Ahmed Bettaieb

Obesity has become so prevalent in many developed countries that it is increasingly perceived as a new norm, despite decades of interventions and drug development. Although research continues to explore novel strategies, no single approach to date has demonstrated sustained success in reducing its population-level dominance. This underscores the need to better evaluate and integrate the growing body of knowledge surrounding obesity’s multifaceted nature. Stamped under one ‘fat’ name, adipose tissue varies by color, location, morphology, composition, and function. This variability suggests a level of complexity that demands deeper investigation. Although the relevance and roles of different adipose types have been extensively discussed throughout the literature, their interdependence, synergy, and collective impact on the body remain to be fully expounded. This review aims to further consolidate and elucidate the available information on the different adipose tissue types and their association with obesity and metabolic health. We also discuss existing and emerging therapeutic strategies, highlighting their respective strengths and limitations.

White adipose tissue (WAT) makes up about 20–25% of total body mass in healthy individuals and is crucial for regulating various metabolic processes, including energy metabolism, endocrine function, immunity, and reproduction. In adipose tissue research, “adipogenesis” is commonly used to refer to the process of adipocyte formation, spanning from stem cell commitment to the development of mature, functional adipocytes. Although, this term should encompass a wide range of processes beyond commitment and differentiation, to also include other stages of adipose tissue development such as hypertrophy, hyperplasia, angiogenesis, macrophage infiltration, polarization, etc.… collectively, referred to herein as the adipogenic cycle. The term “differentiation”, conversely, should only be used to refer to the process by which committed stem cells progress through distinct phases of subsequent differentiation. Recognizing this distinction is essential for accurately interpreting research findings on the mechanisms and stages of adipose tissue development and function. In this review, we focus on the molecular regulation of white adipose tissue development, from commitment to terminal differentiation, and examine key functional aspects of WAT that are crucial for normal physiology and systemic metabolic homeostasis.

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis–targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound 8 ) exhibits a half-maximal degradation concentration in the sub-nM range, is stable in vivo , and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.

Hearing loss represents a multifaceted and pervasive challenge that deeply impacts various aspects of an individual’s life, spanning psychological, emotional, social, and economic realms. Understanding the molecular underpinnings that orchestrate hearing loss remains paramount in the quest for effective therapeutic strategies. This review aims to expound upon the physiological, biochemical, and molecular aspects of hearing loss, with a specific focus on its correlation with diabetes. Within this context, phytochemicals have surfaced as prospective contenders in the pursuit of potential adjuvant therapies. These compounds exhibit noteworthy antioxidant and anti-inflammatory properties, which hold the potential to counteract the detrimental effects induced by oxidative stress and inflammation—prominent contributors to hearing impairment. Furthermore, this review offers an up-to-date exploration of the diverse molecular pathways modulated by these compounds. However, the dynamic landscape of their efficacy warrants recognition as an ongoing investigative topic, inherently contingent upon specific experimental models. Ultimately, to ascertain the genuine potential of phytochemicals as agents in hearing loss treatment, a comprehensive grasp of the molecular mechanisms at play, coupled with rigorous clinical investigations, stands as an imperative quest.

ID 22963 Poster Board 486 Acute pancreatitis (AP) is a frequent gastrointestinal disorder that causes significant morbidity, and its incidence has been progressively increasing in recent years. Pancreatitis starts as a local inflammation in the pancreas, leading to systemic inflammatory response and complications mediated via the NF-κB pathway. Approximately 25% of patients with AP develop a severe disease progression that leads to systemic inflammation and multiple organ dysfunction with mortality rates of up to 50%. AP remains without specific therapy, and understanding its pathogenesis9s molecular mechanisms will aid in therapeutic intervention. a large body of evidence supports the use of phytochemicals and natural herbal extracts with anti-inflammatory properties as a potential adjuvant therapy. However, the lack of mechanistic understanding hampers the ability to refine these approaches into clinically supported treatments. Zyflamend (hereinafter referred to as PHB) is a commercially available well-defined poly-herbal blend of 10 herbal extracts, each included at a low dose relative to single-use compounds. Previous research investigated PHB for its anti-cancer properties because it ability to activate the AMP-activated protein kinase (AMPK). Treatment of pancreatic cancer cells with human equivalent doses of PHB led to inhibition of carcinogenesis through various proposed pathways and processes, including ER stress, autophagy, and the NF-κB pathways. The current study aims to investigate the effects of PHB treatment on AP and characterize the underlying molecular mechanisms. To achieve this goal, complementary in vivo and in vitro approaches were employed to investigate the effects of PHB on cerulein-induced acute pancreatitis in mice and pancreatic acinar cells. Preliminary findings demonstrated that amylase and lipase activities were lower in Zyflamend-treated mice compared with controls injected with cerulein. In addition, while control mice exhibited a significant increase in local and systemic levels of inflammatory cytokines concomitant with pancreatic activation of inflammatory signaling pathways, Zyflamend treatment alleviated systemic and local inflammation. Although still preliminary, our data suggest that Zyflamend may serve a potential natural approach for the treatment and prevention of AP that is less invasive and capable of achieving long-term clinical significance.

ID 23750 Poster Board 422 Acute Kidney Injury (AKI) is a serious health concern that may lead to alterations in the function and morphology of the kidney glomerulus and a significant decline in renal function. Recent research into the metabolic alterations associated with AKI within glomerular epithelial cells (podocytes) revealed significant dysregulations to glucose metabolism and related enzymes, specifically pyruvate kinase M2 (PKM2). However, the role of PKM2 in the pathogenesis of AKI remains to be elucidated. In the current study, we employed Cre-loxP technology to explore the effects of PKM2-specific deletion in podocytes on the activity of pivotal signaling pathways central to the pathophysiology of AKI. Lipopolysaccharide (LPS)-induced AKI was used as the experimental model. We demonstrate that mice with specific PKM2 ablation in podocytes exhibited a significant reduction in LPS-induced protein excretion and alterations to blood serum albumin and urea nitrogen levels. Quantitative immunohistochemical analysis revealed that PKM2 deficiency was also protective against LPS-induced renal injury. These effects were concomitant with a reduction in LPS-induced expression of pro-inflammatory cytokines, local induction of inflammation, endoplasmic reticulum stress, and apoptosis. At the molecular level, the beneficial effects of PKM2 on LPS-induced podocytes injury were mediated, at least in part, through a reduction in β-catenin activity and enhancement of autophagy. Reconstitution of PKM2- knockdown podocytes abrogated the protective effects of PKM2 deficiency. Taken together, our findings highlight a pivotal role for PKM2 in podocyte response to stress and demonstrates that targeting PKM2 in podocytes may be of therapeutic potential in the prevention and treatment of AKI.

ID 14554 Poster Board 60 It is estimated that by 2050 nearly 2.5 billion people are projected to have some degree of hearing loss and at least 700 million will require hearing rehabilitation. Hearing loss can be classified into three groups: sensorineural, conductive, and mixed. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells resulting in hair cell death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling, reactive oxygen species (ROS) generation, and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival and homeostasis in response to palmitate-induced injury. We demonstrated that at a human equivalent dose G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells. Importantly, G-Rc alleviated inflammation, oxidative stress, ER stress, and apoptosis induced by palmitate. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms mediating the beneficial effects of G-Rc on cochlear hair cells.

ID 15100 Poster Board 429 Abstract The continuous rise of obesity has been associated with various comorbidities including type 2 diabetes (T2DM), cardiovascular disease (CVD), and even some types of cancer thus defining it a global health concern. Notably, brown adipose tissue (BAT) development and regulation has been more recently recognized as a potential approach to assist with patient weight loss, metabolic improvement, and obesity prevention. In previous investigations, pyruvate kinase M2 (PKM2) was identified as a novel modulator of brown adipogenesis. However, its specific molecular mechanisms and its role in brown adipogenesis remain implicit. To better understand the role of PKM2 in brown fat cell differentiation, mouse brown precursor cells were isolated and shRNA-mediated knockdown approach was employed to specifically alter PKM2 expression in brown pre-adipocytes. The effects of PKM2 deficiency on brown adipocyte differentiation and lipid accumulation were then investigated. In addition, we investigated changes in the expression of several hallmark genes of brown adipocytes. Our study demonstrates that PKM2 deficiency enhances brown fat cell differentiation and maintenance as evidenced by the markedly increased expression of differentiation and functional markers including FASN, PCB, perilipin, and UCP1. These results highlight PKM2 as a potential modulator of brown adipogenesis and suggestively, a therapeutic target for the treatment and prevention of obesity through increasing brown fat mass which may lead to enhanced energy expenditure and the subsequent prevention of excess body fat.

By 2050, at least 700 million people will require hearing therapy while 2.5 billion are projected to suffer from hearing loss. Sensorineural hearing loss (SNHL) arises from the inability of the inner ear to convert fluid waves into neural electric signals because of injury to cochlear hair cells that has resulted in their death. In addition, systemic chronic inflammation implicated in other pathologies may exacerbate cell death leading to SNHL. Phytochemicals have emerged as a possible solution because of the growing evidence of their anti-inflammatory, antioxidant, and anti-apoptotic properties. Ginseng and its bioactive molecules, ginsenosides, exhibit effects that suppress pro-inflammatory signaling and protect against apoptosis. In the current study, we investigated the effects of ginsenoside Rc (G-Rc) on UB/OC-2 primary murine sensory hair cell survival in response to palmitate-induced injury. G-Rc promoted UB/OC-2 cell survival and cell cycle progression. Additionally, G-Rc enhanced the differentiation of UB/OC-2 cells into functional sensory hair cells and alleviated palmitate-induced inflammation, endoplasmic reticulum stress, and apoptosis. The current study offers novel insights into the effects of G-Rc as a potential adjuvant for SNHL and warrants further studies elucidating the molecular mechanisms.