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  • Through experimental models and clinical experiments those f


    Through experimental models and clinical experiments, those four drugs above can shown efficacy-enhancing and toxicity-reducing effects after compatibility. Our preclinical studies showed that XFC has a definite effect on relieving joint symptoms in RA patients. XFC can improve joint pain, swelling, and early morning stiffness, and it can also improve extra-articular manifestations such as anemia, platelet disease, lipid metabolism disorder, cardiopulmonary function, depression, and quality of life.32, 33 XFC can also reduce paw swelling and AI in an AA rat model, and can improve the cardiopulmonary function and behavior of AA rats. The possible mechanism based on modulation of TGF-β1/Smads, Notch-Jagged/Delta, and several other signaling pathways, as well as regulation of the valeriana te of Tregs and forkhead box P3, have also been studied.34, 35 The mechanism research of the XFC is helpful in understanding the rationale behind the clinic, which is consistent with the requirements of modern pharmaceutical development.
    Introduction Fas-associated factor 1 (FAF1) was first identified as a member of the Fas death-inducing signaling complex [[1], [2], [3]], but data accumulated so far suggest that it is able to interact with a large number of other proteins and is involved in diverse biological processes. For example, FAF1 was previously shown to act as a suppressor of tumor necrosis factor (TNF)-induced nuclear factor (NF)-κB activity by binding to the RelA subunit and IκB kinase β (IKKβ) [4,5]. Importantly, targeted disruption of the mouse Faf1 gene results in embryonic lethality at the two-cell stage [6]. Notably, FAF1 was implicated in the ubiquitin-proteasome pathway, playing a role as a scaffolding protein or ubiquitin receptor and regulating protein degradation [7]. FAF1 contains multiple ubiquitin-related domains that include a ubiquitin-associated (UBA), ubiquitin-like 1 (UBL1), UBL2, and ubiquitin-regulatory X (UBX). The N-terminal UBA domain interacts with polyubiquitinated proteins required for FAF1-mediated apoptosis [7]. The C-terminal UBX domain binds to the valosin-containing protein (VCP; AAA ATPase p97) complexed with the Npl4-Ufd1 heterodimer [7]. The association of FAF1 with the VCP-Npl4-Ufd1 complex and polyubiquitinated proteins promotes endoplasmic reticulum-associated degradation (ERAD) [8]. Additionally, FAF1 inhibits the Wnt/β-catenin pathway by promoting β-catenin degradation [9]. FAF1 also recruits the VCP/β-TrCP complex to target transforming growth factor (TGF)-β type II receptor for polyubiquitination [10]. Further studies showed that FAF1 is a substrate of the E3 ligase, parkin, and is involved in dopaminergic neurodegeneration [11]. Recently, FAF1 was considered to be a tumor suppressor because of its cell death-promoting activity and downregulated expression in various human cancers (reviewed in [12]). It is also noteworthy that FAF1 was found to localize in the nucleus [[13], [14], [15]]. A previous study demonstrated that FAF-1 is a mineralocorticoid receptor (MR)-interacting partner and could modulate the transactivation potential of the MR in neural cells [16], although the underlying mechanism is currently unclear. The MR is a member of the nuclear receptor (NR) superfamily and plays a critical role in controlling ion homeostasis in epithelial tissues such as the kidneys and colon. It belongs to the subgroup of steroid hormone receptors and interacts with both mineralocorticoids and glucocorticoids to mediate transcription of target genes [17]. The MR's functions are directed by specific activation domains, termed activation function 1 (AF1), which resides in the N-terminus, and AF2, which resides in the C-terminal ligand-binding domain (reviewed in [18]). Ligand-mediated interdomain interactions between the N-terminal domain and the C-terminal region (N/C-interaction) of some steroid hormone receptors including the MR have been reported. Furthermore, transcriptional control by the MR is regulated by the dynamics and coordinated recruitment of proteins characterized as coregulators, comprised of coactivators and corepressors (reviewed in [19]). Maximal transcriptional activity requires the synergistic effects of both AF1 and AF2 through their interactions with differential coregulators [20]. Coactivators of the MR act as adapter molecules that spatially recruit histone acetylase CBP/p300 and the basal transcription machinery to overcome the repressive effects of chromatin packing. These coactivators bind the AF2 region of the MR via a conserved NR-box that contains one or more leucine-rich LXXLL motifs [21]. In contrast, corepressors interact with the unliganded NR via a CoRNR box motif, defined as I/L-XX-I/V-I and recruit histone deacetylase proteins to interfere with transactivation [22]. Several MR corepressors have been described, including the widely repressive SMRT and NCoR complexes; the histone chaperone Daxx; Gem (nuclear organelle)-associated protein 4 (GEMIN4); NFYC (nuclear transcription factor Y subunit gamma); and the SUMO E3-ligase PIAS proteins [16,[23], [24], [25], [26]]. Of interest, sumoylation has now emerged as an extremely important post-translational modification (PTM) for regulating many NRs and coregulators, including the MR [23,27,28]. Moreover, MR can be polyubiquitinated, and that proteasome activity seems to be essential for MR-activated transcription. [27]. These observations further increase the complexity of PTM-mediated regulation of NR transcription.