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Abstract: In order to explore the properties of chemotactic N-formylpeptides containing isopeptide bonds within their backbones, a group of lysine-containing analogs of the prototypical chemotactic tripeptide N-formylmethionyl-leucyl-phenylalanine (fMLF) was synthesized. The new analogs were designed by adding to the HCO-Met or Boc-Met residue a dipeptide fragment made up of Lys and Phe residues joined through Lys N[sup α] or N[sup ε] bonds, in all possible combinations. Thus, the following six pairs of tripeptides were synthesized and examined for their bioactivity: RCO-Met-Lys(Z)-Phe-OMe (2a, b), RCO-Met-Lys(Z-Phe)-OMe (3a, b), Z-Lys(RCO-Met)-Phe-OMe (4a, b), Z-Phe-Lys(RCO-Met)-OMe (5a, b), RCO-Met-Phe-Lys(Z)-OMe (6a, b) and Z-Lys(RCO-Met-Phe)-OMe (7a, b), with R=OC(CH[sub 3])[sub 3] and R=H for compounds a and b, respectively. All the new models were characterized fully and their activity (chemotaxis, superoxide anion production and lysozyme release) on human neutrophils determined as agonists (compounds b) and antagonists (compounds a). All N-formyl derivatives 2b-7b are less potent than fMLF-OMe as chemoattractants, but compound 7b exhibits selective activity as superoxide anion producer. Derivatives 2a-7a do not show antagonistic activity towards fMLF induced chemotaxis and O[sub 2][sup -] production, however, all these compounds except 4a antagonize lysozyme release by 60%. [ABSTRACT FROM AUTHOR]

Abstract: In order to obtain chemotactic peptides with selective bioactivity, a new type of structural modification was introduced at the N‐terminal position of HCO‐Nle‐Leu‐Phe‐OMe. Two groups of analogs have been synthesized both containing a N‐terminal residue of the X=C(R)‐CO‐type replacing the native HCO‐NH‐CH(R)‐CO‐. In particular, the A group of pseudopeptides (2a‐d) possesses a N‐terminal oximic fragment (X=HO‐N) and the B group (3a‐d) a formylhydrazone fragment (X=HCO‐NH‐N). These new ligands have been examined for their capacity to induce chemotaxis and other cellular responses such as superoxide anion production and lysozyme release; although significantly active as chemoattractants they have been found to be practically devoid of secretagog activity, thus exhibiting selective behavior. The adopted chemical modification seems extensible in designing a new class of pseudopeptides (hydrazonopeptides) structurally related to both hydrazinopeptides and peptides containing α,β‐unsaturated residues. [ABSTRACT FROM AUTHOR]

The human erythroid myeloid leukaemia cell line K562 was used as target for human neutrophil cytotoxicity. Neutrophils demonstrated cytotoxicity against K562 only in the presence of a second stimulus, tetradecanoil phorbol acetate (TPA), a result consistent with previous observations.We now demonstrate that antibody-coated K562 (using OKT9 and 345 monoclonal antibodies) are similarly only sensitive to neutrophils when TPA is added. The presence of both antibody and TPA in the cytotoxic assay resulted in significantly higher levels of cytotoxicity than in the absence of antibody; the result being consistent with a synergistic action between protein kinase C activation and Fe receptor perturbation in the neutrophil. The cytotoxicity against non-coated and antibody-coated targets was markedly inhibited, particularly against the former, by the protein kinase C inhibitor, l-(5-isoquinollne-sulfonyl)-2-methyl piperazine (H-7). There were marked differences in the extra-cellular calcium dependency of the two types of cytotoxicity reactions. TPA-activated respiratory burst was unaffected by the presence of non-coated and OKT9-coated targets, whereas TPA-induced lysosomal enzyme release was significantly increased by non-coated targets and a further increase occurred in the presence of OKT9-coated K562. [ABSTRACT FROM AUTHOR]

Abstract: for-Met-Ser(Bzl)-Phe-OMe, for-Met-Cys(Bzl)-Phe-OMe, for-Met-Tyr(Bzl)-Phe-OMe and for-Met-Lys(Z)-Phe-OMe were synthesized to investigate the importance of a bulky protecting group on the side-chain of a hydrophilic residue at position 2 on the biological activities of human neutrophils. Our results indicate that these compounds do not trigger a good chemotactic response, which, in any case, is not improved with respect to that induced by the analogs with the unprotected residues. Instead, both superoxide anion production and, particularly, lysozyme release are more efficient. [ABSTRACT FROM AUTHOR]

Abstract: The peptides for-Met-Ser-Phe-OMe 1, for-Met-Cys-Phe-OMe 2, for-Met-Lys-Phe-OMe 3, and for-Met-Tyr-Phe-OMe 4 were synthesized in order to investigate the importance of a hydrophilic side-chain on the residue at position 2 on biological activities of human neutrophils. Our results seem to highlight that this type of substitution does not facilitate good chemotaxis, although it elicits both superoxide anion production and particularly lysozyme release, in some cases even more potent than the parent fMLP-OMe, if the hydrophilicity is associated with steric hindrance. [ABSTRACT FROM AUTHOR]

Abstract: We previously reported the structural and biological properties of the C-terminal sequence (REGDPSSSQHLPSTPSSPRV) coded by the rarely expressed exon 26A of human elastin. It assumes a stable type II β-turn structure spanning the REGD sequence and possesses chemotactic and immunological properties. Here the structural characterization of the sequence coded by this exon was completed. Nuclear magnetic resonance and circular dichroism studies on the N-terminal amino acid sequence (GADEGVRRSLSPELREGD) showed the presence of an α-helix within VRRSL and a type II β-turn within SPEL. The smaller peptides GADEGVRRSLSP and LSPELREGD revealed structural features similar to those identified in the parent peptide. No β-turn was found in the REGD sequence of these peptides and no chemotactic activity was detected, thereby demonstrating that this biological activity is conformation dependent. Structural studies on additional peptides such as LREGD, ELREGD and LSPELREGDPSS showed that the presence of a Glu residue two positions before the Arg residue inhibits the β-turn formation in the REGD sequence. [ABSTRACT FROM AUTHOR]

Abstract: The formyltetrapeptides for‐Met‐Leu‐Leu‐Phe‐OMe 1, for‐Met‐Leu‐Aib‐Phe‐OMe 2, for‐Met‐Leu‐Ac[sub 6]c‐Phe‐OMe 3, for‐Met‐Leu‐Pro‐Phe‐OMe 4, for‐Met‐Pro‐Pro‐Phe‐OMe 5, for‐Met‐Aib‐Aib‐Phe‐OMe 6, for‐Met‐Pro‐Aib‐Phe‐OMe 7 and for‐Met‐Aib‐Pro‐Phe‐OMe 8 were synthesized and biologically tested on human neutrophils in an attempt to evaluate the specific receptor pocket dimensions and features. Our results indicate that the shift in the Phe residue to the fourth position in these compounds strongly reduces chemotactic response, but is efficacious in triggering superoxide anion production and lysozyme release (order of potency 3 > 2 > 1 > 4 > 6 > 8 > 5 > 7). The potency of the two latter responses correlates well with the affinity data obtained in binding experiments. [ABSTRACT FROM AUTHOR]

In an attempt to explore the relationships between conformation of chemotactic peptides related to elastin and their biological activity we have studied five peptides: VGVAPG, VGVPG, VGAPG, GVAPG and GGVPG in solvents of different polarities which may mimic the environmental conditions at the receptor site. CD and NMR studies showed that GVAPG has no preference for structured conformations, while the other peptides may assume folded conformations in organic solvents. All these peptides but GGVPG showed chemotactic activity for monocytes. The chemotactic activity of VGVPG, VGAPG and VGVAPG was inhibited by lactose, while chemotaxis of peptide GVAPG was insensitive to lactose, suggesting the existence of different chemotactic receptors. [ABSTRACT FROM AUTHOR]

Abstract: In order to further examine the properties of pseudopeptides containing the 2-hydrazonoacyl fragment, two new series of analogs of the prototypical chemotactic N-formyl-tripeptide HCO-Met-Leu-Phe-OMe were designed and synthesized. The first group contains the new fragment as the N-terminal residue and is represented by the N-aryl derivatives p-Cl-C[sub 6]H[sub 4]-NH-N=C(R)-CO-Leu-Phe-OMe (2 and 3) and by the corresponding N-aroyl analogs p-CH[sub 3]-C[sub 6]H[sub 4]-CO-NH-N=C(R)-CO-Leu-Phe-OMe (4). The second group contains the new fragment in place of the central Leu residue and is represented by compounds HCO-Xaa-NH-N=C(R)-CO-Phe-OMe (7a and 7b) where Xaa is Nle and Met, respectively. The conformational and biochemical properties of the new products were examined. [ABSTRACT FROM AUTHOR]

The presented review systematizes and summarizes the data on the synthesis of pyrrolidine derivatives, which are precursors for obtaining drugs. Based on the analysis of published data, the most promising directions in the synthesis of biologically active compounds containing a pyrrolidine ring are identified. Stereoselective synthesis methods are classified based on the source of the pyrrolidine ring. The first group includes methods that use a pyrrolidine ring as the starting compound. The second group combines stereoselective methods of cyclization of acyclic starting compounds, which lead to optically pure pyrrolidine derivatives. [ABSTRACT FROM AUTHOR]

Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. This study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a Serpina1a-e knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement (P < 0.001) and diminished lung function, including loss of lung tissue elastance (P = 0.0217) and increases in lung volumes (P = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin (P = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD. NEW & NOTEWORTHY: This study provides evidence for the impact of peptidyl arginine deiminase (PAD) enzymes on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD. [ABSTRACT FROM AUTHOR]

Copyright of Infection is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The synthesis and the biological activity of a pseudopeptide analogue of the chemotactic N-formyltripeptide fMLP-OMe, containing the aza Tic (3,4-dihydro-2( 1H)-phthalazinecarboxylic acid) residue replacing the native phenylalanine, is described. Whereas pseudopeptides containing linear a-azaammo acids are currently studied, data on the new group of analogues containing cyclic α-aza residues capable of limiting the rotameric distribution of the side chains (topological control) are just emerging in the literature. At our best knowledge, the here described [azaTic3]fMLP-OMe represents the first example of the introduction of this new type of α-aza residue into a natural bioactive peptide. [ABSTRACT FROM AUTHOR]

In order to investigate the proper peptide backbone conformation able to elicit a biological activity, HCO-Met-Pro-Phe-OMe, HCO-Met-Ψ[COO]Leu-Phe-OMe, and HCO-Met-OLeu-Phe-OMe, analogues of the prototypical chemotactic peptide HCO-Met-Leu-Phe-OMe, were studied by CD and IR techniques. The results obtained comparing biological and conformational data evidence the critical presence of (i) the NH group at position 2, (ii) a rather flexible backbone, (iii) the chemical structure of the central residue which can affect the stability of a possible active conformer. [ABSTRACT FROM AUTHOR]

Human neutrophils can damage the non-immunized K562 cell line when stimulated by phorbol myristate acetate (PMA). The combination of the activation of protein kinase C by phorbol and the increase of free intracellular calcium by ionophore potentiates the lytic reaction. The OKT9- immunized target cells are not able to induce by themselves the lytic response in neutrophils. hut by combining the two signals, the antigenic stimulus and PMA. a high level of cytolytic response is attained. The addition of EGTA does not affect neutrophil cytotoxicity against antibody-coated targets. while it markedly reduced the lytic reaction against non-immunized targets: in contrast, the addition of ECTA together with the ionophore ionomycin completely suppresses the lysis of immunized and non-immunized targets. The treatment of neutrophils with the protein kinase C inhibitor H-7 causes a dose-related inhibition of the lytic functions that is greater on unsensitized K562. Thus the interaction of Fc receptors with immunized targets is required for reaching the maximal cytolysis. The enhanced lytic activity that occurs in the presence of immunized targets is mediated by calcium flux. as detected by using the monoclonal antibody AB8.28 which hinds to FcIII receptors (FcRIII), thus supporting that both signals are involved. [ABSTRACT FROM AUTHOR]

Microparticles (MPs) are secreted by all cells, where they play a key role in intercellular communication, differentiation, inflammation, and cell energy transfer. P2X7 receptor (P2X7R) activation by extracellular ATP (eATP) causes a large MP release and affects their contents in a cell-specific fashion. We investigated MP release and functional impact in microglial cells from P2X7R-WT or P2X7R-KO mice, as well as mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) P2X7R expression. P2X7R stimulation promoted release of a mixed MP population enriched with naked mitochondria. Released mitochondria were taken up and incorporated into the mitochondrial network of the recipient cells in a P2X7R-dependent fashion. NLRP3 and the P2X7R itself were also delivered to the recipient cells. Microparticle transfer increased the energy level of the recipient cells and conferred a pro-inflammatory phenotype. These data show that the P2X7R is a master regulator of intercellular organelle and MP trafficking in immune cells. Graphical Abstract [ABSTRACT FROM AUTHOR]

In the present research work, we made an effort to a green, efficient, and simple procedure for the one-pot multicomponent synthesis of novel 2-isonicotinoyl-4,6-dihydroimidazo[4,5-c] pyrazole-5 (2H)-one derivative in presence of environmentally sustainable PEG-400 reaction medium and recyclable catalyst bleaching earth clay (pH 12.5, 10% by weight). The benefits of this methodology include a quick reaction time, high product yield, and an easy work-up procedure. The antifungal potency was studied for synthesized derivatives using the agar well diffusion method against Aspergillus niger (MTCC280), Aspergillus flavus (MTCC3008), and Penicillium citrinum fungus strain. Among the tested compounds six from the nine compounds show promising antifungal activity among the tested compounds. The derivatives were characterized using ¹H NMR, 13C NMR, Mass, and IR spectroscopic methods. Molecular docking study 2-isonicotinoyl-4,6-dihydroimidazo[4,5-c] pyrazole-5 (2H)-one derivative was conducted against the PDB : 3KHM, 14 α-demethylase (CYP51) from Trypanosoma cruzi in complex with inhibitor fluconazole protein and PDB : 6UW2 clotrimazole bound complex of Acanthamoeba castellanii CYP51. [ABSTRACT FROM AUTHOR]

Copyright of Arthroskopie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The role and function of neutrophils are well known, but we still have incomplete understanding of the mechanisms by which neutrophils migrate from blood vessels to inflammatory sites. Neutrophil migration is a complex process that involves several distinct steps. To resist the blood flow and maintain their rolling, neutrophils employ tether and sling formation. They also polarize and form pseudopods and uropods, guided by hierarchical chemotactic agents that enable precise directional movement. Meanwhile, chemotactic agents secreted by neutrophils, such as CXCL1, CXCL8, LTB4, and C5a, can recruit more neutrophils and amplify their response. In the context of diapedesis neutrophils traverse the endothelial cells via two pathways: the transmigratory cup and the lateral border recycling department. These structures aid in overcoming the narrow pore size of the endothelial barrier, resulting in more efficient transmembrane migration. Interestingly, neutrophils exhibit a preference for the paracellular pathway over the transcellular pathway, likely due to the former's lower resistance. In this review, we will delve into the intricate process of neutrophil migration by focusing on critical structures that underpins this process. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDSs) are a group of potentially deadly diseases that affect the morphology and function of neutrophils. Rapid diagnosis of MDS is crucial for the initiation of treatment that can vastly improve disease outcome. In this work, we present a new approach for detecting morphological differences between neutrophils isolated from blood samples of high-risk MDS patients and blood bank donors (BBDs). Using fluorescent flow cytometry, neutrophils were stained with 2′,7′-dichlorofluorescin diacetate (DCF), which reacts with reactive oxygen species (ROS), and Hoechst, which binds to DNA. We observed that BBDs possessed two cell clusters (designated H and L), whereas MDS patients possessed a single cluster (L). Later, we used FACS to sort the H and the L cells and used interferometric phase microscopy (IPM) to image the cells without utilizing cell staining. IPM images showed that H cells are characterized by low optical path delay (OPD) in the nucleus relative to the cytoplasm, especially in cell vesicles containing ROS, whereas L cells are characterized by low OPD in the cytoplasm relative to the nucleus and no ROS-containing vesicles. Moreover, L cells present a higher average OPD and dry mass compared to H cells. When examining neutrophils from MDS patients and BBDs by IPM during flow, we identified ~20% of cells as H cells in BBDs in contrast to ~4% in MDS patients. These results indicate that IPM can be utilized for the diagnosis of complex hematological pathologies such as MDS. [ABSTRACT FROM AUTHOR]

To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a–o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients. [ABSTRACT FROM AUTHOR]

Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma. Transcriptomic analysis of the airway epithelia in asthma patients identifies several neutrophilic signatures and targets associated with asthma severity, and highlights the potential therapeutic value of Reperixin in managing deteriorating asthma. [ABSTRACT FROM AUTHOR]

Efficient access to the tetracyclic pyrazolo-fused carbo- and N-heterocyclic systems: naphtho [2',1':3,4]cyclohepta[2,1-c]pyrazolones, naphtho[2',1':5,4]azepino[6,7-c]pyrazolones, naphtho [2',1':5,4]azocino[6,7-c]pyrazolones and naphtho[2',1':6,5]azonino[7,8-c]pyrazolones is described involving intramolecular Friedel--Crafts cycliacylations of synthesized pyrazole-based carboxylic acid or ester derivatives aided by treatment with Lewis and Brønsted acids. The required starting carbaldehyde was obtained by the Vilsmeier--Haack reaction of the corresponding 2-acetylnaphthalene hydrazone. Our developed strategy, involving a three-step route, offers easy access to tetracyclic pyrazole-fused systems in moderate to good yields. [ABSTRACT FROM AUTHOR]

Water-soluble forms of fullerene C60 possess unique physicochemical and biological properties, making them promising candidates for the development of various drugs in the fields of medicine and veterinary science. Of particular interest are studies on the synthesis and characterization of C60 fullerene derivatives with biogenic additives such as amino acids and peptides. This review focuses on different approaches to the synthesis of amino acid derivatives of fullerene C60 and their promising biomedical applications. [ABSTRACT FROM AUTHOR]

Purines and purinergic receptors are widely distributed throughout the human body. Purine molecules within cells play crucial roles in regulating energy metabolism and other cellular processes, while extracellular purines transmit signals through specific purinergic receptors. The ubiquitous purinergic signaling maintains normal neural excitability, digestion and absorption, respiratory movement, and other complex physiological activities, and participates in cell proliferation, differentiation, migration, and death. Pathological dysregulation of purinergic signaling can result in the development of various diseases, including neurodegeneration, inflammatory reactions, and malignant tumors. The dysregulation or dysfunction of purines and purinergic receptors has been demonstrated to be closely associated with tumor progression. Compared with other subtypes of purinergic receptors, the P2X7 receptor (P2X7R) exhibits distinct characteristics (i.e., a low affinity for ATP, dual functionality upon activation, the mediation of ion channels, and nonselective pores formation) and is considered a promising target for antitumor therapy, particularly in patients with poor response to immunotherapy This review summarizes the physiological and pathological significance of purinergic signaling and purinergic receptors, analyzes their complex relationship with tumors, and proposes potential antitumor immunotherapy strategies from tumor P2X7R inhibition, tumor P2X7R overactivation, and host P2X7R activation. This review provides a reference for clinical immunotherapy and mechanism investigation. [ABSTRACT FROM AUTHOR]

To date, histological biomarkers expressed by laryngeal cancer are poorly known. The identification of biomarkers associated with laryngeal squamous cell carcinoma (SCC), would help explain the tumorogenesis and prevent the possible recurrence of the lesion after treatment. For this reason, the aim of this study is to investigate, for the first time, the Orphanin expression in 48 human specimens of laryngeal SCC and evaluate its possible correlation with patients prognosis. We analyzed pathological specimens from 48 patients with laryngeal SCC to detect the presence of Orphanin by using an immunohistochemistry test. We compared the findings with healthy tissue acquired from patients who underwent surgery for mesenchymal benign tumours of the larynx. The specimens were stained with anti-Orphanin monoclonal antibodies. Results were processed through a computerised image analysis system to determine a scale of staining intensity. All the tumoural specimens examined showed a significant immunoreaction for Orphanin when compared with healthy tissues (p < 0.05) but with a different immune reactivity related to clinical-pathological features. A high Orphanin expression was not significantly related to Histological Grading (HG), TNM, and stage (p > 0.05). In the multivariate analysis, the Orphanin expression was significantly related only to the malignant recurrence (p < 0.05). Our study suggests that Orphanin could have a role in tumorigenesis by increasing the recurrence of cancer; therefore, it should be further explored as a possible biomarker for laryngeal cancer. [ABSTRACT FROM AUTHOR]

Imidazothiazole derivatives are becoming increasingly important in therapeutic use due to their outstanding physiological activities. Recently, applying imidazothiazole as the core, researchers have synthesized a series of derivatives with biological effects such as antitumor, anti-infection, anti-inflammatory and antioxidant effects. In this review, we summarize the main pharmacological effects and pharmacological mechanisms of imidazothiazole derivates; the contents summarized herein are intended to advance the research and rational development of imidazothiazole-based drugs in the future. [ABSTRACT FROM AUTHOR]

Finding the ideal antimicrobial drug with improved efficacy and a safety profile that eliminates antibiotic resistance caused by pathogens remains a difficult task. Indeed, there is an urgent need for innovation in the design and development of a microbial inhibitor. Given that many promising antimicrobial peptides with excellent broad-spectrum antibacterial properties are secreted by some frog species (e.g., bombesins, opioids, temporins, etc.), our goal was to identify the antimicrobial properties of amphibian-derived dermorphin and ranatensin peptides, which were combined to produce a hybrid compound. This new chimera (named LENART01) was tested for its antimicrobial activity against E. coli strains K12 and R1–R4, which are characterized by differences in lipopolysaccharide (LPS) core oligosaccharide structure. The results showed that LENART01 had superior activity against the R2 and R4 strains compared with the effects of the clinically available antibiotics ciprofloxacin or bleomycin (MIC values). Importantly, the inhibitory effect was not concentration dependent; however, LENART01 showed a time- and dose-dependent hemolytic effect in hemolytic assays. [ABSTRACT FROM AUTHOR]

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; p = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; p = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Chondropathy of the knee is one of the most frequent degenerative cartilage pathologies with advancing age. Scientific research has, in recent years, advanced new therapies that target adenosine A2 receptors, which play a significant role in human health against many disease states by activating different protective effects against cell sufferance and damage. Among these, it has been observed that intra-articular injections of polydeoxyribonucleotides (PDRN) and Pulsed Electromagnetic Fields (PEMF) can stimulate the adenosine signal, with significant regenerative and healing effects. This review aims to depict the role and therapeutic modulation of A2A receptors in knee chondropathy. Sixty articles aimed at providing data for our study were included in this review. The present paper highlights how intra-articular injections of PDRN create beneficial effects by reducing pain and improving functional clinical scores, thanks to their anti-inflammatory action and the important healing and regenerating power of the stimulation of cell growth, production of collagen, and the extracellular matrix. PEMF therapy is a valid option in the conservative treatment of different articular pathologies, including early OA, patellofemoral pain syndrome, spontaneous osteonecrosis of the knee (SONK), and in athletes. PEMF could also be used as a supporting therapy after an arthroscopic knee procedure total knee arthroplasty to reduce the post-operative inflammatory state. The proposal of new therapeutic approaches capable of targeting the adenosine signal, such as the intra-articular injection of PDRN and the use of PEMF, has shown excellent beneficial results compared to conventional treatments. These are presented as an extra weapon in the fight against knee chondropathy. [ABSTRACT FROM AUTHOR]

The discovery of the P2X7 receptor (P2X7R, originally named P2Z) in immune cells, its cloning, and the identification of its role in a multiplicity of immune-mediated diseases raised great hopes for the development of novel and more potent anti-inflammatory medicaments. Unfortunately, such hopes were partially deluded by the unsatisfactory results of most early clinical trials. This failure substantially reduced the interest of the pharmaceutical and biotech industries in the clinical development of P2X7R-targeted therapies. However, recent findings ushered in a second life for the P2X7R in diagnostic medicine. New P2X7R radioligands proved to be very reliable tools for the diagnosis of neuroinflammation in preclinical and clinical studies, and detection and measurement of free P2X7 receptor (or P2X7 subunit) in human blood suggested its potential use as a circulating marker of inflammation. Here we provide a brief review of these novel developments. [ABSTRACT FROM AUTHOR]

Cancer is the leading cause of death worldwide despite the variety of treatments that are currently used. This is due to an innate or acquired resistance to therapy that encourages the discovery of novel therapeutic strategies to overcome the resistance. This review will focus on the role of the purinergic receptor P2RX7 in the control of tumor growth, through its ability to modulate antitumor immunity by releasing IL-18. In particular, we describe how the ATP-induced receptor activities (cationic exchange, large pore opening and NLRP3 inflammasome activation) modulate immune cell functions. Furthermore, we recapitulate our current knowledge of the production of IL-18 downstream of P2RX7 activation and how IL-18 controls the fate of tumor growth. Finally, the potential of targeting the P2RX7/IL-18 pathway in combination with classical immunotherapies to fight cancer is discussed. [ABSTRACT FROM AUTHOR]

The impact of innovative technologies on the target discovery has been employed here to characterize the interactome of STIRUR 41, a promising 3-fluoro-phenyl-5-pyrazolyl-urea derivative endowed with anti-cancer activity, on neuroblastoma-related cells. A drug affinity responsive target stability-based proteomic platform has been optimized to elucidate the molecular mechanism at the basis of STIRUR 41 action, together with immunoblotting analysis and in silico molecular docking. Ubiquitin Specific Protease 7 (USP-7), one of the deubiquitinating enzymes which protect substrate proteins from proteasomal degradation, has been identified as the most affine STIRUR 41 target. As further demonstrated by in vitro and in-cell assays, STIRUR 41 was able to inhibit both the enzymatic activity of USP-7 and its expression levels in neuroblastoma-related cells, thus laying an encouraging base for the blockade of USP-7 downstream signaling. [ABSTRACT FROM AUTHOR]

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future. [ABSTRACT FROM AUTHOR]