Cellular Self-Digestion and Persistence in Bacteria.

Cellular self-digestion is an evolutionarily conserved process occurring in prokaryotic cells that enables survival under stressful conditions by recycling essential energy molecules. Self-digestion, which is triggered by extracellular stress conditions, such as nutrient depletion and overpopulation, induces degradation of intracellular components. This self-inflicted damage renders the bacterium less fit to produce building blocks and resume growth upon exposure to fresh nutrients. However, self-digestion may also provide temporary protection from antibiotics until the self-digestion-mediated damage is repaired. In fact, many persistence mechanisms identified to date may be directly or indirectly related to self-digestion, as these processes are also mediated by many degradative enzymes, including proteases and ribonucleases (RNases). In this review article, we will discuss the potential roles of self-digestion in bacterial persistence.

BRAF-Inhibitor-Induced Metabolic Alterations in A375 Melanoma Cells.

Acquired drug tolerance has been a major challenge in cancer therapy. Recent evidence has revealed the existence of slow-cycling persister cells that survive drug treatments and give rise to multi-drug-tolerant mutants in cancer. Cells in this dynamic persister state can escape drug treatment by undergoing various epigenetic changes, which may result in a transient metabolic rewiring. In this study, with the use of untargeted metabolomics and phenotype microarrays, we characterize the metabolic profiles of melanoma persister cells mediated by treatment with vemurafenib, a BRAF inhibitor. Our findings demonstrate that metabolites associated with phospholipid synthesis, pyrimidine, and one-carbon metabolism and branched-chain amino acid metabolism are significantly altered in vemurafenib persister cells when compared to the bulk cancer population. Our data also show that vemurafenib persisters have higher lactic acid consumption rates than control cells, further validating the existence of a unique metabolic reprogramming in these drug-tolerant cells. Determining the metabolic mechanisms underlying persister cell survival and maintenance will facilitate the development of novel treatment strategies that target persisters and enhance cancer therapy.

A Transient Metabolic State in Melanoma Persister Cells Mediated by Chemotherapeutic Treatments.

Persistence is a transient state that poses an important health concern in cancer therapy. The mechanisms associated with persister phenotypes are highly diverse and complex, and many aspects of persister cell physiology remain to be explored. We applied a melanoma cell line and panel of chemotherapeutic agents to show that melanoma persister cells are not necessarily preexisting dormant cells; in fact, they may be induced by cancer chemotherapeutics. Our metabolomics analysis and phenotype microarray assays further demonstrated a transient upregulation in Krebs cycle metabolism in persister cells. We also verified that targeting electron transport chain activity can significantly reduce melanoma persister levels. The reported metabolic remodeling feature seems to be a conserved characteristic of melanoma persistence, as it has been observed in various melanoma persister subpopulations derived from a diverse range of chemotherapeutics. Elucidating a global metabolic mechanism that contributes to persister survival and reversible switching will ultimately foster the development of novel cancer therapeutic strategies.

Regulatory effects of oxygen transfer on overexpression of recombinant benzaldehyde lyase production by Escherichia coli BL21 (DE3).

Effects of oxygen transfer (OT) on benzaldehyde lyase (BAL) production by recombinant E. coli BL21 (DE3) pLySs were investigated at an air-inlet rate of Q(O)/V(R) = 0.5 vvm and agitation rates of N = 250, 500, 625, and 750/min; and at constant dissolved oxygen (DO) concentrations of C(DO) = 0.04 and 0.08 mol/m(3), on a glucose based defined medium. The highest cell concentration (C(X) = 3.0 kg/m(3)) and volumetric BAL activity (A = 1095 U/cm(3)) were obtained at C(DO) = 0.08 mol/m(3). K(L)a increased with agitation rate and decreased with C(X). The highest K(L)a (= 0.039 s((-1)) was obtained at Q(O)/V(R) = 0.5 vvm and N = 750/min. Damköhler number increased with decrease in agitation rate and increase in C(X), while the effectiveness factor was inversely proportional to C(X). The specific growth rate and the yield coefficients decreased with cultivation time and higher values were obtained in higher agitation rates. Oxygen consumption and glucose consumption for maintenance were changed proportionally and inverse proportionally with the BAL production, respectively.