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Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

Background: Current pharmacological therapies and treatments targeting pancreatic neuroendocrine tumors (PNETs) have proven ineffective, far too often. Therefore, there is an urgent need for alternative therapeutic approaches. Zyflamend, a combination of anti-inflammatory herbal extracts, that has proven to be effective in various in vitro and in vivo cancer platforms, shows promise. However, its effects on pancreatic cancer, in particular, remain largely unexplored. Methods: In the current study, we investigated the effects of Zyflamend on the survival of beta-TC-6 pancreatic insulinoma cells (β-TC6) and conducted a detailed analysis of the underlying molecular mechanisms. Results: Herein, we demonstrate that Zyflamend treatment decreased cell proliferation in a dose-dependent manner, concomitant with increased apoptotic cell death and cell cycle arrest at the G2/M phase. At the molecular level, treatment with Zyflamend led to the induction of ER stress, autophagy, and the activation of c-Jun N-terminal kinase (JNK) pathway. Notably, pharmacological inhibition of JNK abrogated the pro-apoptotic effects of Zyflamend. Furthermore, Zyflamend exacerbated the effects of streptozotocin and adriamycin-induced ER stress, autophagy, and apoptosis. Conclusion: The current study identifies Zyflamend as a potential novel adjuvant in the treatment of pancreatic cancer via modulation of the JNK pathway.

Background Acute kidney injury (AKI) is associated with a severe decline in kidney function caused by abnormalities within the podocytes' glomerular matrix. Recently, AKI has been linked to alterations in glycolysis and the activity of glycolytic enzymes, including pyruvate kinase M2 (PKM2). However, the contribution of this enzyme to AKI remains largely unexplored. Methods Cre-loxP technology was used to examine the effects of PKM2 specific deletion in podocytes on the activation status of key signaling pathways involved in the pathophysiology of AKI by lipopolysaccharides (LPS). In addition, we used lentiviral shRNA to generate murine podocytes deficient in PKM2 and investigated the molecular mechanisms mediating PKM2 actions in vitro. Results Specific PKM2 deletion in podocytes ameliorated LPS-induced protein excretion and alleviated LPS-induced alterations in blood urea nitrogen and serum albumin levels. In addition, PKM2 deletion in podocytes alleviated LPS-induced structural and morphological alterations to the tubules and to the brush borders. At the molecular level, PKM2 deficiency in podocytes suppressed LPS-induced inflammation and apoptosis. In vitro, PKM2 knockdown in murine podocytes diminished LPS-induced apoptosis. These effects were concomitant with a reduction in LPS-induced activation of β-catenin and the loss of Wilms’ Tumor 1 (WT1) and nephrin. Notably, the overexpression of a constitutively active mutant of β-catenin abolished the protective effect of PKM2 knockdown. Conversely, PKM2 knockdown cells reconstituted with the phosphotyrosine binding–deficient PKM2 mutant (K433E) recapitulated the effect of PKM2 depletion on LPS-induced apoptosis, β-catenin activation, and reduction in WT1 expression. Conclusions Taken together, our data demonstrates that PKM2 plays a key role in podocyte injury and suggests that targetting PKM2 in podocytes could serve as a promising therapeutic strategy for AKI. Trial registration Not applicable.

The use of bioelectrical impedance analysis (BIA) in clinical settings is common. However, the value of BIA-based parameters in diagnosing metabolic syndrome (MetS) in children is under-investigated. Herein, we aimed to study the usefulness of BIA-indices in the diagnoses of MetS in 6–10-year-old girls. Therefore, a diagnostic accuracy case-control study was conducted, which included 75 girls aged 10–16 years, divided into three age-matched groups (normal, None-MetS, and MetS). Anthropometric indices, BIA parameters (including fat-free mass (FFM), body fat percent (BFP), and total body water (TBW)), blood pressure (BP), and blood samples were collected. Our main findings show that for girls in None-MetS and MetS groups, the waist circumference (WC) correlated positively with waist-hip ratio and mid-arm circumference (r = 0.58, 0.47, respectively), but not with BFP based on skinfold thickness (SFT), or mid-arm muscle area. WC was positively correlated with FFM and TBW, while high-density lipoprotein was inversely correlated with FFM. However, fasting blood glucose, triglycerides and BP showed no association with anthropometric measurements and BIA components. WC was the best indicator of MetS (AUC = 0.88, cut-off = 81.5 cm), followed by BMI (AUC = 0.84, cut-off = 26.9 kg/m2), while BFP based on SFT was the least sensitive (62.5%). In conclusion, apart from the FM index, anthropometric parameters such as WC are more valuable in diagnosing MetS in young adolescent girls.

Background Pancreatic cancer is the fourth leading cause of death in the United States with over 53,670 new cases and 80% mortality in 2017. The 5‐year relative survival rate for patients with pancreatic cancer is 8.2%. Currently available therapies have only moderate efficacy, but notable limitations. Hence, there is an urgent need for alternative therapeutic approaches. Zyflamend, touted as a natural herbal extract to treat inflammation, is credited as being able to benefit many other conditions such as cancer including oral, mammary, bone, skin, colorectal, and prostate cancer. However, its effects on pancreatic cancer in particular, remain largely unexplored. Objective The objective of this study is to investigate the effects of Zyflamend on pancreatic cancer survival and decipher the underlying molecular mechanisms Methods Pancreatic cancer cells were treated with Zyflamend and key signaling pathways involved in the survival and proliferation of cells were investigated. Results Zyflamend treatment caused a dose‐dependent decrease in cell proliferation, consistent with an increase in apoptotic cell death. The effects of Zyflamend were mediated, at least partially, through alterations in autophagy and endoplasmic reticulum stress. Conclusion These studies identify Zyflamend as a potential novel approach to treat pancreatic cancer. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Objectives The prevalence of obesity and its comorbidities has sparked a worldwide concern to address rates of adipose tissue accrual. Recent studies have demonstrated a novel role of Zyflamend, a natural herbal extract, in regulating lipid metabolism in several cancer cell lines through the activation of the AMPK signaling pathway. Yet, the role of Zyflamend in adipogenic differentiation and lipid metabolism remains largely unexplored. The objective of this study is to investigate the effects of Zyflamend on white 3T3-MBX pre-adipocyte differentiation and elucidate the molecular mechanisms. Methods 3T3-MBX pre-adipocytes were treated with Zyflamend, and the expression of various key adipogenic and lipolytic regulators was examined. We also investigated the effects of Zyflamend on pre-adipocyte survival, proliferation, and cell cycle. Results Zyflamend treatment altered cell cycle progression, attenuated proliferation, and increased cell death of 3T3-MBX pre-adipocytes. In addition, treatment with Zyflamend inhibited lipid accumulation during the differentiation of 3T3-MBX cells, consistent with decreased expression of lipogenic genes and increased lipolysis. Mechanistically, Zyflamend-induced alterations in adipogenesis were mediated, at least in part, through the activation of AMPK, PKA, and JNK. Inhibition of AMPK partially reversed Zyflamend-induced inhibition of differentiation, whereas the inhibition of either JNK or PKA fully restored adipocyte differentiation and decreased lipolysis. Conclusions Taken together, the present study demonstrates that Zyflamend, as a novel anti-adipogenic bioactive mix, inhibits adipocyte differentiation through the activation of PKA and JNK pathways.Our findings suggest that Zyflamend supplementation might help in developing novel anti-obesity therapeutic strategies. Funding Sources This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.

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