The interplay of p38 MAPK signaling and mitochondrial metabolism, a dynamic target in cancer and pathological contexts.

Mitochondria play a crucial role in cellular metabolism and bioenergetics, orchestrating various cellular processes, including energy production, metabolism, adaptation to stress, and redox balance. Besides, mitochondria regulate cellular metabolic homeostasis through coordination with multiple signaling pathways. Importantly, the p38 mitogen-activated protein kinase (MAPK) signaling pathway is a key player in the intricate communication with mitochondria, influencing various functions. This review explores the multifaced interaction between the mitochondria and p38 MAPK signaling and the consequent impact on metabolic alterations. Overall, the p38 MAPK pathway governs the activities of key mitochondrial proteins, which are involved in mitochondrial biogenesis, oxidative phosphorylation, thermogenesis, and iron homeostasis. Additionally, p38 MAPK contributes to the regulation of mitochondrial responses to oxidative stress and apoptosis induced by cancer therapies or natural substances by coordinating with other pathways responsible for energy homeostasis. Therefore, dysregulation of these interconnected pathways can lead to various pathologies characterized by aberrant metabolism. Consequently, gaining a deeper understanding of the interaction between mitochondria and the p38 MAPK pathway and their implications presents exciting forecasts for novel therapeutic interventions in cancer and other disorders characterized by metabolic dysregulation.

Autophagy inhibition potentiates energy restriction-induced cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy. Additionally, ERMAs have been found to induce autophagy in cancer cells. The role of autophagy in cancer survival remains a subject of debate. Thus, it is crucial to ascertain whether ERMA-induced autophagy is a mechanism for cell survival or cell death in HCC. Our study aims to investigate the effect of autophagy inhibition on the survival of HCC cells treated with ERMAs while also examining the potential of combining an autophagy inhibitor such as spautin-1 with ERMAs to enhance HCC cell death. Our results suggest a cytoprotective role for ERMA-induced autophagy in HCC cells, as combining the autophagy inhibitor spautin-1 with ERMAs effectively suppressed ERMA-induced autophagy and synergistically enhanced their antitumor activity. The treatment combination promoted HCC death through apoptosis, cell cycle arrest, and inhibition of AKT and ERK activation, which are known to play a key role in cellular proliferation. Collectively, our findings highlight a potential strategy to combat HCC by combining energy restriction with autophagy inhibition.

SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies.

PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans. Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission. The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines. METHODOLOGY: A literature review was conducted to summarize, analyze, and interpret the available scientific data related to SARS-CoV-2 S protein in terms of characteristics, vaccines development and potential therapies. RESULTS: The data indicate that S protein subunits and their variable conformational states significantly affect the virus pathogenesis, infectivity, and evolutionary mutation. A considerable number of potential natural and synthetic therapies were proposed based on S protein. Additionally, neutralizing antibodies were recently approved for emergency use. Furthermore, several vaccines utilizing the S protein were developed. CONCLUSION: A better understanding of S protein features, structure and mutations facilitate the recognition of the importance of SARS-CoV-2 S protein in viral infection, as well as the development of therapies and vaccines. The efficacy and safety of these therapeutic compounds and vaccines are still controversial. However, they may potentially reduce or prevent SARS-CoV-2 infection, leading to a significant reduction of the global health burden of this pandemic.