Home The role of Phafin proteins in cell signaling pathways and diseases
Article Open Access

The role of Phafin proteins in cell signaling pathways and diseases

  • Tuoxian Tang EMAIL logo , Jing Sun and Chen Li EMAIL logo
Published/Copyright: June 27, 2024
Download Article (PDF)
Open Life Sciences
From the journal Open Life Sciences Volume 19 Issue 1

Abstract

Membrane-associated proteins are important membrane readers that mediate and facilitate the signaling and trafficking pathways in eukaryotic membrane-bound compartments. The protein members in the Phafin family are membrane readers containing two phosphoinositide recognition domains: the Pleckstrin Homology domain and the FYVE (Fab1, YOTB, Vac1, and early endosome antigen 1) domain. Phafin proteins, categorized into two subfamilies, Phafin1 and Phafin2, associate with cellular membranes through interactions involving membrane-embedded phosphoinositides and phosphoinositide-binding domains. These membrane-associated Phafin proteins play pivotal roles by recruiting binding partners and forming complexes, which contribute significantly to apoptotic, autophagic, and macropinocytotic pathways. Elevated expression levels of Phafin1 and Phafin2 are observed in various cancers. A recent study highlights a significant increase in Phafin1 protein levels in the lungs of idiopathic pulmonary fibrosis patients compared to normal subjects, suggesting a crucial role for Phafin1 in the pathogenesis of pulmonary fibrosis. Additionally, phosphatidylinositol-3-phosphate-binding 2 (Pib2), a close relative of the Phafin1 protein, functions as an amino acid sensor activating the TOCR1 pathway in yeasts. This review focuses on delineating the involvement of Phafin proteins in cellular signaling and their implications in diseases and briefly discusses the latest research findings concerning Pib2.

Graphical abstract

Keywords: Phafin1; Phafin2; Pib2; idiopathic pulmonary fibrosis; cancer

1 Introduction

Membrane proteins are broadly classified into integral and peripheral proteins. Constituting approximately 5% of all human proteins, peripheral membrane proteins are reversibly associated with the lipid bilayer of cellular membranes in a spatiotemporally dependent manner [1,2]. Typically, these peripheral membrane proteins contain lipid-binding domains that recognize specific lipids in the membrane which drive the transient association to a specific membrane. The membrane-associated proteins serve as adaptors and regulatory proteins, rendering them vital in cell signaling and trafficking pathways [3]. About 30 peripheral membrane proteins are currently targeted in drug discovery as the lipid–protein interaction can be potentially regulated [3,4].

In 2005, Phafins were initially defined as proteins containing both Pleckstrin Homology (PH) and Fab1, YOTB, Vac1, and EEA1 (FYVE) domains. The Phafin protein family consists of two subfamilies: Phafin1 and Phafin2 [5]. Phafin1 is also known as LAPF (a lysosome-associated apoptosis-inducing protein containing PH and FYVE domains) or PLEKHF1 (pleckstrin homology and FYVE domain containing 1). Phafin2 is also referred to as EAPF (an endoplasmic reticulum (ER)-associated apoptosis-involved protein containing PH and FYVE domains) and PLEKHF2 (pleckstrin homology and FYVE domain containing 2) [6]. Early studies have identified Phafins as pro-apoptotic proteins. Phafin1 is a lysosome-associated protein that recruits phosphorylated p53 to lysosomes and induces lysosomal membrane permeabilization in apoptosis [7]. Phafin2 is an ER-associated protein that facilitates tumor necrosis factor-alpha (TNF-α)-induced cellular apoptosis through the ER–mitochondrial apoptotic pathway [8].

Recent years have brought forth numerous exciting discoveries regarding the Phafin protein family. After induction of autophagy, Phafin2 was associated with the lysosomal membrane through PtdIns(3)P-binding, and the Phafin2–Akt complex accumulated in the lysosome, which indicated that Phafin2 is involved in autophagy [9]. Both the Phafin2 PH domain and the Phafin2 FYVE domain bind PtdIns(3)P but exhibit distinct PtdIns(3)P-binding properties. An autoinhibition mechanism was identified in Phafin2, where the Phafin2 FYVE domain constitutively binds to PtdIns(3)P, while the Phafin2 PH domain’s PtdIns(3)P-binding is autoinhibited by the conserved C-terminal polyD motif of Phafin2 [10]. A recent study reported Phafin2 as a coincidence detector of PtdIns(3)P and PtdIns(4)P, promoting the internalization and maturation of macropinosomes by coordinating the actin dynamics [11]. Phafin1 has been implicated in the activation of M2 macrophage and exacerbation of pulmonary fibrosis [12]. Moreover, significant progress has been made in the research on a Phafin1-like protein, Pib2, which is identified as a critical regulator of yeast target of rapamycin complex 1 (TORC1) [13]. In this review, we provide a summary of major findings and unanswered questions about the Phafin protein family, with a focus on their roles in signaling pathways and implications in diseases. The latest findings on Pib2 are also briefly discussed due to its close resemblance to Phafin1.

2 Structural features of Phafin proteins and Pib2

2.1 Phafin proteins have two phosphoinositide-binding domains

Phafin proteins are distinguished by the presence of two phosphoinositide-binding domains in their structural elements: the N-terminal PH domain, comprising approximately 120 amino acid residues, and the central FYVE domain, consisting of about 70 amino acid residues (Figure 1a). Rush, a Drosophila homolog of human Phafin1 and Phafin2, exhibits a similar modular organization [14]. The Rush protein is longer than human Phafin1 and Phafin2, containing 316 amino acid residues. Pib2, a relative of Phafin1, is an FYVE domain-containing protein that lacks the PH domain. The other conserved regions of Pib2 include the N-terminal A–D motifs, a helical-E region, and a C-terminal tail (Figure 1a and b) [15,16].

Figure 1 Modular organization of Phafin proteins and Pib2. (a) Schematic diagram of full-length Phafin1, Phafin2, Rush, and Pib2 with defined domains and motifs. (b) Sequence alignment analysis of C-terminal regions of Phafin proteins and Pib2. The C-terminal region of human Phafin1 (240–279 aa), the polyD tail of human Phafin2 (240–249 aa), and the C-terminal domain of Pib2 (620–635 aa) were aligned using the Clustal Omega Multiple Sequence Alignment program.
Figure 1

Modular organization of Phafin proteins and Pib2. (a) Schematic diagram of full-length Phafin1, Phafin2, Rush, and Pib2 with defined domains and motifs. (b) Sequence alignment analysis of C-terminal regions of Phafin proteins and Pib2. The C-terminal region of human Phafin1 (240–279 aa), the polyD tail of human Phafin2 (240–249 aa), and the C-terminal domain of Pib2 (620–635 aa) were aligned using the Clustal Omega Multiple Sequence Alignment program.

The structures of Phafin proteins and Pib2 have not yet been determined. Our structural analysis of Phafin2 has provided valuable insights into the structural features of Phafin proteins. The human Phafin2 is a moderately elongated monomer with an estimated molecular weight of approximately 28 kDa. Circular dichroism analysis suggests that Phafin2 adopts an α/β structure, with an estimated secondary structural content of 23% α-helix, 21% β-strand, 15% β-turn, and 41% random coil [17,18]. Herein, the protein structures of Phafin1, Phafin2, Rush, and Pib2 were predicted using AlphaFold2, an artificial intelligence program used for protein structure prediction (Figure 2a–d) [19]. The N-terminal PH domain exhibits a seven-stranded β-sheet sandwich with a long α-helix and the central FYVE domain displays a pair of two-stranded β-sheets and a small α-helix. Notably, in comparison with the structures of Phafin1, Phafin2, and Rush, Pib2 demonstrates a more relaxed structural arrangement, with a significant portion represented by the random coil (Figure 2a–d). However, it is necessary to point out that predicted protein structures may not accurately represent the real structures of Phafin proteins and Pib2, warranting further structural studies to decipher their structural features and protein–ligand interactions.

Figure 2 Predicted protein structures of Phafin proteins and Pib2. Predicted protein structures of Phafin1 (a), Phafin2 (b), Rush (c), and Pib2 (d). The protein structures were predicted using AlphaFold2. Following protein sequences were used to build the protein structures: Homo sapiens Phafin1, UniProt accession number Q96S99; Homo sapiens Phafin2, UniProt accession number Q9H8W4; Drosophila melanogaster Rush, UniProt accession number O76902; Saccharomyces cerevisiae Pib2, UniProt accession number P53191.
Figure 2

Predicted protein structures of Phafin proteins and Pib2. Predicted protein structures of Phafin1 (a), Phafin2 (b), Rush (c), and Pib2 (d). The protein structures were predicted using AlphaFold2. Following protein sequences were used to build the protein structures: Homo sapiens Phafin1, UniProt accession number Q96S99; Homo sapiens Phafin2, UniProt accession number Q9H8W4; Drosophila melanogaster Rush, UniProt accession number O76902; Saccharomyces cerevisiae Pib2, UniProt accession number P53191.

The association between Phafin proteins and cellular membranes was mediated by their phosphoinositide-binding domains. Both Phafin1 and Phafin2 showed a preference for PtdIns(3)P binding in the lipid–protein overlay assay [20,21]. PtdIns(3)P, or phosphatidylinositol 3-phosphate, is one of the seven phosphoinositides, a group of phospholipids characterized by phosphorylation at the 3-, 4-, and/or 5-positions of the inositol ring. Phosphoinositides are differentially distributed in cellular membranes, playing key roles in cell signaling transduction and membrane remodeling [22,23]. PH domains and FYVE domains exhibit distinct phosphoinositide-binding specificities. The Phafin2 PH domain was shown to bind PtdIns(3)P, PtdIns(4)P, and PtdIns(5)P, while the Phafin2 FYVE domain specifically binds PtdIns(3)P [9,11].

2.2 The C-terminal tail region is a functional motif

In addition to the two conserved phosphoinositide-binding domains, the C-terminal regions of Phafin proteins serve as functional motifs. Specifically, the C-terminal tail of Phafin1 functions as a lysosomal targeting signal. In studies, the wild-type Phafin2, lacking this C-terminal tail, and the Phafin1 mutant with the tail domain deleted, were unable to associate with lysosomes [20]. Similar to Phafin1, Pib2 also possesses a functional C-terminal motif, and there is a notable similarity between their amino acid sequences, which explains why Pib2 is considered a close relative of Phafin1 rather than Phafin2, despite all three sharing a conserved FYVE domain (Figure 1a and b) [15]. It has been reported that the Pib2 tail motif plays a role in TORC1 activation [24,25]. Further details regarding the role of Pib2 in TORC1 regulation will be provided in Section 3.3.

Phafin2 is 30 amino acid residues shorter than Phafin1, as depicted in Figure 1a. Consequently, the amino acid residues beyond the central FYVE domain constitute a shorter C-terminal region. Within the C-terminus of Phafin2 (Figure 1b), a motif rich in aspartic acid residues, referred to as polyD (corresponding to residues 240–249 of Phafin2), was identified. This polyD motif is conserved among Phafin proteins across various species [10]. The polyD motif was shown to intramolecularly inhibit the Phafin2 PH domain’s PtdIns(3)P-binding without disrupting the Phafin2 FYVE domain’s PtdIns(3)P-binding, which represents an autoinhibition mechanism in Phafin2 (Figure 3) [10]. Our unpublished data suggest that the polyD peptide directly interacts with the Phafin2 PH domain, causing perturbations of some PH domain resonances in the NMR spectra. In contrast, the Phafin2 FYVE domain does not interact with the polyD motif, indicating that this motif specifically targets the Phafin2 PH domain [26].

Figure 3 Proposed autoinhibition-relief mechanisms of Phafin2.
Figure 3

Proposed autoinhibition-relief mechanisms of Phafin2.

Autoinhibition is a molecular mechanism by which proteins employ inhibitory modules to regulate the function of other domains through intramolecular interactions [27]. This widespread regulatory strategy plays a significant role in modulating the DNA binding of transcription factors, regulating enzyme activity, and controlling the cellular localization of proteins. Together with counteracting measures to relieve autoinhibition, it adds an extra layer of regulation to cellular systems [27,28]. Functionally, the Phafin2 polyD motif regulates the lipid-binding activity of the PH domain, suppressing excessive membrane association [11]. Autoinhibition in Phafin2 can potentially be alleviated through various mechanisms, including binding to other partners, post-translational modifications, and partial proteolysis of the polyD motif (Figure 3).

Previous studies have identified several binding partners of Phafin2, including Akt (protein kinase B) [9], early endosome antigen 1 (EEA1) [29], and JNK-interacting protein 4 (JIP4) [30]. Interaction with these proteins may induce conformational changes, leading to the relief of autoinhibition. Three residues S239, S247, and S248 within the polyD region of Phafin2 are available for phosphorylation [31], which may present an additional mechanism to counteract the autoinhibition. Further studies are necessary to elucidate how the autoinhibition mechanism in Phafin2 is regulated. It is worth noting that Phafin1 also exhibits an aspartic acid residue-rich motif, followed by additional amino acid residues. However, it remains unknown whether this motif plays regulatory roles in Phafin1 proteins.

3 Phafin proteins and Pib2 in cell signaling pathways

3.1 Role of Phafin1 in apoptosis and autophagy

Apoptosis, a process of programmed cell death, is employed by cells to eliminate unwanted cells during development and aging [32,33]. Phafin1 is a proapoptotic protein, acting as an adaptor that recruits phosphorylated p53 to the lysosomal membrane. The formation of phosphorylated p53 and Phafin1 complex on the lysosomal membrane triggers lysosomal membrane permeabilization and activates the apoptotic pathway. Phafin1 specifically interacts with phosphorylated p53 through its PH domain. Silencing Phafin1 expression hinders the lysosomal translocation of phosphorylated p53, resulting in reduced lysosomal membrane permeabilization and apoptosis [7].

Increased expression of Phafin1 in HEK 293T cells led to the formation of enlarged vesicles and the regulation of certain receptors’ density on the cell membrane, indicating that Phafin1 is involved in endocytosis. Similarly, overexpression of the endosome-associated Rush in Drosophila follicular cells resulted in the enlargement of late endosomes and disrupted the progression of endosomal cargoes [14].

Phafin1-containing vesicles in the cells exhibited positive signals for LysoTracker, a fluorescent dye used for labeling lysosomes, suggesting that Phafin1 is targeted to the lysosomes. Co-transfection of Phafin1 and hLC3A into cells was able to induce autophagy. Autophagy, or macroautophagy, represents a highly conserved eukaryotic cellular digestion mechanism in which cells break down unnecessary or dysfunctional components through lysosomes, subsequently recycling the resulting molecules [34,35]. The C-terminal tail of Phafin1 played a crucial role in lysosomal association and autophagy induction, as a tail domain deletion mutant of Phafin1 failed to associate with lysosomes or induce autophagy [20]. Phafin1 has been identified as an autophagy-related biomarker in dilated cardiomyopathy using machine learning algorithms and bioinformatics tools [36].

3.2 Role of Phafin2 in cell signaling pathways

3.2.1 Apoptosis

Like Phafin1, Phafin2 also functions as a pro-apoptotic protein. A proposed model elucidates the role of Phafin2 in enhancing TNF-α-induced cellular apoptosis: Phafin2 expression levels increase upon TNF-α treatment; Phafin2 partially translocates to the ER through its phospholipid-binding and becomes locally activated; this leads to enhanced calcium efflux from the ER, disrupting Ca2+ homeostasis; the perturbed Ca2+ balance activates ER-resident caspase 12 and caspase 3 cascades, promoting TNF-α-triggered mitochondrial membrane permeabilization and the release of apoptosis-inducing factors (Figure 4a) [8].

Figure 4 Role of Phafin2 in cell signaling pathways. (a) Phafin2 is a pro-apoptotic protein. (b) Phafin2 promotes endosomal fusion. (c) Formation of the Phafin2–Akt complex on lysosomes is a critical step in autophagy. (d) Phafin2 facilitates macropinocytotic membrane tubulation in orchestration with JIP4.
Figure 4

Role of Phafin2 in cell signaling pathways. (a) Phafin2 is a pro-apoptotic protein. (b) Phafin2 promotes endosomal fusion. (c) Formation of the Phafin2–Akt complex on lysosomes is a critical step in autophagy. (d) Phafin2 facilitates macropinocytotic membrane tubulation in orchestration with JIP4.

3.2.2 Endosomal cargo trafficking

Both Phafin1 and Phafin2 are endosome-associated proteins, playing crucial roles as regulators in the endosomal trafficking pathway. The membrane association is primarily mediated by interactions between the FYVE domain of Phafin proteins and PtdIns(3)P, a phosphoinositide abundant in endosomes. Overexpression of Phafin2 leads to the formation of enlarged endosomes, while depletion of Phafin2 decreases the size of early endosomes [21,29]. In cells transfected with Phafin2, the elevated expression precludes the internalization of insulin receptors, resulting in a higher density of insulin receptors on the membrane compared to control cells [21]. Phafin2 strongly colocalizes with EEA1 on the endosome membrane and is identified as an interactor of EEA1. It regulates the trafficking of epidermal growth factor receptors by modulating endosome fusion in coordination with EEA1 (Figure 4b) [29].

3.2.3 Autophagy

Phafin proteins lack transmembrane domains, indicating they are not membrane proteins. Under normal conditions, Phafin2 is diffusely spread in the cytosol. Upon autophagy induction by rapamycin or Hank's balanced salt solution treatment, Phafin2 co-localizes with Akt on lysosomes. The lysosomal accumulation of the Akt–Phafin2 protein complex is enhanced after autophagy induction. Phafin2’s association with lysosomes depends on its interactions with PtdIns(3)P. A PtdIns(3)P interaction-defective mutant of Phafin2 failed to associate with the lysosomal membrane, and lysosomal co-localization of the Phafin2–Akt complex was disrupted. Both Phafin2 and Akt play crucial roles in autophagy induction. Mouse macrophages transfected with Phafin2-siRNA or Akt-siRNA failed to initiate the autophagic process (Figure 4c) [9].

3.2.4 Macropinocytosis

Macropinocytosis is an actin-dependent cellular mechanism utilized by cells to take up extracellular fluids and soluble macromolecules, leading to the formation of large vesicles known as macropinosomes [37,38]. Newly formed macropinosomes are surrounded by a dense actin network. Phafin2 was shown to escort the nascent macropinosomes through a coincidence detection of PtdIns(3)P and PtdIns(4)P. Direct binding of Phafin2 to actin through its PH domain facilitates the shedding of the actin matrix, promoting the maturation of macropinosomes [11]. In addition, Phafin2 recruits JIP4 to tubulating macropinosomes in a PtdIns(3)P-dependent manner. The direct interaction between Phafin2 and JIP4, mediated by the Phafin2 PH domain, targets JIP4 to macropinosome tubules, facilitating the formation of membrane tubules (Figure 4d) [30].

3.3 Pib2 is a TORC1 regulator

TORC1, a universally conserved protein complex in eukaryotes, serves as a crucial regulator of cell growth in response to nutrients, particularly amino acids. Under nutrient-rich conditions, activated TORC1 promotes anabolic reactions such as protein synthesis while inhibiting catabolic processes like autophagy in cells [39]. A well-established regulator of TORC1 in yeasts is the heterodimeric small GTPase complex Gtr1–Gtr2 (mammalian orthologs Rag A/B and Rag C/D, respectively). The Gtr1–Gtr2 complex associates with the vacuolar membrane through the Ego scaffolding protein complex, consisting of Ego1, Ego2, and Ego3 [40–43].

Pib2 has been identified as a significant TORC1 regulator in the budding yeast Saccharomyces cerevisiae [15,24]. The Pib2 FYVE domain plays a crucial role in its association with the vacuole membrane. A truncated Pib2 mutant lacking the FYVE domain failed to bind PtdIns(3)P, preventing proper association with the vacuole membrane. Different regions of Pib2 exhibit antagonistic effects on the TORC1 regulation: the N-terminus inhibits TORC1, while the C-terminus activates TORC1 [16,24]. Pib2 has been reported to play a role in glutamine-responsive TORC1 activation, regulating TORC1 signaling independently of the Ego complex. Acting as a glutamine sensor, Pib2 directly activates TORC1 [25,40,42].

However, conflicting findings arise from another study proposing that both Pib2 and the Ego complex are required for TORC1 activation [43]. Pib2 and the Ego complex synergistically function in the same pathway, resulting in the activation of TORC1 signaling. The discrepancy in understanding the relationship between Pib2 and the Ego complex may be attributed to different experimental settings, which include variations in yeast strains, TORC1 activation stimuli, and TORC1 activity assays. A recent study may offer a possible explanation for this discrepancy, suggesting that Pib2 functions as a cysteine sensor in TORC1 regulation and different amino acids exhibit distinct dependencies on the Gtr and Pib2 pathways [44]. The relationship between the Gtr pathway and the Pib2 pathway in TORC1 regulation is currently contentious and requires further investigation (Figure 5). A dual-phase TORC1 activation model was proposed to reconcile these distinct observations. In Phase-1 (characterized by an acute and transient pulse), Pib2 and the EGO complex synergistically function together, while in Phase-2 (marked by a slow and continuous activation), they work independently [13].

Figure 5 Two models for TORC1 activation by Pib2 and Gtr 1/2 in S. cerevisiae.
Figure 5

Two models for TORC1 activation by Pib2 and Gtr 1/2 in S. cerevisiae.

4 Phafin proteins in diseases

4.1 Cancers

The expression of Phafin proteins is elevated in various cancers, including hepatocellular carcinoma [21], breast cancer [45–47], ovarian cancer [48], osteosarcoma [49], hepatoid adenocarcinoma of the stomach [50], and hereditary non-polyposis colorectal cancer [51] (Table 1). Analysis of a public hepatocellular carcinoma dataset revealed a significantly higher Phafin2 mRNA level in human hepatocellular carcinoma tissues compared to normal livers [21]. Both Phafin1 and Phafin2 are upregulated in breast cancer [45,47]. Phafin1 was identified as a macrophage-related hub gene that is important for the prognosis of triple-negative breast cancer, although its functional annotations are not available [46].

Table 1

Phafin proteins in diseases

Phafin proteins Diseases Short description References
Phafin2 Hepatocellular carcinoma Phafin2 mRNA level is significantly higher than normal cells [21]
Phafin2 Breast cancer Expression profile specifically marks estrogen receptor (ERα)-positive breast cancer cells [47]
Phafin1 Breast cancer Amplified and overexpressed in ERα-negative grade III breast cancer [45]
Phafin1 Breast cancer Identified as a hub gene that is associated with macrophages in triple-negative breast cancer [46]
Phafin1 Ovarian cancer Identified as one of the genes in a prognostic 11-gene signature for ovarian cancer [48]
Phafin1 Osteosarcoma Identified as one of the six genes in a prognostic risk score model for osteosarcoma patients [49]
Phafin1 Hepatoid adenocarcinoma of the stomach (HAS) A frequently amplified gene in HAS tumor tissues [50]
Phafin1 Hereditary non-polyposis colorectal cancer (HNPCC) Increased expression in HNPCC samples vs controls [51]
Phafin1 IPF Upregulation in IPF patients; regulate macrophage M2 activation [12]
Phafin1 Dilated cardiomyopathy A diagnostic autophagy-related biomarker of dilated cardiomyopathy [36]
Phafin1 Chronic graft versus host disease (cGVHD) An RNA biomarker that can distinguish cGVHD cases from non-cGVHD controls [55]
Phafin1 Diabetes mellitus-related atherogenesis Upregulation in diabetes mellitus-associated coronary heart diseases [56]

It is crucial to note that all studies demonstrating the upregulation of Phafin proteins or amplification of phafin genes in cancers rely on bioinformatics tools for the identification of disease-related genes. The functions of Phafin proteins in cancers have remained elusive. The elevated expression levels observed in cancers may suggest that Phafin proteins confer an advantage for the growth of cancer cells. Phafin proteins play a role in autophagy, apoptosis, and macropinocytosis – cellular pathways that cancer cells exploit to promote cellular proliferation, withstand microenvironmental stress, enhance resistance to anti-tumor drugs, and facilitate metastasis [52–54]. It has been hypothesized that the overexpression of Phafin2 could be advantageous to cancer cells, possibly owing to its involvement in the macropinocytotic pathway, which supports nutrient scavenging by cancer cells [11].

4.2 Idiopathic pulmonary fibrosis (IPF)

In addition to its upregulation in cancers, Phafin1 has been identified as an overexpressed protein or an amplified gene in various diseases, including IPF [12], dilated cardiomyopathy [36], chronic graft versus host disease [55], and diabetes mellitus-related atherogenesis [56]. A recently published article has shed light on the role of Phafin1 in IPF, the most prevalent type of interstitial lung disease characterized by lung scarring, leading to symptoms such as dry cough, extreme fatigue, and shortness of breath [12,57]. Phafin1 appears to play a role in the pathogenesis of IPF and holds potential as a therapeutic target for its treatment. The protein level of Phafin1 is approximately 2.5 times higher in IPF patients compared to control subjects. Moreover, Phafin1 is highly expressed in macrophages in mice with bleomycin-induced pulmonary fibrosis. The increased expression of Phafin1 promotes M2 macrophage activation through enhanced PI3K/Akt signaling. Utilizing phafin1 siRNA-loaded liposomes to suppress Phafin1 protein expression resulted in a significantly reduced number of M2 macrophages and mitigated lung fibrosis in mice. This approach may represent a potential treatment strategy for IPF [12].

4.3 In response to environmental factors and treatments

Phafin proteins act as adaptor proteins in apoptotic, autophagic, endosomal trafficking, and macropinocytotic signaling pathways, yet their functions may extend beyond current exploration. Phafin2, for instance, has been recognized as an antibacterial effector in zebrafish embryos, playing a pivotal role in the nonspecific immune defense of fish [58].

The phafin1 gene exhibits upregulation in the striatum, hypothalamus, or hippocampus when mice or rats are exposed to external environmental factors or various treatments, such as early-life stress [59,60], drugs of abuse [61,62], glucocorticoids [63,64], and Levosimendan treatment [65] (Table 2). However, the reasons behind the altered expression levels of the phafin1 gene in response to these environmental factors and treatments remain unclear. Notably, the phafin2 gene expression did not show differential regulation in these studies, suggesting that Phafin1 and Phafin2 may serve distinct functions in animals. Given the upregulation of the phafin1 gene in brains, it becomes intriguing to explore the function of Phafin1 in the central nervous system.

Table 2

Upregulation of the phafin1 gene in response to environmental factors/treatments

Environmental factors/treatments Short description References
Early life stress Upregulation in mouse prefrontal cortex [59,60]
Drugs of abuse Upregulation in mouse striatum [61]
Opioid dependence Upregulation in mouse striatum [62]
Glucocorticoid Upregulation in mouse hippocampus [63]
Glucocorticoid Upregulation in rat hypothalamus [64]
Levosimendan treatment Upregulation in Levosimendan-treated diabetic rats after myocardial infarction [65]
Exploratory locomotion phafin1 as a candidate gene for exploratory locomotion traits [68]
Eyeblink conditioning Upregulation in the early-stage learning [69]
Chronic unpredictable mild stress Upregulation in mouse hippocampus [70]

5 Conclusions and future directions

This review article outlines the domain structure of Phafin proteins, provides a concise summary of their involvement in cellular signaling pathways, and delves into their diverse functions in diseases. Phafin proteins are characterized by two phosphoinositide-binding domains, namely PH and FYVE. Besides, the C-terminal tail emerges as a functional domain. Significant progress has been made in this protein family, but there is still ample opportunity for further research to uncover new findings.

Pib2 (a relative of human Phain1), known for regulating TORC1, assumes a critical role in nutrient sensing in yeasts. Structurally, both Phafin1 and Pib2 contain an FYVE domain and a C-terminal tail. Furthermore, they share some functional similarities, converging on the TORC1 as Phafin1 is involved in apoptosis and autophagy, cellular processes modulated by TORC1. An intriguing question remains regarding whether Phafin1 participates in TORC1 regulation in mammalian cells. To address this issue, it is imperative to develop Phafin1 knock-down or knock-out cell models.

An autoinhibition mechanism has been discovered in Phafin2, wherein the C-terminal polyD motif intramolecularly interacts with its PH domain, thereby regulating phosphoinositide binding. The potential unraveling of Phafin2’s protein structure could shed light on the intricacies of how the polyD tail specifically interacts with the PH domain, providing insights into the regulation of this autoinhibition mechanism in cells and its coordination in signaling pathways.

Phafin proteins are implicated in apoptosis, autophagy, endosomal cargo trafficking, and macropinocytosis – cellular pathways utilized by cancer cells for growth advantage. The upregulation of Phafin protein expression in various cancers prompts the need for further studies to explore the roles of Phafin proteins in cancers. As peripheral membrane proteins, Phafin proteins transiently associate with cellular membranes via two phosphoinositide-binding domains. Given the significance of lipid–protein interactions in drug development [66,67], further studies are warranted to elucidate their lipid interactions, which could serve as potential therapeutic targets.

Moreover, the upregulation of the phafin1 gene in the brains of mice or rats responding to various environmental factors and treatments raises intriguing possibilities. No studies have explored the functions of Phafin proteins in the central nervous system, presenting an untapped area that could yield insightful and unexpected results.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: T.T. prepared figures, wrote the original draft, and edited this manuscript. J.S. and C.L. reviewed and edited this manuscript. All the listed authors reviewed and approved the final version of the submitted manuscript.

  3. Conflict of interest: The authors declare no competing interests. Chen Li, who is the co-author of this article, is a current Editorial Board member of Open Life Sciences. This fact did not affect the peer-review process.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

[1] Overduin M, Kervin TA. The phosphoinositide code is read by a plethora of protein domains. Expert Rev Proteom. 2021;18:483–502.10.1080/14789450.2021.1962302Search in Google Scholar PubMed

[2] Overduin M, Tran A, Eekels DM, Overduin F, Kervin TA. Transmembrane membrane readers form a novel class of proteins that include peripheral phosphoinositide recognition domains and viral spikes. Membranes. 2022;12:1–21. 10.3390/membranes12111161.Search in Google Scholar PubMed PubMed Central

[3] Larsen Andreas H, John Laura H, Sansom Mark SP, Corey Robin A. Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us? Biosci Rep. 2022;42:1–20.10.1042/BSR20211406Search in Google Scholar PubMed PubMed Central

[4] Tiefenauer L, Demarche S. Challenges in the development of functional assays of membrane proteins. Materials. 2012;5:2205–42. 10.3390/ma5112205.Search in Google Scholar

[5] Chen W, Li N, Chen T, Han Y, Li C, Wang Y, et al. The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway *. J Biol Chem. 2005;280:40985–95.10.1074/jbc.M502190200Search in Google Scholar PubMed

[6] Tang T, Hasan M, Capelluto DGS. Phafins are more than phosphoinositide-binding proteins. Int J Mol Sci. 2023;24:1–19. 10.3390/ijms24098096.Search in Google Scholar PubMed PubMed Central

[7] Li N, Zheng Y, Chen W, Wang C, Liu X, He W, et al. Adaptor protein LAPF recruits phosphorylated p53 to lysosomes and triggers lysosomal destabilization in apoptosis. Cancer Res. 2007;67:11176–85.10.1158/0008-5472.CAN-07-2333Search in Google Scholar PubMed

[8] Li C, Liu Q, Li N, Chen W, Wang L, Wang Y, et al. EAPF/Phafin-2, a novel endoplasmic reticulum-associated protein, facilitates TNF-α-triggered cellular apoptosis through endoplasmic reticulum–mitochondrial apoptotic pathway. J Mol Med. 2008;86:471–84.10.1007/s00109-007-0298-7Search in Google Scholar PubMed

[9] Matsuda-Lennikov M, Suizu F, Hirata N, Hashimoto M, Kimura K, Nagamine T, et al. Lysosomal interaction of Akt with Phafin2: a critical step in the induction of autophagy. PLoS One. 2014;9:e79795.10.1371/journal.pone.0079795Search in Google Scholar PubMed PubMed Central

[10] Tang T-X, Finkielstein CV, Capelluto DGS. The C-terminal acidic motif of Phafin2 inhibits PH domain binding to phosphatidylinositol 3-phosphate. Biochim Biophys Acta (BBA) – Biomembr. 2020;1862:183230.10.1016/j.bbamem.2020.183230Search in Google Scholar PubMed

[11] Schink KO, Tan KW, Spangenberg H, Martorana D, Sneeggen M, Stévenin V, et al. The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes. Nat Commun. 2021;12:6577.10.1038/s41467-021-26775-xSearch in Google Scholar PubMed PubMed Central

[12] Yan L, Hou C, Liu J, Wang Y, Zeng C, Yu J, et al. Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization. Sci China Life Sci. 2023;66:2571–86.10.1007/s11427-022-2314-8Search in Google Scholar PubMed

[13] Hatakeyama R. Pib2 as an emerging master regulator of yeast TORC1. Biomolecules. 2021;11:1–14. 10.3390/biom11101489.Search in Google Scholar PubMed PubMed Central

[14] Gailite I, Egger-Adam D, Wodarz A. The phosphoinositide-associated protein Rush hour regulates endosomal trafficking in Drosophila. Mol Biol Cell. 2011;23:433–47.10.1091/mbc.e11-02-0154Search in Google Scholar PubMed PubMed Central

[15] Kim A, Cunningham KW. A LAPF/phafin1-like protein regulates TORC1 and lysosomal membrane permeabilization in response to endoplasmic reticulum membrane stress. Mol Biol Cell. 2015;26:4631–45.10.1091/mbc.E15-08-0581Search in Google Scholar PubMed PubMed Central

[16] Troutman KK, Varlakhanova NV, Tornabene BA, Ramachandran R, Ford MGJ. Conserved Pib2 regions have distinct roles in TORC1 regulation at the vacuole. J Cell Sci. 2022;135.10.1242/jcs.259994Search in Google Scholar PubMed PubMed Central

[17] Ellena JF, Tang T-X, Shanaiah N, Capelluto DGS. Backbone 1H, 15N, and 13C resonance assignments of the Phafin2 pleckstrin homology domain. Biomol NMR Assign. 2022;16:27–30.10.1007/s12104-021-10054-3Search in Google Scholar PubMed PubMed Central

[18] Tang T-X, Jo A, Deng J, Ellena JF, Lazar IM, Davis RM, et al. Structural, thermodynamic, and phosphatidylinositol 3-phosphate binding properties of Phafin2. Protein Sci. 2017;26:814–23.10.1002/pro.3128Search in Google Scholar PubMed PubMed Central

[19] Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–89.10.1038/s41586-021-03819-2Search in Google Scholar PubMed PubMed Central

[20] Lin W-J, Yang C-Y, Li L-L, Yi Y-H, Chen K-W, Lin Y-C, et al. Lysosomal targeting of phafin1 mediated by Rab7 induces autophagosome formation. Biochem Biophys Res Commun. 2012;417:35–42.10.1016/j.bbrc.2011.11.043Search in Google Scholar PubMed

[21] Lin W-J, Yang C-Y, Lin Y-C, Tsai M-C, Yang C-W, Tung C-Y, et al. Phafin2 modulates the structure and function of endosomes by a Rab5-dependent mechanism. Biochem Biophys Res Commun. 2010;391:1043–48.10.1016/j.bbrc.2009.12.016Search in Google Scholar PubMed

[22] Wu Z, Du Y, Kirchhausen T, He K. Probing and imaging phospholipid dynamics in live cells. Life Metab. 2024;3:1–15.10.1093/lifemeta/loae014Search in Google Scholar

[23] Lolicato F, Nickel W, Haucke V, Ebner M. Phosphoinositide switches in cell physiology – from molecular mechanisms to disease. J Biol Chem. 2024;300:105757.10.1016/j.jbc.2024.105757Search in Google Scholar PubMed PubMed Central

[24] Michel AH, Hatakeyama R, Kimmig P, Arter M, Peter M, Matos J, et al. Functional mapping of yeast genomes by saturated transposition. eLife. 2017;6:e23570.10.7554/eLife.23570Search in Google Scholar PubMed PubMed Central

[25] Tanigawa M, Yamamoto K, Nagatoishi S, Nagata K, Noshiro D, Noda NN, et al. A glutamine sensor that directly activates TORC1. Commun Biol. 2021;4:1093.10.1038/s42003-021-02625-wSearch in Google Scholar PubMed PubMed Central

[26] Tang T. Phosphatidylinositol 3-phosphate binding properties and autoinhibition mechanism of Phafin2. PhD thesis. Blacksburg: Virginia Tech; 2021.Search in Google Scholar

[27] Pufall MA, Graves BJ. Autoinhibitory domains: modular effectors of cellular regulation. Annu Rev Cell Dev Biol. 2002;18:421–62.10.1146/annurev.cellbio.18.031502.133614Search in Google Scholar PubMed

[28] Trudeau T, Nassar R, Cumberworth A, Wong Eric TC, Woollard G, Gsponer J. Structure and intrinsic disorder in protein autoinhibition. Structure. 2013;21:332–41.10.1016/j.str.2012.12.013Search in Google Scholar PubMed

[29] Pedersen NM, Raiborg C, Brech A, Skarpen E, Roxrud I, Platta HW, et al. The PtdIns3P-binding protein phafin 2 mediates epidermal growth factor receptor degradation by promoting endosome fusion. Traffic. 2012;13:1547–63.10.1111/j.1600-0854.2012.01400.xSearch in Google Scholar PubMed

[30] Tan KW, Nähse V, Campsteijn C, Brech A, Schink KO, Stenmark H. JIP4 is recruited by the phosphoinositide-binding protein Phafin2 to promote recycling tubules on macropinosomes. J Cell Sci. 2021;134:1–15.10.1242/jcs.258495Search in Google Scholar PubMed PubMed Central

[31] Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010;3:ra3.10.1126/scisignal.2000475Search in Google Scholar PubMed

[32] Castillo Ferrer C, Berthenet K, Ichim G. Apoptosis – fueling the oncogenic fire. FEBS J. 2021;288:4445–63.10.1111/febs.15624Search in Google Scholar PubMed PubMed Central

[33] Erekat NS. Apoptosis and its therapeutic implications in neurodegenerative diseases. Clin Anat. 2022;35:65–78.10.1002/ca.23792Search in Google Scholar PubMed

[34] Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.10.1038/nrm2239Search in Google Scholar PubMed

[35] Nakamura S, Yoshimori T. New insights into autophagosome–lysosome fusion. J Cell Sci. 2017;130:1209–16.10.1242/jcs.196352Search in Google Scholar PubMed

[36] Zhang F, Xia M, Jiang J, Wang S, Zhao Q, Yu C, et al. Machine learning and bioinformatics to identify 8 autophagy-related biomarkers and construct gene regulatory networks in dilated cardiomyopathy. Sci Rep. 2022;12:15030.10.1038/s41598-022-19027-5Search in Google Scholar PubMed PubMed Central

[37] Buckley CM, King JS. Drinking problems: mechanisms of macropinosome formation and maturation. FEBS J. 2017;284:3778–90.10.1111/febs.14115Search in Google Scholar PubMed

[38] Kerr MC, Teasdale RD. Defining macropinocytosis. Traffic. 2009;10:364–71.10.1111/j.1600-0854.2009.00878.xSearch in Google Scholar PubMed

[39] Chantranupong L, Wolfson Rachel L, Sabatini David M. Nutrient-sensing mechanisms across evolution. Cell. 2015;161:67–83.10.1016/j.cell.2015.02.041Search in Google Scholar PubMed PubMed Central

[40] Tanigawa M, Maeda T. An in vitro TORC1 kinase assay that recapitulates the gtr-independent glutamine-responsive TORC1 activation mechanism on yeast vacuoles. Mol Cell Biol. 2017;37:e00075-17.10.1128/MCB.00075-17Search in Google Scholar PubMed PubMed Central

[41] Uemura S, Mochizuki T, Amemiya K, Kurosaka G, Yazawa M, Nakamoto K, et al. Amino acid homeostatic control by TORC1 in Saccharomyces cerevisiae under high hydrostatic pressure. J Cell Sci. 2020;133:1–12.10.1242/jcs.245555Search in Google Scholar PubMed

[42] Ukai H, Araki Y, Kira S, Oikawa Y, May AI, Noda T. Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane. PLOS Genet. 2018;14:e1007334.10.1371/journal.pgen.1007334Search in Google Scholar PubMed PubMed Central

[43] Varlakhanova NV, Mihalevic MJ, Bernstein KA, Ford MGJ. Pib2 and the EGO complex are both required for activation of TORC1. J Cell Sci. 2017;130:3878–90.10.1242/jcs.207910Search in Google Scholar PubMed PubMed Central

[44] Zeng Q, Araki Y, Noda T. Pib2 is a cysteine sensor involved in TORC1 activation in Saccharomyces cerevisiae. Cell Rep. 2024;43:113599.10.1016/j.celrep.2023.113599Search in Google Scholar PubMed

[45] Natrajan R, Mackay A, Wilkerson PM, Lambros MB, Wetterskog D, Arnedos M, et al. Functional characterization of the 19q12 amplicon in grade III breast cancers. Breast Cancer Res. 2012;14:R53.10.1186/bcr3154Search in Google Scholar PubMed PubMed Central

[46] Su P, Peng Z, Xu B, Yang B, Jin F. Establishment and validation of an individualized macrophage-related gene signature to predict overall survival in patients with triple negative breast cancer. PeerJ. 2021;9:e12383.10.7717/peerj.12383Search in Google Scholar PubMed PubMed Central

[47] Weisz A, Basile W, Scafoglio C, Altucci L, Bresciani F, Facchiano A, et al. Molecular identification of ERα-positive breast cancer cells by the expression profile of an intrinsic set of estrogen regulated genes. J Cell Physiol. 2004;200:440–50.10.1002/jcp.20039Search in Google Scholar PubMed

[48] Zheng M, Long J, Chelariu-Raicu A, Mullikin H, Vilsmaier T, Vattai A, et al. Identification of a novel tumor microenvironment prognostic signature for advanced-stage serous ovarian cancer. Cancers. 2021;13:1–19. 10.3390/cancers13133343.Search in Google Scholar PubMed PubMed Central

[49] Yang F, Zhang Y. Apoptosis-related genes-based prognostic signature for osteosarcoma. Aging (Albany NY). 2022;14:3813–25.10.18632/aging.204042Search in Google Scholar PubMed PubMed Central

[50] Zhu M, Chen E, Yu S, Xu C, Yu Y, Cao X, et al. Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach. Cancer Commun (Lond). 2022;42:1032–35.10.1002/cac2.12336Search in Google Scholar PubMed PubMed Central

[51] Neklason DW, Done MW, Milash B, Frey L, Sargent N, Tuohy TM, et al. Deciphering the molecular pathways disrupted in normal and neoplastic colonic tissue in inherited colorectal cancer syndromes. Hereditary Cancer ClPract. 2011;9:O6.10.1186/1897-4287-9-S1-O6Search in Google Scholar

[52] Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17:395–417.10.1038/s41571-020-0341-ySearch in Google Scholar PubMed PubMed Central

[53] Qiu Z, Liu W, Zhu Q, Ke K, Zhu Q, Jin W, et al. The role and therapeutic potential of macropinocytosis in cancer. Front Pharmacol. 2022;13:1–15.10.3389/fphar.2022.919819Search in Google Scholar PubMed PubMed Central

[54] White E. The role for autophagy in cancer. J Clin Invest. 2015;125:42–6.10.1172/JCI73941Search in Google Scholar PubMed PubMed Central

[55] Pidala J, Sigdel TK, Wang A, Hsieh S, Inamoto Y, Martin PJ, et al. A combined biomarker and clinical panel for chronic graft versus host disease diagnosis. J Pathol: Clin Res. 2017;3:3–16.10.1002/cjp2.58Search in Google Scholar PubMed PubMed Central

[56] Huang Q, Deng G, Wei R, Wang Q, Zou D, Wei J. Comprehensive identification of key genes involved in development of diabetes mellitus-related atherogenesis using weighted gene correlation network analysis. Front Cardiovasc Med. 2020;7:1–11.10.3389/fcvm.2020.580573Search in Google Scholar PubMed PubMed Central

[57] Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017;3:17074.10.1038/nrdp.2017.74Search in Google Scholar PubMed

[58] Ren Y, Wang C, Wang H, Chang Q, Guo D, Wang X. Identification of zebrafish PLEKHF2 presents in egg/embryos as an antibacterial protein. Fish Shellfish Immunol. 2022;127:925–32.10.1016/j.fsi.2022.07.038Search in Google Scholar PubMed

[59] Marrocco J, Gray JD, Kogan JF, Einhorn NR, O’Cinneide EM, Rubin TG, et al. Early life stress restricts translational reactivity in CA3 neurons associated with altered stress responses in adulthood. Front Behav Neurosci. 2019;13:1–12.10.3389/fnbeh.2019.00157Search in Google Scholar PubMed PubMed Central

[60] Reshetnikov VV, Kisaretova PE, Ershov NI, Merkulova TI, Bondar NP. Social defeat stress in adult mice causes alterations in gene expression, alternative splicing, and the epigenetic landscape of H3K4me3 in the prefrontal cortex: an impact of early-life stress. Prog Neuro-Psychopharmacol Biol Psychiatry. 2021;106:110068.10.1016/j.pnpbp.2020.110068Search in Google Scholar PubMed

[61] Piechota M, Korostynski M, Solecki W, Gieryk A, Slezak M, Bilecki W, et al. The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum. Genome Biol. 2010;11:R48.10.1186/gb-2010-11-5-r48Search in Google Scholar PubMed PubMed Central

[62] Wu X, Xie S, Wang L, Fan P, Ge S, Xie X-Q, et al. A computational strategy for finding novel targets and therapeutic compounds for opioid dependence. PLOS One. 2018;13:e0207027.10.1371/journal.pone.0207027Search in Google Scholar PubMed PubMed Central

[63] Luo Y, Zeng B, Zeng L, Du X, Li B, Huo R, et al. Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus. Transl Psychiatry. 2018;8:187.10.1038/s41398-018-0240-5Search in Google Scholar PubMed PubMed Central

[64] Sato H, Horikawa Y, Iizuka K, Sakurai N, Tanaka T, Shihara N, et al. Large-scale analysis of glucocorticoid target genes in rat hypothalamus. J Neurochem. 2008;106:805–14.10.1111/j.1471-4159.2008.05489.xSearch in Google Scholar PubMed

[65] Vahtola E, Storvik M, Louhelainen M, Merasto S, Lakkisto P, Lakkisto J, et al. Effects of levosimendan on cardiac gene expression profile and post-infarct cardiac remodelling in diabetic goto-kakizaki rats. Basic Clin Pharmacol Toxicol. 2011;109:387–97.10.1111/j.1742-7843.2011.00743.xSearch in Google Scholar PubMed

[66] Payandeh J, Volgraf M. Ligand binding at the protein–lipid interface: strategic considerations for drug design. Nat Rev Drug Discov. 2021;20:710–22.10.1038/s41573-021-00240-2Search in Google Scholar PubMed

[67] Singaram I, Sharma A, Pant S, Lihan M, Park M-J, Pergande M, et al. Targeting lipid–protein interaction to treat Syk-mediated acute myeloid leukemia. Nat Chem Biol. 2023;19:239–50.10.1038/s41589-022-01150-zSearch in Google Scholar PubMed PubMed Central

[68] Chitre AS, Hebda-Bauer EK, Blandino P, Bimschleger H, Nguyen K-M, Maras P, et al. Genome-wide association study in a rat model of temperament identifies multiple loci for exploratory locomotion and anxiety-like traits. Front Genet. 2023;13:1–19.10.3389/fgene.2022.1003074Search in Google Scholar PubMed PubMed Central

[69] Park J-S, Onodera T, Nishimura S, Thompson RF, Itohara S. Molecular evidence for two-stage learning and partial laterality in eyeblink conditioning of mice. Proc Natl Acad Sci. 2006;103:5549–54.10.1073/pnas.0601150103Search in Google Scholar PubMed PubMed Central

[70] Tao Y, Xie Z, Shi J, Ou R, Wu H, Shi H, et al. Hippocampal mRNA expression profiling in mice exposed to chronic unpredictable mild stress. Brain Res Bull. 2020;162:11–9.10.1016/j.brainresbull.2020.06.001Search in Google Scholar PubMed

Received: 2024-02-11
Revised: 2024-05-14
Accepted: 2024-05-21
Published Online: 2024-06-27

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Biomedical Sciences
  2. Constitutive and evoked release of ATP in adult mouse olfactory epithelium
  3. LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior
  4. PEGylated porcine–human recombinant uricase: A novel fusion protein with improved efficacy and safety for the treatment of hyperuricemia and renal complications
  5. Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons
  6. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor–CaMKII pathway
  7. Brucella infection combined with Nocardia infection: A case report and literature review
  8. Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance
  9. Ang-1, Ang-2, and Tie2 are diagnostic biomarkers for Henoch-Schönlein purpura and pediatric-onset systemic lupus erythematous
  10. PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc
  11. Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features
  12. Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis
  13. Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms
  14. A case of Trousseau syndrome: Screening, detection and complication
  15. Application of the integrated airway humidification device enhances the humidification effect of the rabbit tracheotomy model
  16. Preparation of Cu2+/TA/HAP composite coating with anti-bacterial and osteogenic potential on 3D-printed porous Ti alloy scaffolds for orthopedic applications
  17. Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging
  18. Current research and evidence gaps on placental development in iron deficiency anemia
  19. Single-nucleotide polymorphism rs2910829 in PDE4D is related to stroke susceptibility in Chinese populations: The results of a meta-analysis
  20. Pheochromocytoma-induced myocardial infarction: A case report
  21. Kaempferol regulates apoptosis and migration of neural stem cells to attenuate cerebral infarction by O‐GlcNAcylation of β-catenin
  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
  23. Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
  24. KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
  25. Current state of research on copper complexes in the treatment of breast cancer
  26. Exploring antioxidant strategies in the pathogenesis of ALS
  27. Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
  28. IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
  29. The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
  30. Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
  31. P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
  32. Probiotics for inflammatory bowel disease: Is there sufficient evidence?
  33. Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
  34. Microbial perspective on the skin–gut axis and atopic dermatitis
  35. Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
  36. Highly specific vaginal microbiome signature for gynecological cancers
  37. Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
  38. The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
  39. Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
  40. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
  41. Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
  42. VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
  43. Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
  44. Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
  45. Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
  46. Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
  47. Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
  48. Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
  49. Cystic adenomyoma of the uterus: Case report and literature review
  50. Mesoporous silica nanoparticles as a drug delivery mechanism
  51. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
  52. Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
  53. Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
  54. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
  55. Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
  56. Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
  57. Embedded monitoring system and teaching of artificial intelligence online drug component recognition
  58. Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
  59. Yak meat content in feed and its impact on the growth of rats
  60. A rare case of Richter transformation with breast involvement: A case report and literature review
  61. First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
  62. Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
  63. Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
  64. Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
  65. The role of Phafin proteins in cell signaling pathways and diseases
  66. Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
  67. Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
  68. Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
  69. Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
  70. Imaging manifestations of ductal adenoma of the breast: A case report
  71. Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
  72. Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
  73. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
  74. Circular RNAs as potential biomarkers for male severe sepsis
  75. Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
  76. The expression and biological role of complement C1s in esophageal squamous cell carcinoma
  77. A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
  78. Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
  79. HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
  80. IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
  81. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
  82. Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
  83. Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
  84. Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
  85. Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
  86. Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
  87. Refractory hypertension complicated with Turner syndrome: A case report
  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
https://doi.org/10.1515/biol-2022-0896
Keywords for this article
Phafin1; Phafin2; Pib2; idiopathic pulmonary fibrosis; cancer
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Constitutive and evoked release of ATP in adult mouse olfactory epithelium
  3. LARP1 knockdown inhibits cultured gastric carcinoma cell cycle progression and metastatic behavior
  4. PEGylated porcine–human recombinant uricase: A novel fusion protein with improved efficacy and safety for the treatment of hyperuricemia and renal complications
  5. Research progress on ocular complications caused by type 2 diabetes mellitus and the function of tears and blepharons
  6. The role and mechanism of esketamine in preventing and treating remifentanil-induced hyperalgesia based on the NMDA receptor–CaMKII pathway
  7. Brucella infection combined with Nocardia infection: A case report and literature review
  8. Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance
  9. Ang-1, Ang-2, and Tie2 are diagnostic biomarkers for Henoch-Schönlein purpura and pediatric-onset systemic lupus erythematous
  10. PTTG1 induces pancreatic cancer cell proliferation and promotes aerobic glycolysis by regulating c-myc
  11. Role of serum B-cell-activating factor and interleukin-17 as biomarkers in the classification of interstitial pneumonia with autoimmune features
  12. Effectiveness and safety of a mumps containing vaccine in preventing laboratory-confirmed mumps cases from 2002 to 2017: A meta-analysis
  13. Low levels of sex hormone-binding globulin predict an increased breast cancer risk and its underlying molecular mechanisms
  14. A case of Trousseau syndrome: Screening, detection and complication
  15. Application of the integrated airway humidification device enhances the humidification effect of the rabbit tracheotomy model
  16. Preparation of Cu2+/TA/HAP composite coating with anti-bacterial and osteogenic potential on 3D-printed porous Ti alloy scaffolds for orthopedic applications
  17. Aquaporin-8 promotes human dermal fibroblasts to counteract hydrogen peroxide-induced oxidative damage: A novel target for management of skin aging
  18. Current research and evidence gaps on placental development in iron deficiency anemia
  19. Single-nucleotide polymorphism rs2910829 in PDE4D is related to stroke susceptibility in Chinese populations: The results of a meta-analysis
  20. Pheochromocytoma-induced myocardial infarction: A case report
  21. Kaempferol regulates apoptosis and migration of neural stem cells to attenuate cerebral infarction by O‐GlcNAcylation of β-catenin
  22. Sirtuin 5 regulates acute myeloid leukemia cell viability and apoptosis by succinylation modification of glycine decarboxylase
  23. Apigenin 7-glucoside impedes hypoxia-induced malignant phenotypes of cervical cancer cells in a p16-dependent manner
  24. KAT2A changes the function of endometrial stromal cells via regulating the succinylation of ENO1
  25. Current state of research on copper complexes in the treatment of breast cancer
  26. Exploring antioxidant strategies in the pathogenesis of ALS
  27. Helicobacter pylori causes gastric dysbacteriosis in chronic gastritis patients
  28. IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury
  29. The predictive value of serum NLR, SII, and OPNI for lymph node metastasis in breast cancer patients with internal mammary lymph nodes after thoracoscopic surgery
  30. Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso
  31. P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy
  32. Probiotics for inflammatory bowel disease: Is there sufficient evidence?
  33. Identification of KDM4C as a gene conferring drug resistance in multiple myeloma
  34. Microbial perspective on the skin–gut axis and atopic dermatitis
  35. Thymosin α1 combined with XELOX improves immune function and reduces serum tumor markers in colorectal cancer patients after radical surgery
  36. Highly specific vaginal microbiome signature for gynecological cancers
  37. Sample size estimation for AQP4-IgG seropositive optic neuritis: Retinal damage detection by optical coherence tomography
  38. The effects of SDF-1 combined application with VEGF on femoral distraction osteogenesis in rats
  39. Fabrication and characterization of gold nanoparticles using alginate: In vitro and in vivo assessment of its administration effects with swimming exercise on diabetic rats
  40. Mitigating digestive disorders: Action mechanisms of Mediterranean herbal active compounds
  41. Distribution of CYP2D6 and CYP2C19 gene polymorphisms in Han and Uygur populations with breast cancer in Xinjiang, China
  42. VSP-2 attenuates secretion of inflammatory cytokines induced by LPS in BV2 cells by mediating the PPARγ/NF-κB signaling pathway
  43. Factors influencing spontaneous hypothermia after emergency trauma and the construction of a predictive model
  44. Long-term administration of morphine specifically alters the level of protein expression in different brain regions and affects the redox state
  45. Application of metagenomic next-generation sequencing technology in the etiological diagnosis of peritoneal dialysis-associated peritonitis
  46. Clinical diagnosis, prevention, and treatment of neurodyspepsia syndrome using intelligent medicine
  47. Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas
  48. Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family
  49. Cystic adenomyoma of the uterus: Case report and literature review
  50. Mesoporous silica nanoparticles as a drug delivery mechanism
  51. Dynamic changes in autophagy activity in different degrees of pulmonary fibrosis in mice
  52. Vitamin D deficiency and inflammatory markers in type 2 diabetes: Big data insights
  53. Lactate-induced IGF1R protein lactylation promotes proliferation and metabolic reprogramming of lung cancer cells
  54. Meta-analysis on the efficacy of allogeneic hematopoietic stem cell transplantation to treat malignant lymphoma
  55. Mitochondrial DNA drives neuroinflammation through the cGAS-IFN signaling pathway in the spinal cord of neuropathic pain mice
  56. Application value of artificial intelligence algorithm-based magnetic resonance multi-sequence imaging in staging diagnosis of cervical cancer
  57. Embedded monitoring system and teaching of artificial intelligence online drug component recognition
  58. Investigation into the association of FNDC1 and ADAMTS12 gene expression with plumage coloration in Muscovy ducks
  59. Yak meat content in feed and its impact on the growth of rats
  60. A rare case of Richter transformation with breast involvement: A case report and literature review
  61. First report of Nocardia wallacei infection in an immunocompetent patient in Zhejiang province
  62. Rhodococcus equi and Brucella pulmonary mass in immunocompetent: A case report and literature review
  63. Downregulation of RIP3 ameliorates the left ventricular mechanics and function after myocardial infarction via modulating NF-κB/NLRP3 pathway
  64. Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease
  65. The role of Phafin proteins in cell signaling pathways and diseases
  66. Ten-year anemia as initial manifestation of Castleman disease in the abdominal cavity: A case report
  67. Coexistence of hereditary spherocytosis with SPTB P.Trp1150 gene variant and Gilbert syndrome: A case report and literature review
  68. Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells
  69. Exploratory evaluation supported by experimental and modeling approaches of Inula viscosa root extract as a potent corrosion inhibitor for mild steel in a 1 M HCl solution
  70. Imaging manifestations of ductal adenoma of the breast: A case report
  71. Gut microbiota and sleep: Interaction mechanisms and therapeutic prospects
  72. Isomangiferin promotes the migration and osteogenic differentiation of rat bone marrow mesenchymal stem cells
  73. Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer
  74. Circular RNAs as potential biomarkers for male severe sepsis
  75. Knockdown of Stanniocalcin-1 inhibits growth and glycolysis in oral squamous cell carcinoma cells
  76. The expression and biological role of complement C1s in esophageal squamous cell carcinoma
  77. A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report
  78. Predictive value of serum magnesium levels for prognosis in patients with non-small cell lung cancer undergoing EGFR-TKI therapy
  79. HSPB1 alleviates acute-on-chronic liver failure via the P53/Bax pathway
  80. IgG4-related disease complicated by PLA2R-associated membranous nephropathy: A case report
  81. Baculovirus-mediated endostatin and angiostatin activation of autophagy through the AMPK/AKT/mTOR pathway inhibits angiogenesis in hepatocellular carcinoma
  82. Metformin mitigates osteoarthritis progression by modulating the PI3K/AKT/mTOR signaling pathway and enhancing chondrocyte autophagy
  83. Evaluation of the activity of antimicrobial peptides against bacterial vaginosis
  84. Atypical presentation of γ/δ mycosis fungoides with an unusual phenotype and SOCS1 mutation
  85. Analysis of the microecological mechanism of diabetic kidney disease based on the theory of “gut–kidney axis”: A systematic review
  86. Omega-3 fatty acids prevent gestational diabetes mellitus via modulation of lipid metabolism
  87. Refractory hypertension complicated with Turner syndrome: A case report
  88. Interaction of ncRNAs and the PI3K/AKT/mTOR pathway: Implications for osteosarcoma
  89. Association of low attenuation area scores with pulmonary function and clinical prognosis in patients with chronic obstructive pulmonary disease
  90. Long non-coding RNAs in bone formation: Key regulators and therapeutic prospects
  91. The deubiquitinating enzyme USP35 regulates the stability of NRF2 protein
  92. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential diagnostic markers for rebleeding in patients with esophagogastric variceal bleeding
  93. G protein-coupled receptor 1 participating in the mechanism of mediating gestational diabetes mellitus by phosphorylating the AKT pathway
  94. LL37-mtDNA regulates viability, apoptosis, inflammation, and autophagy in lipopolysaccharide-treated RLE-6TN cells by targeting Hsp90aa1
  95. The analgesic effect of paeoniflorin: A focused review
  96. Chemical composition’s effect on Solanum nigrum Linn.’s antioxidant capacity and erythrocyte protection: Bioactive components and molecular docking analysis
  97. Knockdown of HCK promotes HREC cell viability and inner blood–retinal barrier integrity by regulating the AMPK signaling pathway
  98. The role of rapamycin in the PINK1/Parkin signaling pathway in mitophagy in podocytes
  99. Laryngeal non-Hodgkin lymphoma: Report of four cases and review of the literature
  100. Clinical value of macrogenome next-generation sequencing on infections
  101. Overview of dendritic cells and related pathways in autoimmune uveitis
  102. TAK-242 alleviates diabetic cardiomyopathy via inhibiting pyroptosis and TLR4/CaMKII/NLRP3 pathway
  103. Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age
  104. Profile and antimicrobial susceptibility patterns of bacteria isolated from effluents of Kolladiba and Debark hospitals
  105. The expression and clinical significance of syncytin-1 in serum exosomes of hepatocellular carcinoma patients
  106. A histomorphometric study to evaluate the therapeutic effects of biosynthesized silver nanoparticles on the kidneys infected with Plasmodium chabaudi
  107. PGRMC1 and PAQR4 are promising molecular targets for a rare subtype of ovarian cancer
  108. Analysis of MDA, SOD, TAOC, MNCV, SNCV, and TSS scores in patients with diabetes peripheral neuropathy
  109. SLIT3 deficiency promotes non-small cell lung cancer progression by modulating UBE2C/WNT signaling
  110. The relationship between TMCO1 and CALR in the pathological characteristics of prostate cancer and its effect on the metastasis of prostate cancer cells
  111. Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma
  112. PHB2 alleviates retinal pigment epithelium cell fibrosis by suppressing the AGE–RAGE pathway
  113. Anti-γ-aminobutyric acid-B receptor autoimmune encephalitis with syncope as the initial symptom: Case report and literature review
  114. Comparative analysis of chloroplast genome of Lonicera japonica cv. Damaohua
  115. Human umbilical cord mesenchymal stem cells regulate glutathione metabolism depending on the ERK–Nrf2–HO-1 signal pathway to repair phosphoramide mustard-induced ovarian cancer cells
  116. Electroacupuncture on GB acupoints improves osteoporosis via the estradiol–PI3K–Akt signaling pathway
  117. Renalase protects against podocyte injury by inhibiting oxidative stress and apoptosis in diabetic nephropathy
  118. Review: Dicranostigma leptopodum: A peculiar plant of Papaveraceae
  119. Combination effect of flavonoids attenuates lung cancer cell proliferation by inhibiting the STAT3 and FAK signaling pathway
  120. Renal microangiopathy and immune complex glomerulonephritis induced by anti-tumour agents: A case report
  121. Correlation analysis of AVPR1a and AVPR2 with abnormal water and sodium and potassium metabolism in rats
  122. Gastrointestinal health anti-diarrheal mixture relieves spleen deficiency-induced diarrhea through regulating gut microbiota
  123. Myriad factors and pathways influencing tumor radiotherapy resistance
  124. Exploring the effects of culture conditions on Yapsin (YPS) gene expression in Nakaseomyces glabratus
  125. Screening of prognostic core genes based on cell–cell interaction in the peripheral blood of patients with sepsis
  126. Coagulation factor II thrombin receptor as a promising biomarker in breast cancer management
  127. Ileocecal mucinous carcinoma misdiagnosed as incarcerated hernia: A case report
  128. Methyltransferase like 13 promotes malignant behaviors of bladder cancer cells through targeting PI3K/ATK signaling pathway
  129. The debate between electricity and heat, efficacy and safety of irreversible electroporation and radiofrequency ablation in the treatment of liver cancer: A meta-analysis
  130. ZAG promotes colorectal cancer cell proliferation and epithelial–mesenchymal transition by promoting lipid synthesis
  131. Baicalein inhibits NLRP3 inflammasome activation and mitigates placental inflammation and oxidative stress in gestational diabetes mellitus
  132. Impact of SWCNT-conjugated senna leaf extract on breast cancer cells: A potential apoptotic therapeutic strategy
  133. MFAP5 inhibits the malignant progression of endometrial cancer cells in vitro
  134. Major ozonated autohemotherapy promoted functional recovery following spinal cord injury in adult rats via the inhibition of oxidative stress and inflammation
  135. Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons
  136. Differential expression of phosphoinositide 3-kinase/protein kinase B and Toll-like receptor/nuclear factor kappa B signaling pathways in experimental obesity Wistar rat model
  137. The therapeutic potential of targeting Oncostatin M and the interleukin-6 family in retinal diseases: A comprehensive review
  138. BA inhibits LPS-stimulated inflammatory response and apoptosis in human middle ear epithelial cells by regulating the Nf-Kb/Iκbα axis
  139. Role of circRMRP and circRPL27 in chronic obstructive pulmonary disease
  140. Investigating the role of hyperexpressed HCN1 in inducing myocardial infarction through activation of the NF-κB signaling pathway
  141. Characterization of phenolic compounds and evaluation of anti-diabetic potential in Cannabis sativa L. seeds: In vivo, in vitro, and in silico studies
  142. Quantitative immunohistochemistry analysis of breast Ki67 based on artificial intelligence
  143. Ecology and Environmental Science
  144. Screening of different growth conditions of Bacillus subtilis isolated from membrane-less microbial fuel cell toward antimicrobial activity profiling
  145. Degradation of a mixture of 13 polycyclic aromatic hydrocarbons by commercial effective microorganisms
  146. Evaluation of the impact of two citrus plants on the variation of Panonychus citri (Acari: Tetranychidae) and beneficial phytoseiid mites
  147. Prediction of present and future distribution areas of Juniperus drupacea Labill and determination of ethnobotany properties in Antalya Province, Türkiye
  148. Population genetics of Todarodes pacificus (Cephalopoda: Ommastrephidae) in the northwest Pacific Ocean via GBS sequencing
  149. A comparative analysis of dendrometric, macromorphological, and micromorphological characteristics of Pistacia atlantica subsp. atlantica and Pistacia terebinthus in the middle Atlas region of Morocco
  150. Macrofungal sporocarp community in the lichen Scots pine forests
  151. Assessing the proximate compositions of indigenous forage species in Yemen’s pastoral rangelands
  152. Food Science
  153. Gut microbiota changes associated with low-carbohydrate diet intervention for obesity
  154. Reexamination of Aspergillus cristatus phylogeny in dark tea: Characteristics of the mitochondrial genome
  155. Differences in the flavonoid composition of the leaves, fruits, and branches of mulberry are distinguished based on a plant metabolomics approach
  156. Investigating the impact of wet rendering (solventless method) on PUFA-rich oil from catfish (Clarias magur) viscera
  157. Non-linear associations between cardiovascular metabolic indices and metabolic-associated fatty liver disease: A cross-sectional study in the US population (2017–2020)
  158. Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression
  159. Utility of dairy microbiome as a tool for authentication and traceability
  160. Agriculture
  161. Enhancing faba bean (Vicia faba L.) productivity through establishing the area-specific fertilizer rate recommendation in southwest Ethiopia
  162. Impact of novel herbicide based on synthetic auxins and ALS inhibitor on weed control
  163. Perspectives of pteridophytes microbiome for bioremediation in agricultural applications
  164. Fertilizer application parameters for drip-irrigated peanut based on the fertilizer effect function established from a “3414” field trial
  165. Improving the productivity and profitability of maize (Zea mays L.) using optimum blended inorganic fertilization
  166. Application of leaf multispectral analyzer in comparison to hyperspectral device to assess the diversity of spectral reflectance indices in wheat genotypes
  167. Animal Sciences
  168. Knockdown of ANP32E inhibits colorectal cancer cell growth and glycolysis by regulating the AKT/mTOR pathway
  169. Development of a detection chip for major pathogenic drug-resistant genes and drug targets in bovine respiratory system diseases
  170. Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks
  171. Transcriptome analysis of adipose tissue in grazing cattle: Identifying key regulators of fat metabolism
  172. Comparison of nutritional value of the wild and cultivated spiny loaches at three growth stages
  173. Transcriptomic analysis of liver immune response in Chinese spiny frog (Quasipaa spinosa) infected with Proteus mirabilis
  174. Disruption of BCAA degradation is a critical characteristic of diabetic cardiomyopathy revealed by integrated transcriptome and metabolome analysis
  175. Plant Sciences
  176. Effect of long-term in-row branch covering on soil microorganisms in pear orchards
  177. Photosynthetic physiological characteristics, growth performance, and element concentrations reveal the calcicole–calcifuge behaviors of three Camellia species
  178. Transcriptome analysis reveals the mechanism of NaHCO3 promoting tobacco leaf maturation
  179. Bioinformatics, expression analysis, and functional verification of allene oxide synthase gene HvnAOS1 and HvnAOS2 in qingke
  180. Water, nitrogen, and phosphorus coupling improves gray jujube fruit quality and yield
  181. Improving grape fruit quality through soil conditioner: Insights from RNA-seq analysis of Cabernet Sauvignon roots
  182. Role of Embinin in the reabsorption of nucleus pulposus in lumbar disc herniation: Promotion of nucleus pulposus neovascularization and apoptosis of nucleus pulposus cells
  183. Revealing the effects of amino acid, organic acid, and phytohormones on the germination of tomato seeds under salinity stress
  184. Combined effects of nitrogen fertilizer and biochar on the growth, yield, and quality of pepper
  185. Comprehensive phytochemical and toxicological analysis of Chenopodium ambrosioides (L.) fractions
  186. Impact of “3414” fertilization on the yield and quality of greenhouse tomatoes
  187. Exploring the coupling mode of water and fertilizer for improving growth, fruit quality, and yield of the pear in the arid region
  188. Metagenomic analysis of endophytic bacteria in seed potato (Solanum tuberosum)
  189. Antibacterial, antifungal, and phytochemical properties of Salsola kali ethanolic extract
  190. Exploring the hepatoprotective properties of citronellol: In vitro and in silico studies on ethanol-induced damage in HepG2 cells
  191. Enhanced osmotic dehydration of watermelon rind using honey–sucrose solutions: A study on pre-treatment efficacy and mass transfer kinetics
  192. Effects of exogenous 2,4-epibrassinolide on photosynthetic traits of 53 cowpea varieties under NaCl stress
  193. Comparative transcriptome analysis of maize (Zea mays L.) seedlings in response to copper stress
  194. An optimization method for measuring the stomata in cassava (Manihot esculenta Crantz) under multiple abiotic stresses
  195. Fosinopril inhibits Ang II-induced VSMC proliferation, phenotype transformation, migration, and oxidative stress through the TGF-β1/Smad signaling pathway
  196. Antioxidant and antimicrobial activities of Salsola imbricata methanolic extract and its phytochemical characterization
  197. Bioengineering and Biotechnology
  198. Absorbable calcium and phosphorus bioactive membranes promote bone marrow mesenchymal stem cells osteogenic differentiation for bone regeneration
  199. New advances in protein engineering for industrial applications: Key takeaways
  200. An overview of the production and use of Bacillus thuringiensis toxin
  201. Research progress of nanoparticles in diagnosis and treatment of hepatocellular carcinoma
  202. Bioelectrochemical biosensors for water quality assessment and wastewater monitoring
  203. PEI/MMNs@LNA-542 nanoparticles alleviate ICU-acquired weakness through targeted autophagy inhibition and mitochondrial protection
  204. Unleashing of cytotoxic effects of thymoquinone-bovine serum albumin nanoparticles on A549 lung cancer cells
  205. Erratum
  206. Erratum to “Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM”
  207. Erratum to “Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation”
  208. Retraction
  209. Retraction to “MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB”
  210. Retraction to “A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis”
  211. Special Issue on Advances in Neurodegenerative Disease Research and Treatment
  212. Transplantation of human neural stem cell prevents symptomatic motor behavior disability in a rat model of Parkinson’s disease
  213. Special Issue on Multi-omics
  214. Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma
  215. Gastroesophageal varices in primary biliary cholangitis with anti-centromere antibody positivity: Early onset?
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 22.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0896/html?lang=en
Scroll to top button