Effects of maternal cigarette smoke exposure on renal and other health outcomes in mice offspring

University of Technology Sydney. Faculty of Science.Background: The burden of kidney disease is significantly increased worldwide. Developmental programming of non-communicable diseases is an established paradigm. Therefore, there is increasing attention to the contribution of intrauterine and early post-natal environmental insults to the risk of adulthood kidney diseases. One of such insults is maternal cigarette smoke exposure (SE), which is associated with intrauterine growth retardation (IUGR) and some adulthood diseases in offspring. However, it is unknown whether maternal SE can increase the risk of developing chronic kidney disease (CKD) in offspring. Maternal SE was also shown to increase renal oxidative stress in offspring; while the anti-oxidants L-carnitine (LC) supplementation has been shown to be beneficial in many human diseases, which may benefit such offspring. Objectives: This thesis aimed to study the effect of maternal SE on, 1) kidney development and renal function; 2) glucose and lipid metabolic markers in the liver, and; 3) the effect of maternal LC supplementation during gestation and lactation on health outcome of the SE offspring. Methods: Female Balb/c breeder mice were exposed to cigarette smoke for 6 weeks prior to mating, during gestation and lactation; with sham exposure as control. A subgroup of the SE dams was treated with LC (SE+L-C) during gestation and lactation via drinking water. The offspring were sacrificed at postnatal day (P)1, P20 (weaning age) and 13 weeks (mature age). Blood, urine, kidneys and livers were collected. Renal Morphology and function, renal development factors, and metabolic markers in the liver were examined in the offspring. Results: Reduced nephrons number, enlarged glomerular size and altered renal expression of developmental factors such as glial cell line-derived neurotrophic factor (GDNF) and paired box binding protein (Pax)2 were observed in the offspring. This was linked to increased mRNA expression of pro-inflammatory marker, monocyte chemoattractant protein (MCP)-1, and urine albumin/creatinine ratio at adulthood in the male offspring. However female offspring were protected from such maternal effect. Both genders developed glucose intolerance. mRNA expression of IL-1β and TNF-α was upregulated in the liver in the female offspring, with hyperlipidemia. Maternal LC supplementation during gestation and lactation ameliorated these changes in the offspring by maternal SE. Conclusion: Maternal SE led to kidney underdevelopment, adulthood renal dysfunction, lipid and glucose metabolic disorders, and increased renal and liver inflammation in the offspring in a gender-specific manner. Maternal LC supplementation has a beneficial role in ameliorating the detrimental impact of maternal SE on the offspring

Regulatory challenges in the move to a low-carbon environment

An outcome of the international climate conference in Copenhagen (COP 15, 2009) was that a number of governments have undertaken to reduce their nations\u27 greenhouse gas (GHG) emissions and some have provided targets and deadlines for the achievement of their stated goals. While the transition to a low-carbon environment has the potential to stimulate growth, create jobs and opportunities, and to bring benefits to the economy, there are many challenges in the process. This is an exploratory paper aimed at identifying the major regulatory and governance issues associated with the move to a low-carbon environment. In terms of business governance, CEOs and other executives responsible for corporate oversight will need to monitor, assess, and manage compliance with climate change and carbon-related regulation. In the transition period government regulation encouraging appropriate carbon costs classification and measurement, financial sustainability reporting and disclosure, and responsible carbon citizenship are expected to be predominant.<br /

Fetal Programming of Renal Development-Influence of Maternal Smoking

Smoking is a known risk factor for non-communicable illness including pulmonary disease, cardiovascular disease, and Type 2 diabetes. Smoking also contributes significantly to the rising `epidemic of chronic kidney disease. It is increasingly recognised that maternal programming of fetal development during pregnancy predisposes offspring to future disease. Maternal smoking, particularly in the first trimester, imposes a significant adverse impact on fetal renal development that determines the future risk of chronic kidney disease. Several mechanisms may contribute. Firstly, epigenetic modification of fetal nuclear or mitochondrial DNA, induced by intrauterine exposure to chemicals within the cigarette smoke, may result in an increased risk for metabolic and renal disorders. Secondly, nicotine and other chemicals within the cigarette smoke can cross the blood placental barrier concentrate in the fetus and result in direct toxicity. Thirdly, malnutrition due to the anorexigenic effect of smoking results in nutritional deficits in the fetus and impairs organ growth and development. 10-45% of pregnant women from diverse populations smoke during pregnancy. Hence it is considered a major and significant public health issue that imposes adverse health consequences not only to the pregnant women, but also inherited by their offspring, and potentially affecting future generations

SELECTIVE SMALL MOLECULE TARGETING OF MCL-1 IN MULTIPLE MYELOMA

Multiple Myeloma (MM) is a deadly blood malignancy, characterized by the uncontrolled proliferation of aberrantly differentiated plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic group of Bcl-2 family proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. In this project, we investigated the effect of the novel Mcl-1 inhibiting agent KS18 on MM cells. We demonstrated the molecules in vitro efficacy as well superior potency towards MM. However, Mcl-1 inhibition by KS18 was associated with a significant reduction of MM cell viability. Moreover, we observed that KS18 was able to induce apoptosis in MM cells in a caspase-dependent manner. Our results propose that targeting Mcl-1 by KS18 may represent a new viable strategy for MM treatment. Furthermore, the present study uncovers the mechanism of action of KS18 and provides the foundation for in vivo assessment of this novel molecule

POTENT AND SELECTIVE SMALL MOLECULE MCL-1 INHIBITOR DEMONSTRATES ANTI-MYELOMA ACTIVITY AND OVERCOMES CHEMOTHERAPY RESISTANCE

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are born to survive” which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates that KS18 effectively induces cell death in MM by dual regulatory mechanisms targeting Mcl-1 protein at both transcriptional and post-translational levels. KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates tumor shrinkage in KS18-treated NSG mice without notable toxicity signs, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance

Impact of maternal cigarette smoke exposure on brain inflammation and oxidative stress in male mice offspring

Maternal cigarette smoke exposure (SE) during gestation can cause lifelong adverse effects in the offspring's brain. Several factors may contribute including inflammation, oxidative stress and hypoxia, whose changes in the developing brain are unknown. Female Balb/c mice were exposed to cigarette smoke prior to mating, during gestation and lactation. Male offspring were studied at postnatal day (P) 1, P20 and 13 weeks (W13). SE dams had reduced inflammatory mediators (IL-1β, IL-6 and toll like receptor (TLR)4 mRNA), antioxidant (manganese superoxide dismutase (MnSOD)), and increased mitochondrial activities (OXPHOS-I, III and V) and protein damage marker nitrotyrosine. Brain hypoxia-inducible factor (HIF)1α and its upstream signalling molecule early growth response factor (EGR)1 were not changed in the SE dams. In the SE offspring, brain IL-1R, IL-6 and TLR4 mRNA were increased at W13. The translocase of outer mitochondrial membrane, and MnSOD were reduced at W13 with higher nitrotyrosine staining. HIF-1α was also increased at W13, although EGR1 was only reduced at P1. In conclusion, maternal SE increased markers of hypoxia and oxidative stress with mitochondrial dysfunction and cell damage in both dams and offspring, and upregulated inflammatory markers in offspring, which may render SE dams and their offspring vulnerable to additional brain insults

Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring

© 2016 John Wiley & Sons Australia, Ltd Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to two cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin-1 receptor and Toll-like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood

Oxidative stress, mitochondrial perturbations and fetal programming of renal disease induced by maternal smoking

© 2015 Elsevier Ltd. An adverse in-utero environment is increasingly recognized to predispose to chronic disease in adulthood. Maternal smoking remains the most common modifiable adverse in-utero exposure leading to low birth weight, which is strongly associated with chronic kidney disease (CKD) in later life. In order to investigate underlying mechanisms for such susceptibility, female Balb/c mice were sham or cigarette smoke-exposed (SE) for 6 weeks before mating, throughout gestation and lactation. Offspring kidneys were examined for oxidative stress, expression of mitochondrial proteins, mitochondrial structure as well as renal functional parameters on postnatal day 1, day 20 (weaning) and week 13 (adult age). From birth throughout adulthood, SE offspring had increased renal levels of mitochondrial-derived reactive oxygen species (ROS), which left a footprint on DNA with increased 8-hydroxydeoxyguanosin (8-OHdG) in kidney tubular cells. Mitochondrial structural abnormalities were seen in SE kidneys at day 1 and week 13 along with a reduction in oxidative phosphorylation (OXPHOS) proteins and activity of mitochondrial antioxidant Manganese superoxide dismutase (MnSOD). Smoke exposure also resulted in increased mitochondrial DNA copy number (day 1-week 13) and lysosome density (day 1 and week 13). The appearance of mitochondrial defects preceded the onset of albuminuria at week 13. Thus, mitochondrial damage caused by maternal smoking may play an important role in development of CKD at adult life