Our study, drawing from the NASA Gene Lab data repository, analyzed the effects of space flight on rodent specimens, focusing on lung, colorectal, and skin tissues. We identified 19, 40 and 5 space flight rodents and 35, 57 and 17 control rodents for colorectal (GLDS-247)[6], dorsal skin (GLDS 238[7], 240[8], 243[9]), and lung (GLDS-248)[10] groups respectively. All organ system showed distinct networks with p values less than 0.05 in their relative comparisons. HTR6, GNRHR, PROK1, and NPHS2 were the most uniquely upregulated genes among the colorectal data in the space flight-exposed rodents, while for dorsal skin data they were APOA2, AFP, PCP2, and CRP genes and for lung they were DERL3, NMBR, TRIM69, MAP3K14, and SYNV1. Most of these genes are associated with certain diseases, deficiencies, and types of cancers, such as ovarian cancer, gastric cancer, and pancreatic duct cancer.
Space Flight and Control Cohorts had Distinct PPI Networks
Proteinarium Dendrograms revealed significant clusters from space flight and control rodents. Numerous clusters were chosen for further investigation based on the degree of domination according to the exposure to space flight. Significant clusters dominated by space flight included upregulated genes unique to rodents exposed to space flight and not seen in control rodents.
Colorectal:
The hub or most connected proteins exclusive to the Flight group networks include HTR6, GNRHR, PROK1, and NPHS2, with HTR6 being the most highly connected protein in the network.
HTR6 belongs to the seven-transmembrane G protein-coupled receptor family of proteins, and critically links to AMP-dependent signaling pathway and cholinergic neural transmission in the brain. Accumulating evidence in both rodent and human studies suggests that pharmacological blockade of HTR6 signaling improves memory performance[11–16] and mitigates cognitive deficits in animal models of schizophrenia[17]. Several antidepressants and antipsychotic drugs have a high affinity for this receptor, including but not limited to Asenapine, Clozapine, Iloperidone, Imipramine, Amoxapine, Doxepin, Amitriptyline, Mianserin, Zotepine, Haloperidol, and Sertindole. Interestingly, the study of this neurotransmitter receptor in human breast cancer has revealed a significant correlation with patient outcomes and uncovered HTR6 as a gene associated with survival[18].
GNRHR encodes for the type 1 gonadotropin-releasing hormone receptor and is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Defects in this gene are a cause of hypogonadotropic hypogonadism (HH), and overexpression might result in ovarian cancer and other hormone-related cancers[19]. This gene can be co-expressed with GNRHR-II to decrease its cell surface expression using methods of alternative splicing[20]. Multiple GnRH antagonists, such as Cetrorelix, Ganirelix, and Teverelix, in inhibiting GnRH-mediated intracellular signaling, target GNRHR[21].
PROK1 codes for Prokineticin-1 protein that induces proliferation, migration, and fenestration in capillary endothelial cells derived from endocrine glands. PROK1 expression correlates with malignancy in colorectal cancer along with prostate cancer, neuroblastoma, thyroid cancer, pancreatic duct cancer, gastric cancer, and small intestinal cancer, indicating that PROK1 is important for malignant tumor formation[22–26]. RCAN1-4 gene down modulates calcineurin/NFAT pathway, and can play a regulatory role for the inhibition of PROK1-induced IL-8 expression[27]. Triazinedione Derivatives can be used as Prok1 receptor antagonists[28].
The NPHS2 gene encodes for podocin. Podocin is a protein primarily found in podocytes, which are located in glomeruli. Podocin likely helps bring other proteins that are needed for a functional slit diaphragm to the podocyte cell surface, as well as cell signaling.NPHS2 is also related to Type 2 Nephrotic Syndrome. Corticosteroids (prednisone), cyclophosphamide, and cyclosporine are drugs usually used against NPHS-caused Nephrotic Syndrome.
Dorsal Skin:
The hub or most connected proteins exclusive to the Flight group networks include APOA2, AFP, PCP2, and CRP with APOA2 being the most highly connected protein in the network.
APOA2 is the second most abundant protein of the high-density lipoprotein particles. This is associated with pathways such as the assembly, remodeling, and clearance of plasma lipoproteins, as well as with Familial Hyperlipidemia Type 1. It is closely related to lipid binding. Defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia, while overexpression is associated with obesity and insulin resistance[29]. In the liver, overexpression of the humanFOXA3 gene, which encodes a member of the forkhead class of DNA-binding proteins, significantly induced several genes involved in HDL biogenesis, including APOA2[30]. These hepatocyte nuclear factors function as transcriptional activators for liver-specific transcripts such as albumin and transthyretin, while also interacting with chromatin. APO mimetic peptides are designed to mimic structural and functional features of APOs, which show the therapeutic potential for cancer[31].
The AFP gene is responsible for producing alpha-fetoprotein, a significant protein found in plasma that is synthesized by the yolk sac and liver during the developmental stages of a fetus. Overexpression of AFP could enhance the proliferation, invasion, and migration of hepatocellular carcinoma (HCC) cells. AFP-derived peptides[32], AFP fragments, and recombinant AFP (AFP-inhibiting fragments, AIFs) can inhibit the binding of AFP to intracellular proteins for the treatment of HCC and other cancers[33]. This strategy for treating hepatocellular carcinoma (HCC) and other cancers revolves around using peptides derived from alpha-fetoprotein (AFP), fragments of AFP, and recombinant AFP. These components, known as AFP-inhibiting fragments (AIFs), are employed to prevent AFP from binding to its receptors or to proteins within cells.
PCP2 is a protein-coding gene that is related to pathways such as GPCR downstream signaling and Signal Transduction. Diseases associated with PCP2 include Neuropathy[34], and Gaucher Disease[35]. Pertussis toxin treatment can completely block Pcp2-mediated increased neurite growth[36]. Transient transfection of the β-adrenergic receptor kinase C-terminus to prevent signaling through Gβγ in Pcp2-PC12 cells also inhibits the Pcp2-induced phenotype and reduces the Pcp2-stimulated Ras activation.
CRP encodes C-reactive Protein, which belongs to the pentraxin family involved in complement activation and amplification via communication with complement initiation pattern recognition molecules. Overexpression of CRP may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress[37].
Promising new research suggests that treating rats with a rat CRP-specific ASO causes a reduction of blood CRP[38]. This was found to be associated with improved heart function and pathology after myocardial infarction.
Lung:
The hub or most connected proteins exclusive to the Flight group networks include DERL3, NMBR, TRIM69, MAP3K14, and SYNV1 with DERL3 being one of the most highly connected proteins in the network.
DERL3 encodes Derlin-3 protein that belongs to the derlin family and resides in the endoplasmic reticulum to degrade misfolded glycoproteins. Overexpression of DERL 3 is associated with malignant phenotype of breast cancer cells[39].DERL3 can be repressed with DNA methylation techniques[40].The results from past research indicated that the DERL3 low-expression group significantly responded sensitively to the chemotherapeutic agents gemcitabine, etoposide, and docetaxel[41].
NMBR encodes a 7-transmembrane G protein-coupled receptor that binds neuromedin B, which is a growth factor and mitogen for gastrointestinal epithelial tissue[34] and normal and neoplastic lung. It is also associated with smooth muscle contraction, neuronal responses, and the regulation of cell growth. Diseases associated with NMBR include osteosarcoma[38]. Research found that NMBR can be inhibited using CRISPR-Cpf1-based transcription factors[42]. The C terminus of NMBR was fused with a tail sequence from AVPR2 and exhibited little basal activity without the addition of ligands. It is also shown that an NMB-R antagonist, PD168368, suppresses migration and invasion of the human breast cancer cell line MDA-MB-231[43].
The TRIM69 gene codes for a protein belonging to the RING-B-box-coiled-coil (RBCC) family. Its mouse equivalent is expressed exclusively in germ cells during the round spermatid stages of spermatogenesis. When overexpressed, this gene can trigger apoptosis.
MAP3K14 encodes mitogen-activated protein kinase kinasekinase 14. This kinase binds to TRAF2 and stimulates NF-kappaB activity. The protein participates in an NF-kappaB-inducing signaling cascade common to receptors of the tumor-necrosis/nerve-growth factor family.
A study showed that mice with reduced MAP3K14 activity showed less kidney dysfunction, inflammation, and apoptosis[44]. Exosome-mediated delivery of gaa-miR-20a-5p has been shown to target MAP3K14[45].
SYNV1 encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The protein encoded by this gene functions to eliminate unfolded proteins, which accumulate during ER stress, by transporting them in a retrograde manner from the ER to the cytosol. This protein also uses the ubiquitin-proteasome system for additional degradation of unfolded proteins. Mice overexpressing SYNV1 develop severe spontaneous arthropathy[46]. According to previous research, cryptochlorogenic acid (CCA) shows strong affinity with the binding pocket of SEL1L and inhibits SEL1L protein coded by SYNV1[47].