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A chemical genetics approach identifies the Raf-MEK-ERK signaling system downstream of PKC in formation of the antimicrobial cell structures called neutrophil extracellular traps. The signaling mechanisms leading to the formation of neutrophil extracellular traps (NETs), relevant in infections, sepsis and autoimmune diseases, are poorly understood. Neutrophils are not amenable to studies with conventional genetic techniques. Using a new chemical genetic analysis we show that the Raf-MEK-ERK pathway is involved in NET formation through activation of NADPH oxidase and upregulation of antiapoptotic proteins. We identify potential targets for drugs addressing NET-associated diseases.

Abstract Pediatric sarcomas represent a heterogeneous group of malignancies that exhibit variable response to DNA damaging chemotherapy. Schlafen family member 11 protein (SLFN11) increases sensitivity to replicative stress, and SLFN11 gene silencing has been implicated as a common mechanism of drug resistance in tumors in adults. We found SLFN11 to be widely expressed in our cohort of pediatric sarcomas. In sarcoma cell lines, protein expression strongly correlated with response to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN), with SLFN11 knockout resulting in significant loss of sensitivity in vitro and in vivo. However, SLFN11 expression was not associated with favorable outcomes in a retrospective analysis of our patient cohort; instead, the protein was retained and promoted tumor growth and evasion. Furthermore, we show that pediatric sarcomas develop resistance to TAL and IRN through impaired intrinsic apoptosis, and that resistance can be reversed by selective inhibition of BCL-XL. Statement of Significance The role of SLFN11 in pediatric sarcomas has not been thoroughly explored. In contrast to its activity in adult tumors, SLFN11 did not predict favorable outcomes in pediatric patients, was not silenced, and promoted tumor growth. Resistance to replicative stress in SLFN11-expressing sarcomas was reversed by selective inhibition of BCL-XL. Competing Interest Statement The authors have declared no competing interest. Footnotes * Financial support: This work was supported, in part, by the American Lebanese Syrian Associated Charities (E.A.S., A.A.S.). E.A.S. was supported by the National Comprehensive Cancer Network and is a St. Baldrick’s Scholar with generous support from the Invictus Fund. A.A.S. was supported by research grants from the Sarcoma Foundation of America and the St. Baldrick’s Foundation. * The authors declare there are no conflicts of interest.

Intramolecular charge transfer (ICT) effects are responsible for the photoluminescent properties of coumarins. Hence, optical properties with different applications can be obtained by ICT modulation. Herein, four 3-acetyl-2H-chromen-2-ones (1a–d) and their corresponding fluorescent hybrids 3- (phenylhydrazone)-chromen-2-ones (2a–d) were synthesized in 74–65% yields. The UV-Vis data were in the 295–428 nm range. The emission depends on the substituent in position C-7 bearing electron-donating groups. Compounds 1b–d showed good optical properties due to the D-π-A structural arrangement. In compounds 2a–d, there is a quenching effect of fluorescence in solution. However, in the solid, an increase is shown due to an aggregation-induced emission (AIE) effect given by the rotational restraints and stacking in the crystal. Computational calculations of the HOMO-LUMO orbitals indicate high absorbance and emission values of the molecules, and gap values represent the bathochromic effect and the electronic efficiency of the compounds. Compounds 1a–d and 2a–d are good candidates for optical applications, such as OLEDs, organic solar cells, or fluorescence markers.

Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL‐2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR‐Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state. TOMM20 increases cancer aggressiveness by maintaining a reduced state with increased NADH and NADPH levels, oxidative phosphorylation (OXPHOS), and apoptosis resistance while reducing reactive oxygen species (ROS) levels. Conversely, CRISPR‐Cas9 knockdown of TOMM20 alters these cancer‐aggressive traits.

Exacerbations of chronic obstructive pulmonary disease (COPD) are a source of substantial morbidity. In this randomized, controlled trial involving patients with moderately severe COPD, daily treatment with azithromycin for 1 year was associated with fewer exacerbations. Acute exacerbations of chronic obstructive pulmonary disease (COPD) result in frequent visits to physicians' offices and emergency rooms and numerous hospitalizations and days lost from work; they also account for a substantial percentage of the cost of treating COPD. 1 – 5 Patients who have acute exacerbations of COPD, as compared with patients with COPD who do not have acute exacerbations, have an increased risk of death, a more rapid decline in lung function, and reduced quality of life. 6 – 11 Although inhaled glucocorticoids, long-acting beta 2 -agonists, and long-acting muscarinic antagonists reduce the frequency of acute exacerbations of COPD, 12 – 24 patients receiving . . .

This work reports the crystallographic study of two benzenesulfonamides, 1 ((E)-N-benzyl-3-((benzylimino)methyl)-4-hydroxybenzenesulfonamide) and 2 (N-benzyl-3-(3-(N-benzylsulfamoyl)-2-oxo-2H-chromene-6-sulfonamide). These compounds share structural features with belinostat, an FDA-approved histone deacetylase (HDAC) inhibitor used in the treatment of peripheral T-cell lymphoma. Compound 1 contains one sulfonamide group, meanwhile compound 2 contains two sulfonamide moieties and presents four independent molecules in its unit cell. The crystal packing of 1 and 2 is mainly governed by N–H···O=S hydrogen bonding interactions. π → π* and n → π* stacking interactions also contribute to the molecular assembly. Hirshfeld surface (HS) analysis was carried out to further examine the intermolecular interactions of compounds 1 and 2, revealing that N–H∙∙∙O and C–H∙∙∙O hydrogen bonding interactions, along with O∙∙∙H/H∙∙∙O interactions, are the strongest contributors to the individual surfaces. Interaction energy analysis was also performed to evaluate the relative strength and nature of the intermolecular contacts. Additionally, molecular docking studies of compounds 1 and 2 were performed on the crystal structure of the enzyme HDAC2, an enzyme overexpressed in several cancers, particularly breast cancer. The results revealed that both compounds exhibit a binding mode and binding energies similar to those of belinostat, suggesting their potential as novel therapeutic agents.

Background Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer’s disease and Parkinson’s disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins. Results Our findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1β. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac-YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age. Conclusions Taken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain.

Proper homogenization of semen samples is crucial for assisted reproductive technology (ART) and analysis of sperm motility kinematics in experimental research. Accurate homogenization ensures a consistent number of sperm per insemination in ART and uniforms number of sperm per treatment in research. Homogenization is particularly important when sperm are treated with exogenous compounds that must be evenly distributed throughout the experiment. Traditionally, semen samples are homogenized manually with a \"gentle\" approach or with commercial devices that are not specifically designed for this purpose. In this study, we designed, constructed, and validated an open-hardware semen homogenizer for sperm motility analysis. For validity, the hardware was used to investigate the effects of serotonin (5-HT) on boar sperm kinematics at the subpopulation level using a computer-assisted sperm analysis (CASA). All components of the homogenizer are readily available, including the STL files for the 3D-printed parts, firmware, assembly instructions, and operation guidelines. Objective homogenization was evaluated by measuring sperm density at different numbers of homogenization cycle, while \"gentle\" homogenization was assessed based on manual duration and inclination angle. Sperm motility kinematics showed no changes at the average level, however distinct effects emerged within subpopulations. Exposure to 5-HT differentially affected sperm motility kinematics across subpopulations displaying no change, increase or decrease in velocity indices. Under over-homogenization conditions, a clear interaction between prolonged homogenization and 5-HT exposure was observed in all subpopulations. Results suggest that objective homogenization is essential to ensure consistent sperm density, whereas over-homogenization alters sperm responses, potentially leading to biological misinterpretations.

Background: Annona muricata L. (guanabana) leaves are rich in bioactive compounds with potential antioxidant properties. In the state of Colima, both ethanolic extracts and infusions are traditionally used in folk medicine to address various ailments. This study aimed to evaluate and compare the phytochemical composition and antioxidant activities of ethanolic extracts and infusions of A. muricata leaves from three geographic regions in Colima, Mexico, with a focus on how geographic origin affects their bioactive properties. Methods: Ethanolic extracts and infusions were prepared from A. muricata leaves and analyzed using phytochemical screening; DPPH, total antioxidant capacity (TAC), and total phenolic content (TPC) measurements; and HPLC. TLC was also conducted to examine the presence of specific compounds, such as flavonoids and phenols. Results: Both the ethanolic extracts and infusions contained significant levels of alkaloids, flavonoids, tannins, and phenolic compounds. The infusions demonstrated superior antioxidant capacity, with DPPH inhibition values of 72.5%, 68.3%, and 65.1% in the northern, central, and southern regions, respectively, compared to the ethanolic extracts’ values of 50.3%, 48.9%, and 45.0%. HPLC identified quercetin as a major compound across all samples. Geographically, the northern region exhibited higher concentrations of bioactive compounds, particularly total flavonoid content (TFC) and iron-reducing power (FRPA). Conclusions: Both the ethanolic extracts and infusions of A. muricata leaves exhibited significant antioxidant properties, with the infusions showing superior performance. The results suggest that A. muricata infusions may have potential applications in managing oxidative stress-related diseases such as cancer and diabetes. Exploring their use in traditional medicine and employing this type of approach can help discern the metabolite profile responsible for these bioactivities. Geographic factors influence the bioactive profile of the plant, and further research is needed to isolate specific bioactive compounds and elucidate their therapeutic mechanisms.

A series of three 1,3-phenylene bis-oxamides 3a–c, structurally related to the GPR35 receptor-agonist drug lodoxamide, has been synthesized by reacting the 1,3-phenylene bis-oxalamates 2a and 2b with amines. The obtained compounds were characterized by 1H and 13C NMR, and IR spectroscopy, they showed characteristic signals for the aromatic, N―H, and C=O groups. Molecular structure was determined using single-crystal X-ray diffraction. The supramolecular architecture is driven by N―H···O=C, N―H···N, C—H···π, and O=C···O=C interactions depicting a supramolecular helix (3a) and tapes (3b–c). Intermolecular interactions were studied using Hirshfeld surface analysis, where N―H∙∙∙X (X = N, O) hydrogen bonding represents 30.2% to the surface of 3a and 17.8–18.8% to the surface of 3b–c. The most energetic interactions involve the amide N—H∙∙∙O hydrogen bonding, contributing in the −113.9 to −97.0 kJ mol−1 range to the crystal energy, being more dispersive than electrostatic in nature. The molecular docking study was performed to evaluate the binding ability of 3a–c compounds to the GPR35 receptor, showing a favorable binding in a similar way to lodoxamide.