Amidine containing compounds: Antimicrobial activity and its potential in combating antimicrobial resistance.

Antimicrobial resistance (AMR) is a growing and concerning threat to global public health, necessitating innovative strategies to combat this crisis. Amidine-containing compounds have emerged as promising agents in the battle against AMR. This review gives a summary of recent advances from the past decade in studies of antimicrobial amidine-containing compounds with the aim to feature their structural diversity and the pharmacological relevance of the moiety to antimicrobial activity and their potential use in combating antimicrobial resistance, to the greatest extent possible. Highlighting is put on chemical structure of such compounds in relation to antimicrobial activities such as antibacterial, antifungal, and antiparasitic activities. Researchers commonly modify molecules containing amidine or incorporate amidine into existing antimicrobial agents to enhance their pharmacological attributes and combat antimicrobial resistance. This comprehensive review consolidates the current knowledge on amidine-containing compounds, elucidating their antimicrobial mechanisms and highlighting their promise in addressing the global AMR crisis. By offering a multidisciplinary perspective, we aim to inspire further research and innovation in this critical area of antimicrobial research.

CO2 Responsive Thin-Film Transistors Using Conjugated Polymer Complexes with Single-Walled Carbon Nanotubes.

Introduction of amidine groups within the side chains of a conjugated polyfluorene was carried out using copper-catalyzed azide-alkyne cycloaddition. The resulting polymer was shown to form strong supramolecular interactions with the sidewalls of single-walled carbon nanotubes (SWNTs), forming polymer-nanotube complexes that exhibited solubility in various organic solvents. It was shown that the polymer-SWNT complexes were responsive to CO2, where the amidine groups formed amidinium bicarbonate salts upon CO2 exposure, causing the polymer-SWNT complexes to precipitate. This reaction could be reversed by bubbling N2 through the solution, which caused the polymer-SWNT complexes to redissolve. Incorporation of the polymer-SWNT complexes within thin-film transistor (TFT) devices as the active layer resulted in a CO2-responsive TFT sensor. It was found that the sensory device underwent a reversible shift in its threshold voltage from 5 to -1 V as well as a 1 order of magnitude decrease in its on-current upon exposure to CO2. This work shows that conjugated polymer-wrapped SWNTs having sensory elements within the polymer side chain can be used as the active layer within functional SWNT-based TFT sensors.

Peptidyl arginine deiminase-4 inhibitor ameliorates pulmonary fibrosis through positive regulation of developmental endothelial locus-1.

Recurring lung injury, chronic inflammation, aberrant tissue repair and impaired tissue remodelling contribute to the pathogenesis of pulmonary fibrosis (PF). Neutrophil extracellular traps (NETs) are released by activated neutrophils to trap, immobilise and kill invading pathogen and is facilitated by peptidyl arginine deiminase-4 (PAD-4). Dysregulated NETs release and abnormal PAD-4 activation plays a crucial role in activating pro-fibrotic events in PF. Developmental endothelial locus-1 (Del-1), expressed by the endothelial cells of lungs and brain acts as an endogenous inhibitor of inflammation and fibrosis. We have hypothesised that PAD-4 inhibitor exerts anti-inflammatory and anti-fibrotic effects in mice model of PF. We have also hypothesised by PAD-4 regulated the transcription of Del-1 through co-repression and its inhibition potentiates anti-fibrotic effects of Del-1. In our study, the PAD-4 inhibitor chloro-amidine (CLA) demonstrated anti-NETotic and anti-inflammatory effects in vitro in differentiated HL-60 cells. In a bleomycin-induced PF mice model, CLA administration in two doses (3 mg/kg, I.P and 10 mg/kg, I.P) improved lung function, normalized bronchoalveolar lavage fluid parameters, and attenuated fibrotic events, including markers of extracellular matrix and epithelial-mesenchymal transition. Histological analyses confirmed the restoration of lung architecture and collagen deposition with CLA treatment. ELISA, IHC, IF, RT-PCR, and immunoblot analysis supported the anti-NETotic effects of CLA. Furthermore, BLM-induced PF reduced Del-1 and p53 expression, which was normalized by CLA treatment. These findings suggest that inhibition of PAD-4 results in amelioration of PF in animal model and may involve modulation of Del-1 and p53 pathways, warranting further investigation.

Thioimidates provide general access to thioamide, amidine, and imidazolone peptide-bond isosteres.

Thioamides, amidines, and heterocycles are three classes of modifications that can act as peptide-bond isosteres to alter the peptide backbone. Thioimidate protecting groups can address many of the problematic synthetic issues surrounding installation of these groups. Historically, amidines have received little attention in peptides due to limitations in methods to access them. The first robust and general procedure for the introduction of amidines into peptide backbones exploits the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. Further, amidines formed on-resin can be reacted to form (4H)-imidazolone heteorcycles which have recently been shown to act as cis-amide isosteres. General methods for heterocyclic installation capable of geometrically restricting peptide conformation are also under-developed. This work is significant because it describes a generally applicable and divergent approach to access unexplored peptide designs and architectures.

Amphiphilic amidines as potential plasmic membrane-targeting antifungal agents: synthesis, bio-activities and QSAR.

BACKGROUND: Cationic antimicrobial peptides (AMPs) possess broad-spectrum biological activities with less inclination to inducing antibiotic resistance. Herein a battery of amphiphilic amidines were designed by mimicking the characteristics of AMPs. The antifungal activities and the effects to the hyphal morphology and membrane permeability were investigated. RESULTS: The results indicated the inhibitory rates of ten compounds were over 80% to Botrytis cinerea and ten compounds over 90% to Valsa mali Miyabe et Yamada at 50 mg L-1. The half maximal effective concentration (EC50) values of compound 5g and 6g to V. mali were 1.21 and 1.90 mg L-1 respectively. The protective rate against apple canker of compound 5g reached 93.4% at 100 mg L-1 on twigs, superior to carbendazim (53.3%). When treated with 5g, the cell membrane permeability and leakage of content of V. mali increased, accompanied with the decrease of superoxide dismutase (SOD) and catalase (CAT) level. Concurrently, the mycelial hyphae contracted, wrinkled, and collapsed, providing evidence of membrane perturbation. A three-dimensional quantitative structure-activity relationship (3D-QSAR) between the topic compounds and the EC50 to V. mali was established showing good predictability (r2 = 0.971). CONCLUSION: Amphiphilic amidines can acquire antifungal activities by acting on the plasmic membrane. Compound 5g could be a promising lead in discovering novel fungicidal candidates. © 2024 Society of Chemical Industry.

Novel Amidine Derivative K1586 Sensitizes Colorectal Cancer Cells to Ionizing Radiation by Inducing Chk1 Instability.

Checkpoint kinase 1 (Chk1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair, and DNA replication. Small-molecule Chk1 inhibitors sensitize cancer cells to genotoxic agents and have shown preclinical activity as single agents in cancers characterized by high levels of replication stress. However, the underlying genetic determinants of Chk1-inhibitor sensitivity remain unclear. Although treatment options for advanced colorectal cancer are limited, radiotherapy is effective. Here, we report that exposure to a novel amidine derivative, K1586, leads to an initial reduction in the proliferative potential of colorectal cancer cells. Cell cycle analysis revealed that the length of the G2/M phase increased with K1586 exposure as a result of Chk1 instability. Exposure to K1586 enhanced the degradation of Chk1 in a time- and dose-dependent manner, increasing replication stress and sensitizing colorectal cancer cells to radiation. Taken together, the results suggest that a novel amidine derivative may have potential as a radiotherapy-sensitization agent that targets Chk1.

PAD-mediated citrullination is a novel candidate diagnostic marker and druggable target for HPV-associated cervical cancer.

Citrullination is an emerging post-translational modification catalyzed by peptidyl-arginine deiminases (PADs) that convert peptidyl-arginine into peptidyl-citrulline. In humans, the PAD family consists of five isozymes (PADs 1-4, 6) involved in multiple diseases, including cancer. Given that high-risk (hr) human papillomaviruses (HPVs) are the etiological agents of cervical cancer, in this study, we sought to determine whether PAD-mediated protein citrullination would play a functional role in the HPV-driven transformation of epithelial cells. Here we show that both total protein citrullination and PAD4 expression levels are significantly associated with cervical cancer progression. Specifically, epithelial immunostaining for PAD4 revealed an increasingly higher histoscore from low-grade (CIN1) to high-grade (CIN2, CIN3) cervical intraepithelial neoplasia, and invasive squamous cell carcinoma (SCC) lesions, raising the attractive possibility that PAD4 may be used as tumor staging markers. Furthermore, taking advantage of the epidermoid cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV16 genome, we show that the expression of E6 and E7 HPV oncoproteins is impaired by treatment with the pharmacological pan-PAD inhibitor BB-Cl-amidine. Consistently, p53 and p21, two targets of HPV oncoproteins, are upregulated by the PAD inhibitor, which undergoes cell growth arrest and apoptosis. Altogether, these findings highlight a novel mechanism by which hrHPVs alter host regulatory pathways involved in cell cycle and survival to gain viral fitness, raising the possibility that PADs may represent an attractive target for developing novel host-targeting antivirals effective in preventing cervical cancer progression.

Stannylenes and Germylenes Stabilized by Tetradentate Bis(amidine) Ligands with a Rigid Naphthalene Backbone.

An unusual series of germylenes and stannylenes stabilized by new tetradentate bis(amidine) ligands RNC(R')N-linker-NC(R')NR with a rigid naphthalene backbone has been prepared by protonolysis reaction of Lappert's metallylenes [M(HMDS)2] (M = Ge or Sn). Germylenes and stannylenes were fully characterized by NMR spectroscopy and X-ray diffraction analysis. DFT calculations have been performed to clarify the structural and electronic properties associated with tetradentate bis(amidine) ligands. Stannylene L1Sn shows reactivity through oxidation, oxidative addition, and transmetalation reactions, affording the corresponding gallium and aluminum derivatives.

A novel amidine-based fluorescent probe TPE-4+ for rapid detection of anionic surfactant sodium dodecyl sulfate.

An accurate, fast, and simple surfactant detection method is of great significance for monitoring surfactants pollution. Sodium dodecyl sulfate (SDS) is one of the most commonly used anionic surfactants and has been listed as an important monitoring pollutant for surfactant residues. Herein, a novel fluorescent probe named TPE-4+ with four amidines as the recognition functional group and tetraphenylethene as the fluorophore was fabricated. Due to the special intramolecular environment, the probe showed selectively identification towards SDS which made an aggregation induced fluorescence enhencement. Under the optimum conditions, the fluorescence enhencement of TPE-4+ is linearly related to the concentration of SDS in the range of 5.0-60.0 µM with limit of detection (LOD) of 0.010 µM and limit of quantification (LOQ) of 0.034 µM. Relative to the reported methods, the probe in our work showed better selectivity and sensitivity. The proposed method was successfully applied for the SDS determination of disinfecting bowls.

Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury.

BACKGROUND: Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. METHODS: Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2'3'-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. RESULTS: Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2'3'-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. CONCLUSION: Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI.

Inhibition of protein arginine deiminase II suppresses retinoblastoma in orthotopic transplantation in mice.

Chemotherapies are used for treating retinoblastoma; however, numerous patients suffer from recurrence or symptoms due to chemotherapy, which emphasizes the need for alternative therapeutic strategies. The present study demonstrated that protein arginine deiminase Ⅱ (PADI2) was highly expressed in human and mouse retinoblastoma tissues due to the overexpression of E2 factor (E2F). By inhibiting PADI2 activity, the expression of phosphorylated AKT was reduced, and cleaved poly (ADP­ribose) polymerase level was increased, leading to induced apoptosis. Similar results were obtained in orthotopic mouse models with reduced tumor volumes. In addition, BB­Cl­amidine showed low toxicity in vivo. These results suggested that PADI2 inhibition has potential clinical translation. Furthermore, the present study highlights the potential of epigenetic approaches to target RB1­deficient mutations at the molecular level. The current findings provide new insights into the importance of retinoblastoma intervention by managing PADI2 activity according to the treatment of specific inhibitors and depletion approaches in vitro and in orthotopic mouse models.

Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis.

Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis.

Developing aerogel surfaces via switchable-hydrophilicity tertiary amidine coating for improved oil recovery.

Blanket aerogels (i.e., Cabot™ Thermal Wrap® (TW) and Aspen™ Spaceloft® (SL)) with surfaces that have controllable wettability are promising advanced materials for oil recovery applications, where high oil uptake during deployment could be coupled with high oil release to enable reusability of recovered oil. The study presented here details the preparation of CO2-switchable aerogel surfaces through the application of switchable tertiary amidine (i.e., tributylpentanamidine (TBPA)) onto aerogel surfaces using drop casting, dip coating, and physical vapor deposition techniques. TBPA is synthesized via two step processes: (1) synthesis of N, N-dibutylpentanamide, (2) synthesis of N, N-tributylpentanamidine. The deposition of TBPA is confirmed by X-ray photoelectron spectroscopy. Our experiments revealed that surface coating of TBPA onto aerogel blankets was partially successful within limited set of process conditions (e.g., 290 ppm CO2 and 5500 ppm humidity for PVD, 106 ppm CO2 and 700 ppm humidity for drop casting and dip coating), but that the post-aerogel modification strategies yielded poor, heterogeneous reproducibility. Overall, more than 40 samples were tested for their switchability in the presence of CO2 and water vapor, respectively, and the success rate was 6.25 %, 11.7 % and 18 % for PVD, drop casting, and dip coating, respectively. The most likely reasons for unsuccessful coating onto aerogel surfaces are: (1) the heterogeneous fiber structure of the aerogel blankets, (2) poor distribution of the TBPA over the aerogel blanket surface.

Cl-amidine attenuates lipopolysaccharide-induced inflammation in human gingival fibroblasts via the JNK/MAPK, NF-κB, and Nrf2 signalling pathways.

Cl-amidine has been reported to have anti-inflammatory properties in a variety of diseases. However, the role of Cl-amidine in periodontal disease remains unclear. Here, the purpose of this study was to investigate the effect of Cl-amidine on lipopolysaccharide (LPS)-induced inflammation in human gingival fibroblasts (HGFs). The cytotoxic effect of Cl-amidine was measured with the Cell Counting Kit-8 (CCK-8) assay and Annexin V-FITC/PI staining. The protein levels of IL-6 and IL-8 in culture supernatants were measured with enzyme-linked immunosorbent assay (ELISA). The mRNA levels of inflammatory cytokines, TLR4 and MyD88 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The expression patterns of IL-6, TNF-ɑ, and IL-1ß in HGFs were tested with western blot. The levels of NF-κB, MAPK, and Nrf2 pathway-related proteins were detected by western blot. Immunofluorescence (IF) staining was used to examine the nuclear translocation of NF-κB p65. Moreover, a rat gingivitis model was established to further clarify the role of Cl-amidine. Our results showed that Cl-amidine suppressed LPS-induced gingival inflammation both in vitro and in vivo. Mechanistically, Cl-amidine inhibited LPS-induced MyD88 expression, NF-κB activation, and JNK phosphorylation. Additionally, Cl-amidine upregulated Nrf2 and Ho-1 expression both with and without LPS stimulation but did not alter ROS levels or Keap1 expression. Overall, our data suggest that Cl-amidine acts as an inhibitor of LPS-induced gingival inflammation via the JNK/MAPK, NF-κB, and Nrf2 signalling pathways.

Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells.

OBJECTIVE: Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients' complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets. METHODS: AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not. RESULTS: PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells. CONCLUSION: Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.

Lipid Peroxidation Has Major Impact on Malondialdehyde-Derived but Only Minor Influence on Glyoxal and Methylglyoxal-Derived Protein Modifications in Carbohydrate-Rich Foods.

In the present work, the contribution of lipid peroxidation on modifications of lysine and arginine residues of proteins was investigated. Lipid peroxidation had a major impact on malondialdehyde-derived protein modifications; however, the influence on glyoxal and methylglyoxal-derived modifications in flat wafers was negligible. Therefore, vegetable oils (either linseed oil, sunflower oil, or coconut oil) were added to respective batters, and flat wafers were baked (150 °C, 3-10 min). Analysis of malondialdehyde indicated oxidation in linseed wafers, which was supported by the direct quantitation of three malondialdehyde protein adducts in the range of 0.09-23.5 mg/kg after enzymatic hydrolysis. In contrast, levels of free glyoxal and methylglyoxal were independent of the type of oil added, which was in line with the analysis of 13 advanced glycation end products. Comprehensive incubations of 40 mM N2-t-Boc-lysine (100 mM phosphate buffer, pH 7.4) with either 10% oil or an equimolar concentration of carbohydrates led to magnitudes higher (103-105) amounts of N6-carboxymethyl lysine, N6-glycolyl lysine, and N6-carboxyethyl lysine in the latter. Furthermore, malondialdehyde exceeded glyoxal and methylglyoxal in incubations of pure oils at 150 °C by factors of 30 and 100, respectively.

Inhibition of Neutrophil Extracellular Traps Formation by Cl-Amidine Alleviates Lipopolysaccharide-Induced Endometritis and Uterine Tissue Damage.

Endometritis is a common disease that affects the production in dairy cows and leads to severe losses in the dairy industry. Neutrophil extracellular traps (NETs) formation promotes pathogenic invasions of the lumen of the tissue, leading to inflammatory diseases such as mastitis, pancreatitis, and septic infection. However, research that could show the relationship between NETs and endometritis is scarce. Cl-amidine has been shown to ameliorate the disease squealing and clinical manifestation in various disease models. In this study, we investigated the role of NETs in LPS-triggered endometritis in rats and evaluated the therapeutic efficiency of Cl-amidine. An LPS-induced endometritis model in rats was established and found that the formation of NETs can be detected in the rat's uterine tissues in vivo. In addition, Cl-amidine treatment can inhibit NETs construction in LPS-induced endometritis in rats. Myeloperoxidase (MPO) activity assay indicated that Cl-amidine treatment remarkably alleviated the inflammatory cell infiltrations and attenuated the damage to the uterine tissue. The Western blot results indicated that Cl-amidine decreased the expression of citrullinated Histone H3 (Cit-H3) and high-mobility group box 1 protein (HMGB1) protein in LPS-induced rat endometritis. The ELISA test indicated that Cl-amidine treatment significantly inhibited the expression of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. The NETs were determined by Quant-iTTMPicoGreen dsDNA kit®, which indicated that Cl-amidine significantly inhibited the NETs in rat serum. All results showed that Cl-amidine effectively reduced the expression of Cit-H3 and HMGB1 proteins by inhibiting the formation of NETs, thereby attenuating the inflammatory response to LPS-induced endometritis in rats. Hence, Cl-amidine could be a potential candidate for the treatment of endometritis.

Protonation-Induced Antiaromaticity in Octaaza[8]circulenes: Cyclooctatetraene Scaffolds Constrained with Four Amidine Moieties.

The switching of cyclic π-conjugation pathways using external stimuli is an attractive research topic in the field of organic chemistry. Here, we synthesized C4h -symmetric octaaza[8]circulenes with four peripherally arranged amidine moieties that exhibit enhanced antiaromaticity upon protonation. Titration experiments with methanesulfonic acid revealed the formation of the tetraprotonated forms of the octaaza[8]circulenes in solution. Single-crystal X-ray diffraction analyses and theoretical calculations indicated that the contribution of the 8π antiaromatic character of the octaaza[8]circulenes is enhanced by the delocalization of charge through the protonation of the pyridine rings.

Ninety Years of Pentamidine: The Development and Applications of Pentamidine and its Analogs.

Pentamidine, an FDA-approved human drug for many protozoal infections, was initially synthesized in the late 1930s and first reported to be curative for parasitosis in the 1940s. After ninety years of sometimes quiet growth, pentamidine and its derivatives have gone far beyond antibacterial agents, including but not limited to the ligands of DNA minor groove, modulators of PPIs (protein-protein interactions) of the transmembrane domain 5 of lateral membrane protein 1, and the blockers of the SARS-CoV-2 3a channel. This mini-review highlights the development and applications of pentamidine and its analogs, aiming to provide insights for further developing pentamidine derivatives in the following decades.

Neutrophil Extracellular Traps in Atherosclerosis and Thrombosis.

Despite effective therapeutic and preventive strategies, atherosclerosis and its complications still represent a substantial health burden. Leukocytes and inflammatory mechanisms are increasingly recognized as drivers of atherosclerosis. Neutrophil granulocytes within the circulation were recently shown to undergo neutrophil extracellular trap (NET) formation, linking innate immunity with acute complications of atherosclerosis. In this chapter, we summarize mechanisms of NET formation, evidence for their involvement in atherosclerosis and thrombosis, and potential therapeutic regimens specifically targeting NET components.