Increased aerobic glycolysis in keratinocytes has been reported as a hallmark of skin diseases while its pharmacological inhibition restores keratinocyte homeostasis. Pyruvate kinase muscle (PKM) isoforms are key enzymes in the glycolytic pathway and, therefore, an attractive therapeutic target. Simon Nold and colleagues used CRISPR/Cas9‐mediated gene editing to investigate the outcomes of PKM splicing perturbations and specific PKM1 or PKM2 deficiency in human HaCaT keratinocytes. Collectively, the study demonstrated different effects of PKM1 or PKM2 depletion on the reciprocal PKM isoform and on keratinocyte gene expression, metabolism and proliferation. Findings from this study provide novel insights into the role of PKM in keratinocyte homeostasis, warranting additional investigations into the underlying molecular mechanisms and potential therapeutic applications.

Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate. M1 and M2 are alternatively spliced isoforms of the Pkm gene. The PKM1 isoform promotes oxidative metabolism, whereas PKM2 enhances aerobic glycolysis. We hypothesize that the PKM isoforms are involved in the shift away from butyrate oxidation towards glycolysis in CRC cells. Here, we find that PKM2 is increased and PKM1 is decreased in human colorectal carcinomas as compared to non-cancerous tissue. To test whether PKM1/2 alter colonocyte metabolism, we created a knockdown of PKM2 and PKM1 in CRC cells to analyze how butyrate oxidation and glycolysis would be impacted. We report that butyrate oxidation in CRC cells is regulated by PKM1 levels, not PKM2. Decreased butyrate oxidation observed through knockdown of PKM1 and PKM2 is rescued through re-addition of PKM1. Diminished PKM1 lowered mitochondrial basal respiration and decreased mitochondrial spare capacity. We demonstrate that PKM1 suppresses glycolysis and inhibits hypoxia-inducible factor-1 alpha. These data suggest that reduced PKM1 is, in part, responsible for increased glycolysis and diminished butyrate oxidation in CRC cells.

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.

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.

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.