Pyrimidine Derivative Ameliorates Spinal Cord Injury via Anti-apoptotic, Anti-inflammatory, and Antioxidant Effects and by Regulating Rho GTPases

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. One of the most important strategies for the treatment of spinal cord injury is searching for new and effective pharmacological neuroprotectors and regeneration stimulators. The derivatives of pyrimidine are universal stimulators of the regeneration of various tissues as they support the recovery of nervous structures. The protective effect of the cocrystal of 1,2-dihydro-4,6-dimethyl-1-(2-hydroxyethyl)-pyrimidinone-2 with para-aminobenzoic acid (compound conjugate III, CCIII) was explored on a rat model with a contusion spinal cord injury. Injection of CCIII significantly reduced the expression of tumor necrosis factor α (TNF-α), inhibited the synthesis of myeloperoxidase (MPO), matrix metalloproteinase 9 (MPP9), cyclooxygenase-2 (COX2), and macrophage marker CD68, and increased the level of superoxide dismutase 1 (SOD1). Additionally, the expression of caspase-7 markers in the damaged tissue decreased under the action of CCIII. Treatment with the CCIII maintained a population of Olig2-positive myelin-forming cells at 30 days post-injury. The detected therapeutic effect is comparable with that of riluzole

Pyrimidine Derivative Ameliorates Spinal Cord Injury via Anti-apoptotic, Anti-inflammatory, and Antioxidant Effects and by Regulating Rho GTPases

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. One of the most important strategies for the treatment of spinal cord injury is searching for new and effective pharmacological neuroprotectors and regeneration stimulators. The derivatives of pyrimidine are universal stimulators of the regeneration of various tissues as they support the recovery of nervous structures. The protective effect of the cocrystal of 1,2-dihydro-4,6-dimethyl-1-(2-hydroxyethyl)-pyrimidinone-2 with para-aminobenzoic acid (compound conjugate III, CCIII) was explored on a rat model with a contusion spinal cord injury. Injection of CCIII significantly reduced the expression of tumor necrosis factor α (TNF-α), inhibited the synthesis of myeloperoxidase (MPO), matrix metalloproteinase 9 (MPP9), cyclooxygenase-2 (COX2), and macrophage marker CD68, and increased the level of superoxide dismutase 1 (SOD1). Additionally, the expression of caspase-7 markers in the damaged tissue decreased under the action of CCIII. Treatment with the CCIII maintained a population of Olig2-positive myelin-forming cells at 30 days post-injury. The detected therapeutic effect is comparable with that of riluzole

The Effect of Antimicrobial Photodynamic Inactivation on the Protein Profile of Dormant <i>Mycolicibacterium smegmatis</i> Containing Endogenous Porphyrins

During transition into a dormant state, Mycolicibacterium (Mycobacterium) smegmatis cells are able to accumulate free porphyrins that makes them sensitive to photodynamic inactivation (PDI). The formation of dormant cells in a liquid medium with an increased concentration of magnesium (up to 25 mM) and zinc (up to 62 µM) resulted in an increase in the total amount of endogenous porphyrins in dormant M. smegmatis cells and their photosensitivity, especially for bacteria phagocytosed by macrophages. To gain insight into possible targets for PDI in bacterial dormant mycobacterial cells, a proteomic profiling with SDS gel electrophoresis and mass spectrometry analysis were conducted. Illumination of dormant forms of M. smegmatis resulted in the disappearance of proteins in the separating SDS gel. Dormant cells obtained under an elevated concentration of metal ions were more sensitive to PDI. Differential analysis of proteins with their identification with MALDI-TOF revealed that 45.2% and 63.9% of individual proteins disappeared from the separating gel after illumination for 5 and 15 min, respectively. Light-sensitive proteins include enzymes belonging to the glycolytic pathway, TCA cycle, pentose phosphate pathway, oxidative phosphorylation and energy production. Several proteins involved in protecting against oxygen stress and protein aggregation were found to be sensitive to light. This makes dormant cells highly vulnerable to harmful factors during a long stay in a non-replicative state. PDI caused inhibition of the respiratory chain activity and destroyed enzymes involved in the synthesis of proteins and nucleic acids, the processes which are necessary for dormant cell reactivation and their transition to multiplying bacteria. Because of such multiple targeting, PDI action via endogenous porphyrins could be considered as an effective approach for killing dormant bacteria and a perspective to inactivate dormant mycobacteria and combat the latent form of mycobacteriosis, first of all, with surface localization

Acquiring of photosensitivity by Mycobacterium tuberculosis in vitro and inside infected macrophages is associated with accumulation of endogenous Zn–porphyrins

Abstract Mycobacterium tuberculosis (Mtb) is able to transition into a dormant state, causing the latent state of tuberculosis. Dormant mycobacteria acquire resistance to all known antibacterial drugs and can survive in the human body for decades before becoming active. In the dormant forms of M. tuberculosis, the synthesis of porphyrins and its Zn-complexes significantly increased when 5-aminolevulinic acid (ALA) was added to the growth medium. Transcriptome analysis revealed an activation of 8 genes involved in the metabolism of tetrapyrroles during the Mtb transition into a dormant state, which may lead to the observed accumulation of free porphyrins. Dormant Mtb viability was reduced by more than 99.99% under illumination for 30 min (300 J/cm2) with 565 nm light that correspond for Zn–porphyrin and coproporphyrin absorptions. We did not observe any PDI effect in vitro using active bacteria grown without ALA. However, after accumulation of active cells in lung macrophages and their persistence within macrophages for several days in the presence of ALA, a significant sensitivity of active Mtb cells (ca. 99.99%) to light exposure was developed. These findings create a perspective for the treatment of latent and multidrug-resistant tuberculosis by the eradication of the pathogen in order to prevent recurrence of this disease

Dealing with revered past

Research Summary This paper examines how strategy‐makers attempt to reconcile change initiatives with organizational values and principles laid out long before, still encased in strategic identity statements such as corporate mottos and philosophies. It reveals three discursive strategies that strategy‐makers use to establish a sense of continuity in time of change: elaborating (transferring part of the content of the historical statement into a new one), recovering (forging a new statement based on the retrieval and re‐use of historical references), and decoupling (allowing the co‐existence of the historical statement and a contemporary one). By so doing, our study advances research on uses of the past, establishes important linkages between identity and strategy research, and enhances our understanding of the intergenerational transfer of values in family firms. Managerial Summary Crafting a new corporate philosophy or mission statement can help implement strategic change, but can also be experiencedas a disruption in people's sense of “who we are” as an organization. This paper reveals a variety of strategies that managers can use to deal with the tension between promoting change and maintaining a sense of continuity with a distant, revered past. By doing so, it helps managers confronting these issues deal with the enabling and constraining effects of the past. While this is a more general challenge for organizations with historical legacies, it is a particularly delicate issue for family firms grappling with the need to transfer values from one generation to the next, while retaining flexibility to change and adapt over time.Peer reviewe