Casin

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new β-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam...

Acinetobacter baumannii is a nosocomial pathogen capable of causing serious infections associated with high rates of morbidity and mortality. Due to its antimicrobial drug resistance profile, A. baumannii is categorized as an urgent priority pathogen by the Centers for Disease Control and Prevention in the United States and a priority group 1 critical microorganism by the World Health Organization. Understanding how A. baumannii adapts to different host environments may provide critical insights into strategically targeting this pathogen with novel antimicrobial and biological therapeutics...

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown...

Cardiovascular disease is the leading cause of death in the U.S. While various studies have shown the beneficial impact of exogenous hydrogen sulfide (H2 S)-releasing drugs, few have demonstrated the influence of endogenous H2 S production. Modulating the predominant enzymatic sources of H2 S-cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase-is an emerging and promising research area. This review frames the discussion of harnessing endogenous H2 S within the context of a non-ischemic form of cardiomyopathy, termed diabetic cardiomyopathy, and heart failure...

Nucleic acid-based molecular diagnosis has gained special importance for the detection and early diagnosis of genetic diseases as well as for the control of infectious disease outbreaks. The development of systems that allow for the detection and analysis of nucleic acids in a low-cost and easy-to-use way is of great importance. In this context, we present a combination of a nanotechnology-based approach with the already validated dynamic chemical labeling (DCL) technology, capable of reading nucleic acids with single-base resolution...

In a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR) Acinetobacter baumannii is a pathogen described as an "urgent threat." Infection with this bacterium manifests as different diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, infections of the urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, an unwelcome complication of neurosurgery caused by extensively-drug resistant (XDR) A...

Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs). We show here that aged HFSCs present with a decrease in canonical Wnt signaling and a shift towards non-canonical Wnt5a driven signaling which antagonizes canonical Wnt signaling. Elevated expression of Wnt5a in HFSCs upon aging results in elevated activity of the small RhoGTPase Cdc42 as well as a change in the spatial distribution of Cdc42 within HFSCs...

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, HPC and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSCs further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSCs upon aging...

BACKGROUND: Lithium chloride (LiCl) is widely used for the treatment of manic and other psychotic disorders, but the administration of lithium can result in several congenital defects in the fetus, including cleft palate (Meng, Wang, Torensma, Jw & Bian, 2015) (Szabo, 1970). However, the mechanism of Lithium's action as a developmental toxicant in palatogenesis is not well known. METHODS: In this study, hematoxylin-eosin and immunofluorescence staining were employed to evaluate the phenotypes and the expression of related markers in the LiCl-treated mice model...

Soybean isoflavones, such as genistein, daidzein, and its metabolite, S-equol, are widely known as phytoestrogens. Their biological actions are thought to be exerted via the estrogen signal transduction pathway. Estrogens, such as 17β-estradiol (E2), play a crucial role in the development and functional maintenance of the central nervous system. E2 bind to the nuclear estrogen receptor (ER) and regulates morphogenesis, migration, functional maturation, and intracellular metabolism of neurons and glial cells...

Disruption of the histone-like nucleoid structuring protein (H-NS) was shown to affect the ability of Gram-negative bacteria to regulate genes associated with virulence, persistence, stress response, quorum sensing, biosynthesis pathways, and cell adhesion. Here, we used the expression of metallo-β-lactamases (MBLs), known to elicit envelope stress by the accumulation of toxic precursors in the periplasm, to interrogate the role of H-NS in Acinetobacter baumannii , together with other stressors. Using a multidrug-resistant A...

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a premature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75-week-old) female C57BL/6 mice with a Cdc42 activity-specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan...

The molecular mechanisms involved in the terminal differentiation of erythroblasts have been elucidated by comparing enucleation and cell division. Although various similarities and differences between erythroblast enucleation and cytokinesis have been reported, the mechanisms that control enucleation remain unclear. We previously reported that dynein and microtubule-organizing centers mediated the polarization of nuclei in human erythroblasts. Moreover, the accumulation of F-actin was noted during the enucleation of erythroblasts...

Endothelial dysfunction is prominent in atherosclerosis, hypertension, diabetes, peripheral and cardiovascular diseases, and stroke. Novel therapeutic approaches to these conditions often involve development of tissue-engineered veins with ex vivo expanded endothelial cells. However, high cell number requirements limit these approaches to become applicable to clinical applications and highlight the requirement of technologies that accelerate expansion of vascular-forming cells. We have previously shown that novel small molecules could induce hematopoietic stem cell expansion ex vivo...

Cardiovascular disease is the leading cause of the death for both men and women. Although baseline heart physiology and the response to disease are known to differ by sex, little is known about sex differences in baseline molecular signaling, especially with regard to redox biology. In this review, we describe current research on sex differences in cardiac redox biology with a focus on the regulation of nitric oxide and aldehyde signaling. Furthermore, we argue for a new perspective on cardiovascular sex differences research, one that focuses on baseline redox biology without the elimination or disruption of sex hormones...

Ginsenoside Rg3 is a steroidal saponin abundant in Korean red ginseng that has high anti-inflammatory activity. Rg3 exerts an immunomodulatory effect in acute inflammatory conditions such as bacterial infections. In this study, we determined the effect of Rg3 on bacterial uptake by macrophages and the related intracellular signaling pathways. Rg3 increased macrophage phagocytosis of IgG-opsonized Escherichia coli and IgG-opsonized beads (IgGbeads), but not of non-opsonized beads. Rg3 also enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38 MAPK), but not that of Akt...

Multiple myeloma (MM) drug resistance highlights a need for alternative therapeutic strategies. In this study, we show that CASIN, a selective inhibitor of cell division cycle 42 (Cdc42) GTPase, inhibited proliferation and survival of melphalan/bortezomib-resistant MM cells more profoundly than that of the sensitive cells. Furthermore, CASIN was more potent than melphalan/bortezomib in inhibiting melphalan/bortezomib-resistant cells. In addition, CASIN sensitized melphalan/bortezomib-resistant cells to this drug combination...

The main aim of this research is to investigate the characteristics of milk and milk proteins as natural emulsifiers. It is still largely unclear how the two main fractions of the milk proteins behave as emulsifier in highly concentrated emulsions. The surface-active effect of these is determined experimentally for emulsions with a high oil content (φ > 0.7), in this case fully refined rapeseed oil. Recent publications have not yet sufficiently investigated how proteins from native milk behave in emulsions in which a jamming transition is observed...

TRIM72 is a membrane repair protein that protects against ischemia reperfusion (I/R) injury. We previously identified Cys144 (C144) on TRIM72 as a site of S-nitrosylation. To study the importance of C144, we generated a knock-in mouse with C144 mutated to a serine (TRIM72 C144S). We subjected ex vivo perfused mouse hearts to 20 min of ischemia followed by 90 min of reperfusion and observed less injury in TRIM72 C144S compared to WT hearts. Infarct size was smaller (54 vs 27% infarct size) and cardiac functional recovery (37 vs 62% RPP) was higher for the TRIM72 C144S mouse hearts...

Pyrvinium tosylate (PT) is an anthelminthic drug that has recently been shown to suppress various human cancers. However, whether PT is effective in nasopharyngeal carcinoma (NPC) has not been determined to date. In this work, we show the selective efficacy of PT in NPC while sparing normal nasopharyngeal epithelial cells, and its ability to increase chemosensitivity. We show that PT at 100 and 500 nmol/l significantly inhibits growth and induces apoptosis in several NPC cell lines without affecting normal nasopharyngeal epithelial cells...