Obesity is now a widespread disorder, and its prevalence has become a critical concern worldwide, due to its association with common co-morbidities like cancer, cardiovascular diseases and diabetes. Adipose tissue is an endocrine organ and therefore plays a critical role in the survival of an individual, but its dysfunction or excess is directly linked to obesity. The journey from multipotent mesenchymal stem cells to the formation of mature adipocytes is a well-orchestrated program which requires the expression of several genes, their transcriptional factors, and signaling intermediates from numerous pathways. Understanding all the intricacies of adipogenesis is vital if we are to counter the current epidemic of obesity because the limited understanding of these intricacies is the main barrier to the development of potent therapeutic strategies against obesity. In particular, AMP-Activated Protein Kinase (AMPK) plays a crucial role in regulating adipogenesis - it is arguably the central cellular energy regulation protein of the body. Since AMPK promotes the development of brown adipose tissue over that of white adipose tissue, special attention has been given to its role in adipose tissue development in recent years. In this review, we describe the molecular mechanisms involved in adipogenesis, the role of signaling pathways and the substantial role of activated AMPK in the inhibition of adiposity, concluding with observations which will support the development of novel chemotherapies against obesity epidemics.
Despite significant advancements in screening, diagnosis, and treatment of non-small cell lung cancer (NSCLC), it remains the primary cause of cancer-related deaths globally. DNA damage is caused by the exposure to exogenous and endogenous factors and the correct functioning of DNA damage repair (DDR) is essential to maintain of normal cell circulation. The presence of genomic instability, which results from defective DDR, is a critical characteristic of cancer. The changes promote the accumulation of mutations, which are implicated in cancer cells, but these may be exploited for anti-cancer therapies. NSCLC has a distinct genomic profile compared to other tumors, making precision medicine essential for targeting actionable gene mutations. Although various treatment options for NSCLC exist including chemotherapy, targeted therapy, and immunotherapy, drug resistance inevitably arises. The identification of deleterious DDR mutations in 49.6% of NSCLC patients has led to the development of novel target therapies that have the potential to improve patient outcomes. Synthetic lethal treatment using poly (ADP-ribose) polymerase (PARP) inhibitors is a breakthrough in biomarker-driven therapy. Additionally, promising new compounds targeting DDR, such as ATR, CHK1, CHK2, DNA-PK, and WEE1, had demonstrated great potential for tumor selectivity. In this review, we provide an overview of DDR pathways and discuss the clinical translation of DDR inhibitors in NSCLC, including their application as single agents or in combination with chemotherapy, radiotherapy, and immunotherapy.
The prevalence of obesity is increasing rapidly globally and has recently reached pandemic proportions. It is a multifactorial disorder linked to a number of non-communicable diseases such as type-2 diabetes, cardiovascular disease, and cancer. Over-nutrition and a sedentary lifestyle are considered the most significant causes of obesity; a healthy lifestyle and behavioural interventions are the most powerful ways to achieve successful weight loss, but to maintain this in the long term can prove difficult for many individuals, without medical intervention. Various pharmacological anti-obesogenic drugs have been tested and marketed in the past and have been moderately successful in the management of obesity, but their adverse effects on human health often outweigh the benefits. Natural products from plants, either in the form of crude extracts or purified phytochemicals, have been shown to have anti-obesogenic properties and are generally considered as nontoxic and cost-effective compared to synthetic alternatives. These plant products combat obesity by targeting the various pathways and/or regulatory functions intricately linked to obesity. Their mechanisms of action include inhibition of pancreatic lipase activities, an increase in energy expenditure, appetite regulation, lipolytic effects, and inhibition of white adipose tissue development. In this review, we discuss the distinct anti-obesogenic properties of recently reported plant extracts and specific bioactive compounds, along with their molecular mechanisms of action. This review will provide a common platform for understanding the different causes of obesity and the possible approaches to using plant products in tackling this worldwide health issue.
The BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Its expression level in CML patients is monitored by a real-time quantitative polymerase chain reaction defined by the International Scale (qPCRIS). BCR-ABL1 has also been found in asymptomatic normal individuals using a non-qPCRIS method. In the present study, we examined the prevalence of BCR-ABL1 in a normal population in southern Sarawak by performing qPCRIS for BCR-ABL1 with ABL1 as an internal control on total white blood cells, using an unbiased sampling method. While 146 of 190 (76.8%) or 102 of 190 (53.7%) samples showed sufficient amplification of the ABL1 gene at > 20,000 or > 100,000 copy numbers, respectively, in qPCRIS, one of the 190 samples showed amplification of BCR-ABL1 with positive qPCRIS of 0.0023% and 0.0032% in two independent experiments, the sequence of which was the BCR-ABL1 e13a2 transcript. Thus, we herein demonstrated that the BCR-ABL1 fusion gene is expected to be present in approximately 0.5-1% of normal individuals in southern Sarawak.
Brown and beige adipose tissues are the primary sites for adaptive non-shivering thermogenesis. Although they have been known principally for their thermogenic effects, in recent years, it has emerged that, just like white adipose tissue (WAT), brown and beige adipose tissues also play an important role in the regulation of metabolic health through secretion of various brown adipokines (batokines) in response to various physiological cues. These secreted batokines target distant organs and tissues such as the liver, heart, skeletal muscles, brain, WAT, and perform various local and systemic functions in an autocrine, paracrine, or endocrine manner. Brown and beige adipose tissues are therefore now receiving increasing levels of attention with respect to their effects on various other organs and tissues. Identification of novel secreted factors by these tissues may help in the discovery of drug candidates for the treatment of various metabolic disorders such as obesity, type-2 diabetes, skeletal deformities, cardiovascular diseases, dyslipidemia. In this review, we comprehensively describe the emerging secretory role of brown/beige adipose tissues and the metabolic effects of various brown/beige adipose tissues secreted factors on other organs and tissues in endocrine/paracrine manners, and as well as on brown/beige adipose tissue itself in an autocrine manner. This will provide insights into understanding the potential secretory role of brown/beige adipose tissues in improving metabolic health.
In this study, the anti-obesity effects of 5,7,3',4',5-pentamethoxyflavone (PMF) and 6,2',4'-trimethoxyflavone (TMF) were evaluated through two distinct mechanisms of action: inhibition of crude porcine pancreatic lipase (PL), and inhibition of adipogenesis in 3T3-L1 pre-adipocytes. Both flavones show dose dependent, competitive inhibition of PL activity. Molecular docking studies revealed binding of the flavones to the active site of PL. In 3T3-L1 adipocytes, both flavones reduced the accumulation of lipids and triglycerides. PMF and TMF also lowered the expression of adipogenic and lipogenic genes. They both reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), CCAAT/enhancer-binding protein α and β (C/EBP α and β), sterol regulatory element-binding protein 1 (SREBF 1), fatty acid synthase (FASN), adipocyte binding protein 2 (aP2), and leptin gene. In addition, these flavones enhanced adiponectin mRNA expression, increased lipolysis and enhanced the expression of lipolytic genes: adipose triglycerides lipase (ATGL), hormone sensitive lipase (HSL) and monoglycerides lipase (MAGL) in mature 3T3-L1 adipocytes. Overall, PMF was seen to be a more potent inhibitor of both PL activity and adipogenesis versus TMF. These results suggest that PMF and TMF possess anti-obesity activities and can be further evaluated for their anti-obesity effects.
Hydroxylated polymethoxyflavones (HPMFs) have been shown to possess various anti-disease effects, including against obesity. This study investigates the anti-obesity effects of HPMFs in further detail, aiming to gain understanding of their mechanism of action in this context. The current study demonstrates that two HPMFs; 3'-hydroxy-5,7,4',5'-tetramethoxyflavone (3'OH-TetMF) and 4'-hydroxy-5,7,3',5'-tetramethoxyflavone (4'OH-TetMF) possess anti-obesity effects. They both significantly reduced pancreatic lipase activity in a competitive manner as demonstrated by molecular docking and kinetic studies. In cell studies, it was revealed that both of the HPMFs suppress differentiation of 3T3-L1 mouse embryonic fibroblast cells during the early stages of adipogenesis. They also reduced expression of key adipogenic and lipogenic marker genes, namely peroxisome proliferator-activated receptor-gamma (PPARγ), CCAAT/enhancer-binding protein α and β (C/EBP α and β), adipocyte binding protein 2 (aP2), fatty acid synthase (FASN), and sterol regulatory element-binding protein 1 (SREBF 1). They also enhanced the expression of cell cycle genes, i.e., cyclin D1 (CCND1) and C-Myc, and reduced cyclin A2 expression. When further investigated, it was also observed that these HPMFs accelerate lipid breakdown (lipolysis) and enhance lipolytic genes expression. Moreover, they also reduced the secretion of proteins (adipokines), including pro-inflammatory cytokines, from mature adipocytes. Taken together, this study concludes that these HPMFs have anti-obesity effects, which are worthy of further investigation.