Lactoferrin improves symptoms of dextran sulfate sodium-induced colitis in mice through modulation of cellular senescence.

The multifaceted effects of lactoferrin (LF) on the digestive and immune systems make it an attractive therapeutic option in inflammatory bowel diseases. In this study, we aimed to explore the anti-inflammatory effects of LF in colitis, particularly in relation to cellular senescence. We hypothesize that LF has the potential to modulate the senescence process. The effects of LF on senescence were tested in vitro using HCT116 and SW480 cell lines, and in vivo, the dextran sulfate sodium-induced mouse model of colitis. LF (500 mg/kg) alleviated symptoms of colitis in mice with a significant decrease in colon damage (P < .0001 vs. control) and microscopic (P < .05 vs. control) scores. Cellular senescence markers p16 and p21 were significantly upregulated in the mouse colon during inflammation (both P < .01 vs. control), and LF at 500 mg/kg decreased these markers (both P < .05 vs. dextran sulfate sodium-treated mice). In vitro, LF significantly affected the expression of p16 and p21 (P < .05-P < .0001 vs. control), senescence associated secretory phenotype (P < .01-P < .0001 vs. control), and telomere-specific proteins: telomeric repeat binding factor 1 and 2 (P < .05-P < .0001 vs. control) in a concentration-dependent manner. LF modulates the expression of cellular senescence markers and shows hallmarks of senolytic and pro-senescent activity, depending on dose. Further studies are needed to fully understand the anti-inflammatory effect of LF in the context of senescence and safe utilization in patients with inflammatory bowel diseases.

New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking.

The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE1). N,N'-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC50 = 0.056 µM, while the IC50 for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC50 value was 9.01 µM compared to that for quercetin, with IC50 = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme.

A new face of old cells: An overview about the role of senescence and telomeres in inflammatory bowel diseases.

Cellular senescence is a pivotal factor contributing to aging and the pathophysiology of age-related diseases. Despite the presence of inflammation and abnormal immune system function in both inflammatory bowel diseases (IBD) and senescence, the relationship between the two remains largely unexplored. Therefore, our study aimed to investigate the intricate connection between cellular senescence, telomeres, and IBD. The review highlights the presence of senescence markers, particularly p16 and p21, in IBD patients, suggesting their potential association with disease progression and mucosal inflammation. We emphasize the critical role of macrophages in eliminating senescent cells and how disturbance in effective clearance may contribute to persistent senescence and inflammation in IBD. Additionally, we shed light on the involvement of telomeres in IBD, as their dysfunction impairs enterocyte function and disrupts colonic barrier integrity, potentially exacerbating the pathogenesis of the disease. Targeting senescence and telomere dysfunctions holds promise for the development of innovative therapeutic approaches to mitigate intestinal inflammation and alleviate symptoms in IBD patients. By unraveling the precise role of senescence in IBD, we can pave the way for the discovery of novel therapeutic interventions that effectively address the underlying mechanisms of intestinal inflammation, offering hope for improved management and treatment of IBD patients.

Lactoferrin: an overview of its main functions, immunomodulatory and antimicrobial role, and clinical significance.

Lactoferrin (LF), a glycoprotein found in mucosal secretions, is characterized by a wide range of functions, including immunomodulatory and anti-inflammatory activities. Moreover, several investigations confirmed that LF displays high effectiveness against multiple bacteria and viruses and may be regarded as a potential inhibitor of enveloped viruses, such as presently prevailing SARS-CoV-2. In our review, we discuss available studies about LF functions and bioavailability of different LF forms in in vitro and in vivo models. Moreover, we characterize the potential benefits and side effects of LF use; we also briefly summarize the latest clinical trials examining LF application. Finally, we point potential role of LF in inflammatory bowel disease and indicate its use as a marker for disease severity.

Ruthenium Olefin Metathesis Catalysts Featuring N-Heterocyclic Carbene Ligands Tagged with Isonicotinic and 4-(Dimethylamino)benzoic Acid Rests: Evaluation of a Modular Synthetic Strategy.

A modular and flexible strategy towards the synthesis of N-heterocyclic carbene (NHC) ligands bearing Brønsted base tags has been proposed and then adopted in the preparation of two tagged NHC ligands bearing rests of isonicotinic and 4-(dimethylamino)benzoic acids. Such tagged NHC ligands represent an attractive starting point for the synthesis of olefin metathesis ruthenium catalysts tagged in non-dissociating ligands. The influence of the Brønsted basic tags on the activity of such obtained olefin metathesis catalysts has been studied.

Synthesis, Spectroscopic, and Theoretical Study of Copper and Cobalt Complexes with Dacarbazine.

Dacarbazine (DAC) 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide is an imidazole-carboxamide derivative that is structurally related to purines. DAC belongs to the triazene compounds, which are a group of alkylating agents with antitumor and mutagenic properties. DAC is a non-cell cycle specific drug, active in all phases of the cellular cycle. In the frame of this work the 3d metal complexes (cobalt and copper) with dacarbazine were synthesized. Their spectroscopic properties by the use of FT-IR, FT-Raman, and 1HNMR were studied. The structures of dacarbazine and its complexes with copper(II) and cobalt(II) were calculated using DFT methods. The effect of metals on the electronic charge distribution of dacarbazine was discussed on the basis of calculated NBO atomic charges. The reactivity of metal complexes in relation to ligand alone was estimated on the basis of calculated energy of HOMO and LUMO orbitals. The aromaticity of the imidazole ring in dacarbazine and the complexes were compared (on the basis of calculated geometric indices of aromaticity). Thermal stability of the investigated 3d-metal complexes with dacarbazine and the products of their thermal decomposition were analyzed.

Supplementation of Bovine Colostrum in Inflammatory Bowel Disease: Benefits and Contraindications.

Inflammatory bowel disease (IBD) is a group of chronic relapsing disorders whose etiology has not been fully explained. Therefore, available therapeutic approaches for IBD patients are still insufficient. Current treatment strategies are targeted to immune system dysfunctions, often associated with alternations in the microbiota, which contribute to the development of chronic intestinal inflammation. Therapeutics include anti-inflammatory drugs such as aminosalicylates and corticosteroids, immunosuppressive agents, antibiotics, and biological agents such as infliximab and vedolizumab. Auxiliary therapies involve a balanced and personalized diet, healthy lifestyle, avoiding stress, as well as dietary supplements. In this review, we discuss the use of bovine colostrum (BC) as a therapeutic agent, including its advantages and contraindications. We summarize our knowledge on well-researched BC constituents and their effects on the gastrointestinal tract as evidenced in in vitro and in vivo studies.

(2R)-8-Benzyl-2-[(S)-hy-droxy(phen-yl)meth-yl]-8-aza-bicyclo-[3.2.1]octan-3-one.

The crystal of the title compound, C(21)H(23)NO(2), was chosen from a conglomerate formed by a racemic mixture. An intra-molecular hydrogen bond is formed between hy-droxy group and heterocyclic N atom of the aza-bicyclo-[3.2.1]octan-3-one system. The crystal structure is stabilized by C-H⋯O inter-actions between aliphatic C-H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms.

Strategy for the synthesis of polymeric supports with hydrazone linkers for solid-phase alkylation of ketones and aldehydes.

A new approach to polymeric supports useful for the immobilization of aldehydes and ketones via hydrazone linkers is reported. The new strategy gives supports with better properties and is effective for the synthesis of all supports previously used for the alkylation of ketones anchored as hydrazones. In contrast to other approaches, the new strategy also provided a polymer with an economical C2 spacer linker. The supports were used for immobilization of ketones 3-pentanone, acetone, N-benzylpiperidone, and aldehydes hexanal and 3-phenylpropanal in the form of their hydrazones. The polymer-supported hydrazones were subjected to alpha-alkylation (LDA/RX) followed by acidic, reductive, or oxidative cleavage/workup procedures to provide alpha-alkylated aldehydes or ketones as well as corresponding primary amines, alcohols, nitriles or acids.