Objective: The aim of this review is to provide an overview of the state of the art of aptamer-based antimicrobial therapeutic strategies, new methods of detection of bacteria, and their potential use as delivery systems. Conclusion: Recent applications on research about aptamers suggest their important potential in discovering novel pharmacological tools for the treatment of microbial infections.

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.

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

Under different pathological conditions, aberrant induction of neuronal nitric oxide synthase (nNOS) generates overproduction of NO that can cause irreversible cell damage. The aim of this study was to develop an amidoxime prodrug of a potent nNOS inhibitor, the benzhydryl acetamidine. We synthesized the benzhydryl acetamidoxime, which was evaluated in vitro to ascertain the potential NOS inhibitory activity, as well as conducting bioconversion into the parent acetamidine. The prodrug was also profiled for in vitro physicochemical properties, by determining the lipophilicity, passive permeation through the human gastrointestinal tract and across the blood‐brain barrier by PAMPA, and chemical, enzymatic, and plasma stability. The obtained data demonstrate that the amidoxime prodrug shows an improved pharmacokinetic profile with respect to the acetamidine nNOS inhibitor, thus suggesting that it could be a promising lead compound to treat all those pathological conditions in which nNOS activity is dysregulated., Re‐regulating nNOS: Amidoxime 2 has been developed as prodrug of a potent nNOS inhibitor, acetamidine 1. The prodrug was found to be completely converted into the acetamidine after incubation with mARC enzymes. It was profiled for its in vitro physicochemical properties, and found to have improved drug‐like properties compared to the parent amidine and promising PAMPA‐BBB penetration.

Several epidemiologic, clinical and experimental reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) could have a potential as anticancer agents. The aim of this study was the evaluation of cytotoxic potential in human glioblastoma cells of novel synthesized NSAID derivatives, obtained by linking, through a spacer, α-lipoic acid (ALA) to anti-inflammatory drugs, such as naproxen (AL-3, 11 and 17), flurbiprofen (AL-6, 13 and 19) and ibuprofen (AL-9, 15 and 21). The effects on the level of gene expression were also determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. According to our results, NSAID derivatives exhibited concentration dependent cytotoxic effects on U87-MG cell line when compared with the control group. Moreover, treatment of the most active compounds (AL-3, AL-6 and AL-9) caused upregulation of tumor suppressor gene PTEN and downregulation of some oncogenes such as AKT1, RAF1 and EGFR. In conclusion, our results revealed that AL-3, AL-6 and AL-9 could be suitable candidates for further investigation to develop new pharmacological strategies for the prevention of cancer.

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.

To date, microbial infections are also difficult to eradicate due to the increasing capability of bacteria to form a biofilm. In the era of antibiotic resistance, antibody-based approaches represent great promise in curing infective pathogens. The authors of US2019338018 patent propose a method for the treatment of biofilm-related disorders by using specific antibody fragments.The US2019338018 patent reports antibody fragments, pharmaceutical composition that contains it, and their application for the treatment of biofilm-linked disorders. Proof concept and preclinical results show that mAb mIhfB4Fab fragments of the US2019338018 patent are new in a general concept to treat bacterial biofilms and biofilm-linked disorders. However, pre-clinical data are only shown for the treatment with Fab fragments of infections caused by

(1) Background: Capsaicin is the main capsaicinoid of the Capsicum genus and it is responsible for the pungent taste. Medical uses of the fruits of chili peppers date from the ancient time until nowadays. Most of all, they are used topically as analgesic in anti-inflammatory diseases as rheumatism, arthritis and in diabetic neuropathy. Reports state that the Capsicum genus, among other plant genera, is a good source of antimicrobial and antifungal compounds. The aim of this study was the preparation of a pharmaceutical Carbopol-based formulation containing capsaicin and the evaluation of its in vitro release and antimicrobial and antifungal properties. (2) Methods: It was first stabilized with an extraction method from the Capsicum annuum fruits with 98% ethanol and then the identification and determination of Capsaicin in this extract was realized by HPLC. (3) Results and Conclusions: Rheological analyses revealed that the selected formulation exhibited a pseudo-plastic behavior. In vitro release studies of capsaicin from a Carbopol-based formulation reported that approximately 50% of capsaicin was release within 52 h. Additionally, the Carbopol-based formulation significantly increased the antimicrobial effects of capsaicin towards all tested bacteria and fungi strains.

An adolescent male with a history of autoimmune enteropathy, autoimmune hypothyroidism, aphthous stomatitis and recurrent oral Candida infections only in the setting of curative antibiotic courses presented with cryptococcal pneumonia and perihilar adenitis, which was successfully treated with antifungal therapy. The patient had a complex history with several immunological anomalies. Whole exome sequencing revealed a known STAT1 pathogenic variant, associated with gain of function (GOF). This case expands our understanding of the broad clinical phenotype manifested by STAT1 GOF and emphasises the importance of consideration of this diagnosis in patients presenting with opportunistic infections and autoimmunity.

Background: Carvacrol, an essential oil with antimicrobial activity against a wide range of pathogens, and its water soluble carvacrol prodrugs (WSCP1-3) were intercalated into montmorillonite (VHS) interlayers to improve their stability in physiological media and promote their absorption in the intestine. Methods: Intercalation of prodrugs by cation exchange with montmorillonite interlayer counterions was verified by X-ray powder diffraction and confirmed by Fourier transform infrared spectroscopy and thermal analysis. Results: In vitro release studies demonstrated that montmorillonite successfully controlled the release of the adsorbed prodrugs and promoted their bioactivation only in the intestinal tract where carvacrol could develop its maximum antimicrobial activity. The amount of WSCP1, WSCP2, and WSCP3 released from VHS were 38%, 54%, and 45% at acid pH in 120 min, and 65%, 78%, and 44% at pH 6.8 in 240 min, respectively. Conclusions: The resultant hybrids successfully controlled conversion of the prodrugs to carvacrol, avoiding premature degradation of the drug., Ministry of Education, Universities and Research (MIUR) FAR2018

The fibrous silicates, Palygorskite and Sepiolite, were investigated as low-cost nanocarriers for three carvacrol prodrugs to ameliorate their pharmacokinetic and biopharmaceutic profiles. Adsorption equilibrium studies were performed in order to obtain a drug-clay hybrid system. These hybrid systems were characterized by thermal analysis, X-ray diffraction, and Fourier transform infrared spectroscopy, to study the degree and kind of interactions between the organic and inorganic components. In vitro release and chemical stability of prodrug-clay hybrids were studied in physiological gastrointestinal simulated fluids. The results showed an improvement of the chemical stability of prodrugs in hybrids systems, as well as a sustained release and a retained bioconversion of the prodrugs into the pharmacologically active carvacrol, to improve the antimicrobial activity., This research was funded by MIUR, grant number “FAR2018” and CGL2016-80833-R (Spanish Project) and P18-RT-3786 (Andalusian Project).

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.

Neurodegenerative diseases share a common pathogenetic mechanism involving aggregation and deposition of misfolded proteins, oxidative stress, metal dyshomeostasis, and glutamate exicitotoxicity, which lead to progressive dysfunction of central nervous system (CNS). A potential strategy to counteract these deleterious events at neuronal level is represented by the employment of a novel class of multi-target therapeutic agents that selectively and simultaneously hit these targets In this paper, we report the metal binding and antioxidant properties of a novel metal-protein attenuating peptide, GSH-LD, a tetrapeptide obtained by linking glutathione, a well-known antioxidant tripeptide, to L-Dopa. Results demonstrated that GSH-LD possesses chelating capabilities in order to selectively target the excess of metals without interfere with metal-containing antioxidant enzymes. Moreover, antioxidant assays revealed a large contribution of GSH-LD to restore the antioxidant defences of damaged neuronal cells.

In recent years, essential oils constituents have attracted interest as alternative approach in the traditional medicine for their therapeutics properties. In this field, carvacrol, since it showed strong antimicrobial activity against a wide range of Gram-positive and -negative bacteria, has emerged as active molecule for therapeutic purpose. This review focuses on the antimicrobial properties of carvacrol and highlights the advantageous impact of the medicinal chemistry and technological-based approaches employed to improve its therapeutic profile.

Parkinson's Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension. Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system. Expert opinion: The prodrug strategy remains one of the most promising approaches to improve pharmaceutical, pharmacokinetic, and pharmacodynamic properties of hydrophilic compounds, such as anti-Parkinson drugs (DA and LD). Prodrugs developed in recent years have demonstrated good pharmacokinetic profiles, affording a sustained release of LD and reducing its plasma level fluctuations. The development of new prodrugs that may reach the BBB unaltered and with a good ADME (Absorption, Distribution, Metabolism, Elimination) profile and pharmacological efficacy represents an exciting challenge for medicinal chemists.

The use of food supplements or functional food has significantly increased in the past decades, especially to compensate both the modern lifestyle and the food shortages of the industrialized countries. Despite food supplements are habitually intended to correct nutritional deficiencies or to support specific physiological functions, they are often combined with common drug therapies to improve the patient's health and/or mitigate the symptoms of many chronic diseases such as cardiovascular diseases, cystic fibrosis, cancer, liver and gastrointestinal diseases. In recent years, increased attentions are given to the patient's diet, and the use of food supplements and functional food rich in vitamins and antioxidants plays a very important role in the treatment and prevention of neurodegenerative diseases such as Parkinson's disease (PD). Natural compounds, phytochemicals, vitamins, and minerals can prevent, delay, or alleviate the clinical symptoms of PD in contrast to some of the main physiopathological mechanisms involved in the development of the disease, like oxidative stress, free radical formation, and neuroinflammation. The purpose of this review is to collect scientific evidences which support the use of specific biomolecules and biogenic elements commonly found in food supplements or functional food to improve the clinical framework of patients with PD.

Parkinson&rsquo, s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of substantia nigra pars compacta. To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-l-Dopa (LD) derivatives (SP1&ndash, 6) obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2&rsquo, 7&rsquo, dichlorodihydrofluorescein diacetate (H2DCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of SP1&ndash, 6 were also performed. Biological data revealed that SP6 has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and H2O2 in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. SP6, endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood&ndash, brain barrier. SP6 has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).

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.

Early-life exposure (from postnatal day 6 to postnatal day 21) to permethrin has been associated with long-term development of dopaminergic neurodegeneration in rats. Here, we first investigated if the dopamine decrease observed following early postnatal exposure to permethrin, an oxidative stressor, can impair the dopamine level in the brain of their untreated offspring. Secondly, we evaluated whether this adverse event affects the epigenome of both directly exposed rats (F0) and their untreated offspring (F1). The results show that early-life exposure to the stressor is associated with changes in global DNA methylation and hydroxymethylation in adult age. Furthermore, parental exposure leads to a significant reduction in dopamine level in the offspring (F1) born from parents or just mothers early-life treated (72.72% and 47.35%, respectively). About 2/3 of pups from exposed mothers showed a significant reduction in dopamine level compared to controls. Global DNA methylation and hydroxymethylation impairment was associated with the F1 pups that showed reduced dopamine. This study provides pivotal evidences on intergenerational effects of postnatal exposure to permethrin emphasizing that this xenobiotic can influence the epigenetic memory of early-life parental perturbations disturbing offspring health.

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.

6072 Background: Effective screening tests for ovarian cancer (OC) are lacking; most cases present at advanced stage and portend poor prognosis. DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. In DNA extracted from tissues, we first discovered, then validated discriminant methylated DNA marker (MDM) candidates for OC and subsequently tested independent plasma from women with and without OC. Methods: For discovery, DNA from 67 frozen tissues (18 high grade serous (HGS), 18 endometrioid, 15 clear cell (CC), 6 mucinous OCs; 10 benign fallopian tube epithelium (FT); and 19 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with OC. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent FFPE tissues from OCs (36 HGS, 22 endometrioid, 21 CC, and 14 mucinous) and 29 FT. Top performing MDMs in tissue were tested using long-probe quantitative amplified signal assays in independent pre-treatment plasma samples from women newly-diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. Results: After RRBS discovery and biological validation, 33 MDMs showed marked methylation fold changes (10 to > 1000) across all OC histologies vs FT. The top 11 MDMs ( GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, DSCR6, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (76 (84%) HGS) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95%CI 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86 - 0.96)). Among HGS, the panel correctly identified 83%, including 5/6 stage I/II, and the majority of other subtypes (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded outstanding candidate MDMs for OC that performed with promisingly high sensitivity and specificity in plasma. Larger plasma-based OC MDM testing studies, with larger numbers of non-HGS histologies are warranted. [Table: see text]

In this paper, we report the development and viscoelastic properties of hyaluronic acid formulations (HA5, HA30, and HA60, containing 0.5, 3, and 6% HA, respectively) loaded with carvacrol prodrugs (WSCPS) with antibacterial properties. Notably, antimicrobial studies revealed that WSCP1-2 in both HA5 and HA30 formulations showed the best minimum inhibitory concentration (MIC) values against Enterococcus faecium (128 mg/L) and Enterococcus faecalis (256 mg/L) compared to those of carvacrol alone or in formulations with HA. Moreover, rheological analyses showed that HA30 composites exhibited a semi-solid consistency, while HA5 formulations possessed a fluid consistency. Considering these data, HA30 is a useful formulation which guarantees a good percentage of prodrug release (e.g., 30 and 60% for WSCP1 and 2, respectively) as well as a texture suitable for topical administration to treat wounds and/or skin infections.

An adolescent male with a history of autoimmune enteropathy, autoimmune hypothyroidism, aphthous stomatitis and recurrent oral Candida infections only in the setting of curative antibiotic courses presented with cryptococcal pneumonia and perihilar adenitis, which was successfully treated with antifungal therapy. The patient had a complex history with several immunological anomalies. Whole exome sequencing revealed a known STAT1 pathogenic variant, associated with gain of function (GOF). This case expands our understanding of the broad clinical phenotype manifested by STAT1 GOF and emphasises the importance of consideration of this diagnosis in patients presenting with opportunistic infections and autoimmunity.

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-1β, IL-18, and TNF-α) in Aβ25–35-, 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.

As the resistance to antimicrobial molecules increases among bacteria, the need for new antimicrobial molecules increases. Antimicrobial peptides (AMP), which may be a new generation of antibiotic candidates, are important in this respect. AMPs are small, cationic and amphipathic peptide sequences. In eukaryotes, they are synthesized as a part of the immune system. Substantially, AMPs are discovered in all kingdoms of life such as bacteria, fungi and protozoa. Approximately 3,000 AMPs have been reported in the literature. However, most of these AMPs have been synthesized through chemical synthesis. Nature has a huge source of microorganisms, and in the literature, there is a tendency to increase every year the number of bacteria and fungus-derived AMPs thanks to their biotechnological importance. The exploration of AMP and antibiofilm peptide (ABP) producer microorganisms brings with it a lot of challenges experimentally. In this review study, we want to highlight the importance and challenge of these natural peptides derived from microorganisms. We will also propose a new explanation for ABPs.

S. aureus under the biofilm mode of growth is often related to several nosocomial infections, more frequently associated with indwelling medical devices (catheters, prostheses, portacaths or heart valves). As a biofilm, the biopolymer matrix provides an excellent growth medium, increasing the tolerance to antibiotics and host immune system. To date, the antimicrobial therapy alone is not effective. A novel strategy to prevent biofilm formation is based on the interference with the bacterial cell–cell communication, a process known as quorum sensing (QS) and mediated by the RNA-III-activating peptide (RAP) and its target protein TRAP (Target of RAP). The RNAIII inhibiting peptide (RIP) is able to inhibit S. aureus pathogenesis by disrupting QS mechanism competing with RAP, thus inhibiting the phosphorylation of TRAP. This alteration leads to a reduced adhesion and to the inhibition of RNAIII synthesis, with the subsequent suppression of toxins synthesis. The present paper will provide an overview on the activity and potential applications of RIP as biofilm inhibiting compound, useful in the management of S. aureus biofilm infections. Moreover, medicinal chemistry strategies have been examined to better understand which modifications and/or structure alterations were able to produce new derivatives of this QS inhibitor with an improved antibiofilm activity.