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Lin SP, Chiu FY, Wang Y, Yen ML, Kao SY, Hung SC

Abbreviations ALT: Alanine transaminase AST: Aspartate transaminase AKT/mTOR: Protein kinase B (also known as AKT)/mechanistic target of rapamycin hTERT-HSC: Immortal activated human hepatic stellate cells IL: Interleukin JAK/STAT: Janus kinasesignal transducer and activator of transcriptions JNK pathways: c-Jun N-terminal kinase (a type of MAPK pathway) MAPK/ERK: Mitogen-activated protein kinase/extracellular signal-regulated kinase MTX: Methotrexate MTX-PGs: Methotrexate-polyglutamate STAT3: Signal transducer and activator of transcription 3 TGF-1: Transforming growth factor receptor beta-1 TLRs: Toll like receptors TNF-: Tissue necrosis factors-alpha TWEAK Pathways: TNF-like weak inducer of apoptosis References Komiski P, Halik PK, Chesori R, Gniazdowska E (2020) Overview of dual-acting drug methotrexate in different neurological diseases, autoimmune pathologies and cancers

Table 2 summarizes NADs successfully applied in clinical experiments for treating human diseases

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However, despite extensive clinical and preclinical research efforts, there is still a fundamental lack of understanding about the specific biological changes that give rise to depressive symptoms

No large-scale, long-term RCT in European populations has been completed