The mammalian target of rapamycin (mTOR) pathway is a central regulator of cellular growth, metabolism, and homeostasis, integrating a wide array of intracellular and extracellular cues, including nutrient availability, growth factors, and cellular stress, to coordinate anabolic and catabolic processes such as protein, lipid, and nucleotide synthesis; autophagy; and proteasomal degradation. The dysregulation of this signaling hub has broad implications for health and disease. To commemorate the 50th anniversary of the discovery of rapamycin, we provide a comprehensive synthesis of five decades of mTOR research. This review traces the historical trajectory from the early characterization of the biological effects of rapamycin to the elucidation of its molecular target and downstream pathways. We integrate fundamental and emerging insights into the roles of mTOR across nearly all domains of cell biology and development, with a particular focus on the expanding landscape of therapeutic interventions targeting this pathway. Special emphasis is placed on the crosstalk between mTOR signaling and mitochondrial regulation, highlighting the mechanisms by which these two metabolic hubs co-regulate cellular adaptation, survival, and disease progression. The dynamic interplay between mTOR and mitochondrial networks governs key aspects of bioenergetics, redox balance, and cell fate decisions and is increasingly implicated in pathophysiological contexts ranging from cancer and aging to neurodegenerative and immune disorders.
Tuberculosis (TB) is a contagious disease that threatens human health worldwide. Combination chemotherapy is usually recommended for this disease. Recently, 2 nitroimidazole-based agents, namely, delamanid and pretomanid, have been approved by regulatory agencies. JDB0131 is a novel, structurally optimized third-generation nitroimidazole antituberculosis agent that incorporates the advantages of earlier compounds. This multicenter, prospective, randomized phase 2a trial was conducted to evaluate its efficacy and safety in patients with tuberculosis (NCT06224036). In total, 52 patients with newly diagnosed TB were recruited. JDB0131 was tested in a dose escalation manner (cohort 1: 100 mg bid, cohort 2: 200 mg qd, and cohort 3: 200 mg bid). For comparison, delamanid (100 mg bid) and classic fixed-dose combination (FDC) regimens were included as controls. The primary endpoint was logarithmic changes in the number of colony formation units (CFUs) in the solid media culture of sputum TB (log10 CFU). The early bactericidal activity (EBA) of JDB0131 was better than that of delamanid. During the time interval between days 0 and 14, JDB0131 at a dose of 200 mg bid (cohort 3) showed superior efficacy over delamanid. At the end of drug intervention (day 14), JDB0131 (all 3 dose levels) achieved superior time to positivity (TTP) over delamanid. Ninety-one adverse events (AEs), including no serious AEs, were attributed to JDB0131 in 30 patients. This trial identified a promising new drug for the increasing TB burden worldwide.
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