The role of the customer management system at an automotive retail multifranchise operation in KZN.

Master of Business Administration. University of KwaZulu-Natal, Durban 2015.Information plays a critical role in any organisation today no matter what their core business entails. Information Systems have transformed from a basic support service to a critical function impacting a firm’s daily operations and strategic business plans. The explosion in innovation surrounding Information Technology and communications has led firms to continuously transform the way they do business to remain relevant. Business is at risk if they do not innovate. However innovation of Information Systems can disturb existing work practices and staff may resist the new technology. Therefore it is imperative that staff understand the role of the Information Systems within the overall strategy of the organisation. The results of this study can assist organisational decision-making processes and provide a basis for review. The aim of the study was to examine the various factors that impacted the effective use of the Customer Management System by motor vehicles sales persons at XYZ Company. Furthermore the study aimed to establish management support of the CMS system and the effectiveness of the system. Since the study was descriptive in nature, a quantitative research approach was taken. The overall results of this study revealed that sales executives found the CMS system easy to use, easy to understand and used it as a vital tool to manage their customers. However it was noted that sales executives had various concerns regarding the privacy of their customers’ details, duplication of customer records, over-burdened data input processes and lack of follow-up reminders on the system. Furthermore Internet leads management was highlighted as a persistent issue that needed to be addressed by management. Also noted in the study was a call for the workshop and finance departments to be linked to the CMS system to increase sales leads and pre-qualify customers for finance. The sales executives also suggested having access to their CMS system via a mobile application so as to alleviate the problem of not being at their workstations when a lead comes in. The findings from the research presented recommendations for improvements to the CMS system for example upgrading the CMS system and developing a leads management system. Further recommendations include linking the finance and workshop departments to the CMS system. The limitations of the study have been discussed and recommendations for future research provided

KEAP₁ inhibition is neuroprotective and suppresses the development of epilepsy

Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy

Pirin, an Nrf2-regulated protein, is overexpressed in human colorectal tumors

The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in comparison with matched normal tissue. The overexpression of pirin correlates with activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and increased expression of the classical Nrf2 target NAD(P)H:quinone oxidoreductase 1 (NQO1), but interestingly and unexpectedly, not with expression of the aldo-keto reductase (AKR) family members AKR1B10 and AKR1C1, which are considered to be the most overexpressed genes in response to Nrf2 activation in humans. Using pharmacologic and genetic approaches to either downregulate or upregulate Nrf2, we show that pirin is regulated by Nrf2 in human and mouse cells and in the mouse colon in vivo. The small molecule pirin inhibitor TPhA decreased the viability of human colorectal cancer (DLD1) cells, but this decrease was independent of the levels of pirin. Our study demonstrates the Nrf2-dependent regulation of pirin and encourages the pursuit for specific pirin inhibitors

Author Correction:C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape

Correction to: Scientific Reportshttps://doi.org/10.1038/s41598-018-26269-9, published online 23 May 2018 This Article contains an error in Figure 3.As a result of an error during the preparation of the figures for this Article, the western blots shown in Figure 3A and 3B contained an additional lane for the protein Tubulin. This is because an additional sample was loaded in the last lane of the gel to prevent potential stretching of the gel in this lane during electrophoresis if left empty. It was subsequently left uncropped from the tubulin blot shown in the published figure. The corrected Figure 3 and its accompanying legend appear below. C151 in KEAP1 is the primary sensor for MCE-23 and MCE-1 in MEF cells. Western blot analyses of total cell lysates of KEAP1-knockout MEF cells rescued with either wild-type (WT), single cysteine mutant C151S, double cysteine mutant C273W/C288E or triple cysteine mutant C151S/C273W/C288E of mouse N-terminally tagged HA-KEAP1. Cells (3 × 105 per well), growing in 6-well plates, were exposed to vehicle (0.1% DMSO) (A,B), MCE-23 (A) or MCE-1 (B) for 3 h, after which the cells were lysed. Immunoblotting was performed on cell lysates using antibodies raised against NRF2, HA and α-tubulin.</p

Nrf2 depletion in the context of loss-of-function Keap1 leads to mitolysosome accumulation

Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the principal determinant of the cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator of Nrf2 is Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets Nrf2 for ubiquitination and proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently in lung cancer, leading to constitutive Nrf2 activation. We used the human lung cancer cell line A549 and its CRISPR/Cas9-generated homozygous Nrf2-knockout (Nrf2-KO) counterpart to assess the role of Nrf2 on mitochondrial health. To confirm that the observed effects of Nrf2 deficiency are not due to clonal selection or long-term adaptation to the absence of Nrf2, we also depleted Nrf2 by siRNA (siNFE2L2), thus creating populations of Nrf2-knockdown (Nrf2-KD) A549 cells. Nrf2 deficiency decreased mitochondrial respiration, but increased the mitochondrial membrane potential, mass, DNA content, and the number of mitolysosomes. The proportion of ATG7 and ATG3 within their respective LC3B conjugates was increased in Nrf2-deficient cells with mutant Keap1, whereas the formation of new autophagosomes was not affected. Thus, in lung cancer cells with loss-of-function Keap1, Nrf2 facilitates mitolysosome degradation thereby ensuring timely clearance of damaged mitochondria

The isoquinoline PRL-295 increases the thermostability of Keap1 and disrupts its interaction with Nrf2

Transcription factor Nrf2 and its negative regulator Keap1 orchestrate a cytoprotective response against oxidative, metabolic, and inflammatory stress. Keap1 is a drug target, with several small molecules in drug development. Here, we show that the isoquinoline PRL-295 increased Keap1 thermostability in lysates from cells expressing fluorescently tagged Keap1. The thermostability of endogenous Keap1 also increased in intact cells and murine liver following PRL-295 treatment. Fluorescence Lifetime Imaging–Förster Resonance Energy Transfer (FLIM-FRET) experiments in cells co-expressing sfGFP-Nrf2 and Keap1-mCherry further showed that PRL-295 prolonged the donor fluorescence lifetime, indicating disruption of the Keap1-Nrf2 protein complex. Orally administered PRL-295 to mice activated the Nrf2transcriptional target NAD(P)H:quinone oxidoreductase 1 (NQO1) in liver and decreased the levels of plasma alanine aminotransferase and aspartate aminotransferase upon acetaminophen-induced hepatic injury. Thus, PRL-295 engages the Keap1 protein target in cells and in vivo, disrupting its interaction with Nrf2, leading to activation of Nrf2-dependent transcription and hepatocellular protection