Search

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease [NAFLD]) and metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) are leading chronic liver diseases, driving cirrhosis, hepatocellular carcinoma, and mortality. MASLD/MASH is associated with increased senescence proteins, including Activin A, and senolytics have been proposed as a therapeutic approach. To test the role of Activin A, we induced hepatic expression of Activin A in a murine MASLD/MASH model. Surprisingly, overexpression of hepatic Activin A dramatically mitigated MASLD, reducing liver steatosis and inflammation as well as systemic fat accumulation, while improving insulin sensitivity. Further studies identified a dramatic decrease in the lipid-associated macrophages marker glycoprotein NMB (Gpnmb) by Activin A, and Gpnmb knockdown in the same model produced similar benefits and transcriptional changes to Activin A expression. These studies reveal a surprising protective role for Activin A in MASLD and the potential for SASP proteins to have context-specific beneficial effects. Moreover, they implicate both Activin A and Gpnmb as potential therapeutic targets for this condition. Article Highlights: Cellular senescence may promote metabolic dysfunction-associated steatotic liver disease/ metabolic dysfunction-associated steatohepatitis (MASLD/MASH), leading to chronic liver diseases associated with obesity and metabolic disease with no approved medical treatment. Circulating Activin A, a senescence-associated secretory phenotype (SASP) protein, increases in MASLD/MASH patients. Surprisingly, hepatic Activin A overexpression or Gpnmb knockdown dramatically mitigated MASLD phenotypes and fat accumulation, SASP gene expression, and dysglycemia, underscoring the need for nuanced understanding of SASP biology. Hepatic Activin A overexpression dramatically decreased liver Gpnmb, a lipid-associated macrophage upregulated in MASLD, and Gpnmb knockdown produced similar benefits and transcriptional changes to Activin A overexpression, identifying Gpnmb as a tractable potential therapeutic target. [ABSTRACT FROM AUTHOR]

Both hedgehog (Hh) and target of rapamycin complex 2 (TORC2) are central, evolutionarily conserved signaling pathways that regulate development and metabolism. In C. elegans, loss of the essential TORC2 component RICTOR (rict-1) causes delayed development, shortened lifespan, reduced brood, small size and increased fat. Here, we report that knockdown of both the hedgehog-related morphogen grd-1 and its patched-related receptor ptr-11 rescues delayed development in TORC2 loss-of-function mutants, and grd-1 and ptr-11 overexpression delays wild-type development to a similar level to that in TORC2 loss-of-function animals. These findings potentially indicate an unexpected role for grd-1 and ptr-11 in slowing developmental rate downstream of a nutrient-sensing pathway. Furthermore, we implicate the chronic stress transcription factor pqm-1 as a key transcriptional effector in this slowing of whole-organism growth by grd-1 and ptr-11. We propose that TORC2, grd-1 and ptr-11 may act linearly or converge on pqm-1 to delay organismal development. [ABSTRACT FROM AUTHOR]

The article presents the author's views on the compliments and complaints of patients regarding the nature of the care they received from physicians. The author, who was an intern at an academic medical center, says the most common and persistent question that would be ready for him every morning was can I eat yet. The author also discusses how patients deal with nil per os (NPO) a medical instruction meaning to withhold oral food and fluids from a patient for various reasons.

The article discusses on a case of a 52-year-old man with a metastatic solitary fibrous tumor who experienced recurrent episodes of hypoglycemia. It also include the patient's medical history, diagnostic findings, treatment approaches and clinical course, including disease progression and management of complications.