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Microorganisms May 2024The competitive colonization of bacteria on similar ecological niches has a significant impact during their establishment. The synthesis speeds of different chemical...
The competitive colonization of bacteria on similar ecological niches has a significant impact during their establishment. The synthesis speeds of different chemical classes of molecules during early competitive colonization can reduce the number of competitors through metabolic effects. In this work, we demonstrate for the first time that Cp1 previously isolated from the seeds of R. P. produced volatile organic compounds (VOCs) during competitive colonization against SM2, affecting soft rot symptoms in serrano chili ( L.). The pathogen SM2 was isolated from the fruits of var. Serrano with soft rot symptoms. The genome of the SM2 strain carries a 5,037,920 bp chromosome with 51.46% G + C content and 4925 predicted protein-coding genes. It presents 12 genes encoding plant-cell-wall-degrading enzymes (PCDEWs), 139 genes involved in five types of secretion systems, and 16 genes related to invasion motility. Pathogenic essays showed soft rot symptoms in the fruits of L., , and and the tubers of . During the growth phases of Cp1, a mix of VOCs was identified by means of HS-SPME-GC-MS. Of these compounds, 2,5-dimethyl-pyrazine showed bactericidal effects and synergy with acetoin during the competitive colonization of Cp1 to completely reduce soft rot symptoms. This work provides novel evidence grounding a better understanding of bacterial interactions during competitive colonization on plant tissue, where VOC synthesis is essential and has a high potential capacity to control pathogenic microorganisms in agricultural systems.
PubMed: 38792761
DOI: 10.3390/microorganisms12050930 -
Molecules (Basel, Switzerland) May 2024Ligustrazine (TMP) is the main active ingredient extracted from , which is used in the treatment of cardiovascular and cerebrovascular diseases, with the drawback of...
Ligustrazine (TMP) is the main active ingredient extracted from , which is used in the treatment of cardiovascular and cerebrovascular diseases, with the drawback of being unstable and readily sublimated. Cocrystal technology is an effective method to improve the stability of TMP. Three benzoic acid compounds including P-aminobenzoic acid (PABA), 3-Aminobenzoic acid (MABA), and 3,5-Dinitrobenzoic acid (DNBA) were chosen for co-crystallization with TMP. Three novel cocrystals were obtained, including TMP-PABA (1:2), TMP-MABA (1.5:1), and TMP-DNBA (0.5:1). Hygroscopicity was characterized by the dynamic vapor sorption (DVS) method. Three cocrystals significantly improved the hygroscopicity stability, and the mass change in TMP decreased from 25% to 1.64% (TMP-PABA), 0.12% (TMP-MABA), and 0.03% (TMP-DNBA) at 90% relative humidity. The melting points of the three cocrystals were all higher than TMP, among which the TMP-DNBA cocrystal had the highest melting point and showed the best stability in reducing hygroscopicity. Crystal structure analysis shows that the mesh-like structure formed by the O-H⋯N hydrogen bond in the TMP-DNBA cocrystal was the reason for improving the stability of TMP.
Topics: Pyrazines; Crystallization; Wettability; Drug Stability; Hydrogen Bonding; Crystallography, X-Ray; Molecular Structure; X-Ray Diffraction
PubMed: 38792070
DOI: 10.3390/molecules29102208 -
Molecular Medicine (Cambridge, Mass.) May 2024The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been...
BACKGROUND
The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies.
METHODS
A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations.
RESULTS
Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-β1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6.
CONCLUSIONS
Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.
Topics: Animals; Male; Mice; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Bleomycin; Bortezomib; CD4-Positive T-Lymphocytes; Chemokine CXCL16; Chemotaxis; Disease Models, Animal; Lectins, C-Type; Macrophages; Mice, Inbred C57BL; Pulmonary Fibrosis; Receptors, CXCR6
PubMed: 38789926
DOI: 10.1186/s10020-024-00836-5 -
The Journal of Physical Chemistry. A Jun 2024Heteroaromatic molecules are found in areas ranging from biochemistry to photovoltaics. We analyze the ,π* excited states of 6π-electron heteroaromatics with in-plane...
Heteroaromatic molecules are found in areas ranging from biochemistry to photovoltaics. We analyze the ,π* excited states of 6π-electron heteroaromatics with in-plane lone pairs (, herein ) and use qualitative theory and quantum chemical computations, starting at Mandado's 2 + 1 rule for aromaticity of separate spins. After excitation of an electron from to π*, a (4 + 2)π-electron species has 2 + 2 π-electrons and 2 + 1 π-electrons (or ) and becomes π-antiaromatic and π-aromatic. Yet, the antiaromatic π- and aromatic π-components seldom cancel, leading to residuals with aromatic or antiaromatic character. We explore vertically excited triplet ,π* states (,π*), which are most readily analyzed, but also singlet ,π* states (,π*), and explain which compounds have ,π* states with aromatic residuals as their lowest excited states (e.g., pyrazine and the phenyl anion). If the π-electron population becomes more (less) uniformly distributed upon excitation, the system will have an (anti)aromatic residual. Among isomers, the one that has the most aromatic residual in ,π* is often of the lowest energy in this state. Five-membered ring heteroaromatics with one or two N, O, and/or S atoms never have ,π* states as their first excited states (T and S), while this is nearly always the case for six-membered ring heteroaromatics with electropositive heteroatoms and/or highly symmetric () diheteroaromatics. For the complete compound set, there is a modest correlation between the (anti)aromatic character of the ,π* state and the energy gap between the lowest ,π* and π,π* states ( = 0.42), while it is stronger for monosubstituted pyrazines ( = 0.84).
PubMed: 38787346
DOI: 10.1021/acs.jpca.4c02580 -
Lab on a Chip Jun 2024The volume and composition of airway surface liquid (ASL) is regulated by liquid secretion and absorption across airway epithelia, controlling the pH, solute...
The volume and composition of airway surface liquid (ASL) is regulated by liquid secretion and absorption across airway epithelia, controlling the pH, solute concentration, and biophysical properties of ASL in health and disease. Here, we developed a method integrating explanted tracheal tissue with a micro-machined device (referred to as " trachea-chip") to study the dynamic properties of ASL volume regulation. The trachea-chip allows real-time measurement of ASL transport () with intact airway anatomic structures, environmental control, high-resolution, and enhanced experimental throughput. Applying this technology to freshly excised tissue we observed ASL absorption under basal conditions. The apical application of amiloride, an inhibitor of airway epithelial sodium channels (ENaC), reduced airway liquid absorption. Furthermore, the basolateral addition of NPPB, a Cl channel inhibitor, reduced the basal rate of ASL absorption, implicating a role for basolateral Cl channels in ASL volume regulation. When tissues were treated with apical amiloride and basolateral methacholine, a cholinergic agonist that stimulates secretion from airway submucosal glands, the net airway surface liquid production shifted from absorption to secretion. This trachea-chip provides a new tool to investigate ASL transport dynamics in pulmonary disease states and may aid the development of new therapies targeting ASL regulation.
Topics: Trachea; Amiloride; Animals; Lab-On-A-Chip Devices; Humans; Microfluidic Analytical Techniques; Respiratory Mucosa
PubMed: 38779981
DOI: 10.1039/d4lc00134f -
Cancer Reports (Hoboken, N.J.) May 2024Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with... (Observational Study)
Observational Study
The efficacy and tolerability of bortezomib, thalidomide, and dexamethasone induction therapy with a thalidomide dose step-up strategy in patients with newly diagnosed multiple myeloma: A prospective observational study.
BACKGROUND
Thalidomide-containing regimens cause adverse events (AEs) that may require a reduction in treatment intensity or even treatment discontinuation in patients with multiple myeloma. As thalidomide toxicity is dose-dependent, identifying the most appropriate dose for each patient is essential.
AIMS
This study aimed to investigate the effects of a thalidomide dose step-up strategy on treatment response and progression-free survival (PFS).
METHODS AND RESULTS
This prospective observational study included 93 patients with newly diagnosed multiple myeloma (NDMM) who received bortezomib, thalidomide, and dexamethasone (VTD). The present study assessed the incidence of thalidomide dose reduction and discontinuation, the overall dose intensity, and their effects on therapeutic efficacy. Furthermore, this study used Cox proportional hazard models to analyze the factors contributing to thalidomide intolerability. The results showed the overall response rates in all patients and the evaluable patients were 78.5% and 98.7%, respectively. The median PFS in the study cohort was not reached. The most common thalidomide-related AEs were constipation (32.3%) and skin rash (23.7%), resulting in dose reduction and discontinuation rates of 22.6% and 21.5%, respectively. The responders had a significantly higher average thalidomide dose intensity than the nonresponders (88.6% vs. 42.9%, p < .001).
CONCLUSION
The thalidomide dose step-up approach is a viable option for patients with NDMM receiving VTD induction therapy with satisfactory efficacy and tolerability. However, thalidomide intolerance may lead to dose reduction or discontinuation due to unpredictable AEs, leading to lower dose intensity and potentially inferior treatment outcomes. In addition to a dose step-up strategy, optimal supportive care is critical for patients with multiple myeloma receiving VTD induction therapy.
Topics: Humans; Multiple Myeloma; Thalidomide; Female; Dexamethasone; Male; Bortezomib; Prospective Studies; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Induction Chemotherapy; Progression-Free Survival; Aged, 80 and over; Dose-Response Relationship, Drug
PubMed: 38775249
DOI: 10.1002/cnr2.2102 -
Journal of the American Heart... May 2024Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in...
BACKGROUND
Many cardiomyopathy-associated pathogenic variants are heterozygous truncations, and pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely understood.
METHODS AND RESULTS
We describe an individual with biallelic pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib, null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II. null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib. null engineered heart tissues had impaired function after low-dose bortezomib.
CONCLUSIONS
pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.
Topics: Filamins; Humans; Proteostasis; Female; Induced Pluripotent Stem Cells; Arrhythmias, Cardiac; Myocytes, Cardiac; Cardiomyopathies; Male; Adult; Mutation; Bortezomib
PubMed: 38761081
DOI: 10.1161/JAHA.123.030467 -
Food Research International (Ottawa,... May 2024A large number of volatile compounds are formed during the baking of foods by reactions such as caramelization and Maillard reactions. Elucidating the reaction...
Unravelling caramelization and Maillard reactions in glucose and glucose + leucine model cakes: Formation and degradation kinetics of volatile markers extracted during baking.
A large number of volatile compounds are formed during the baking of foods by reactions such as caramelization and Maillard reactions. Elucidating the reaction mechanisms may be useful to predict and control food quality. Ten reaction volatile markers were extracted during baking of solid model cakes implemented with known amounts of precursors (glucose with or without leucine) and then quantified by Thermal desorption-Gas chromatography-Mass spectrometry. The kinetic data showed that the level of air convection in the oven had no significant influence on the reaction rates. In contrast, increasing baking temperatures had a nonlinear accelerating impact on the generation of newly formed volatile compounds with a bell-shaped kinetic curve found for most of the markers at 200 °C. The presence of leucine triggered the activation of the Maillard and Strecker routes with a specific and very rapid formation of 3-Methylbutanal and pyrazines. A dynamic model was developed, combining evaporation flow rate and kinetic formation and consumption of reaction markers. It can be used to describe, for two furanic compounds of different volatilities, the vapor concentrations in the oven from the concentrations measured in the model cakes.
Topics: Maillard Reaction; Kinetics; Volatile Organic Compounds; Cooking; Glucose; Leucine; Gas Chromatography-Mass Spectrometry; Hot Temperature; Aldehydes; Pyrazines
PubMed: 38760123
DOI: 10.1016/j.foodres.2024.114183 -
Technology in Cancer Research &... 20241q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in...
OBJECTIVE
1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp.
METHODS
Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed.
RESULTS
Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% 37.0%, = 0.034), lower disease progression rate (31.8% 70.3%, = 0.002), longer sustained remission (median 49.7 months 18.3 months, = 0.030), and longer PFS (median 61.9 months 22.9 months, = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% 77.8%, = 0.532) or CR (27.3% 13.0%, = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (= 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (= 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (= 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS.
CONCLUSIONS
When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.
Topics: Humans; Bortezomib; Lenalidomide; Multiple Myeloma; Female; Male; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Aged; Chromosomes, Human, Pair 1; Adult; Retrospective Studies; Prognosis; Treatment Outcome; Chromosome Aberrations; Aged, 80 and over; Dexamethasone
PubMed: 38759699
DOI: 10.1177/15330338241252605 -
PLoS Genetics May 2024Regulation of transcription is a fundamental process that allows bacteria to respond to external stimuli with appropriate timing and magnitude of response. In the soil...
Regulation of transcription is a fundamental process that allows bacteria to respond to external stimuli with appropriate timing and magnitude of response. In the soil bacterium Bacillus subtilis, transcriptional regulation is at the core of developmental processes needed for cell survival. Gene expression in cells transitioning from exponential phase to stationary phase is under the control of a group of transcription factors called transition state regulators (TSRs). TSRs influence numerous developmental processes including the decision between biofilm formation and motility, genetic competence, and sporulation, but the extent to which TSRs influence bacterial physiology remains to be fully elucidated. Here, we demonstrate two TSRs, ScoC and AbrB, along with the MarR-family transcription factor PchR negatively regulate production of the iron chelator pulcherrimin in B. subtilis. Genetic analysis of the relationship between the three transcription factors indicate that all are necessary to limit pulcherrimin production during exponential phase and influence the rate and total amount of pulcherrimin produced. Similarly, expression of the pulcherrimin biosynthesis gene yvmC was found to be under control of ScoC, AbrB, and PchR and correlated with the amount of pulcherrimin produced by each background. Lastly, our in vitro data indicate a weak direct role for ScoC in controlling pulcherrimin production along with AbrB and PchR. The layered regulation by two distinct regulatory systems underscores the important role for pulcherrimin in B. subtilis physiology.
Topics: Bacillus subtilis; Gene Expression Regulation, Bacterial; Bacterial Proteins; Transcription Factors; DNA-Binding Proteins; Transcription, Genetic; Biofilms; Pyrazines
PubMed: 38753885
DOI: 10.1371/journal.pgen.1011283