Regulation Of Metabolism Research Articles

Oxytocin: A key regulator of mitochondrial metabolism and energy homeostasis

Oxytocin, traditionally recognized for its roles in social bonding and reproductive behaviors, is emerging as a crucial regulator of mitochondrial metabolism and energy homeostasis. This review synthesizes current research illustrating how oxytocin influences cellular energy processes, particularly within the context of metabolic disorders. By interacting with oxytocin receptors in key metabolic organs, oxytocin modulates mitochondrial biogenesis, enhances glucose uptake, and optimizes energy utilization, thereby contributing to overall metabolic stability. Recent studies in rodent models highlight the potential of oxytocin analogs in ameliorating symptoms of metabolic syndromes, such as obesity and diabetes, by improving mitochondrial function and energy expenditure. This review aims to consolidate these findings, propose mechanisms of action, and discuss the therapeutic prospects of oxytocin in managing metabolic diseases. The implications of oxytocin’s metabolic effects extend beyond traditional reproductive and social domains, suggesting a multifaceted hormone with significant potential for addressing public health challenges related to metabolic disorders.

Beyond blood pressure, fluid and electrolyte homeostasis - Role of the renin angiotensin aldosterone system in the interplay between metabolic diseases and breast cancer.

The classical renin angiotensin aldosterone system (RAAS), as well as the recently described counter-regulatory or non-canonical RAAS have been well characterized for their role in cardiovascular homeostasis. Moreover, extensive research has been conducted over the past decades on both paracrine and the endocrine roles of local RAAS in various metabolic regulations and in chronic diseases. Clinical evidence from patients on RAAS blockers as well as pre-clinical studies using rodent models of genetic manipulations of RAAS genes documented that this system may play important roles in the interplay between metabolic diseases and cancer, namely breast cancer. Some of these studies suggest potential therapeutic applications and repurposing of RAAS inhibitors for these diseases. In this review, we discuss the mechanisms by which RAAS is involved in the pathogenesis of metabolic diseases such as obesity and type-2 diabetes as well as the role of this system in the initiation, expansion and/or progression of breast cancer, especially in the context of metabolic diseases.

MTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.

Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.

Characterization of the genetic variation and evolutionary divergence of the CLEC18 family.

The C-type lectin family 18 (CLEC18) with lipid and glycan binding capabilities is important to metabolic regulation and innate immune responses against viral infection. However, human CLEC18 comprises three paralogous genes with highly similar sequences, making it challenging to distinguish genetic variations, expression patterns, and biological functions of individual CLEC18 paralogs. Additionally, the evolutionary relationship between human CLEC18 and its counterparts in other species remains unclear. To identify the sequence variation and evolutionary divergence of human CLEC18 paralogs, we conducted a comprehensive analysis using various resources, including human and non-human primate reference genome assemblies, human pangenome assemblies, and long-read-based whole-genome and -transcriptomesequencing datasets. We uncovered paralogous sequence variants (PSVs) and polymorphic variants (PVs) of human CLEC18 proteins, and identified distinct signatures specific to each CLEC18 paralog. Furthermore, we unveiled a novel segmental duplication for human CLEC18A gene. By comparing CLEC18 across human and non-human primates, our research showed that the CLEC18 paralogy probably occurred in the common ancestor of human and closely related non-human primates, and the lipid-binding CAP/SCP/TAPS domain of CLEC18 is more diverse than its glycan-binding CTLD. Moreover, we found that certain amino acids alterations at variant positions are exclusive to human CLEC18 paralogs. Our findings offer a comprehensive profiling of the intricate variations and evolutionary characteristics of human CLEC18.

Sr-Incorporated Bioactive Glass Remodels the Immunological Microenvironment by Enhancing the Mitochondrial Function of Macrophage via the PI3K/AKT/mTOR Signaling Pathway.

The repair of critical-sized bone defects continues to pose a challenge in clinics. Strontium (Sr), recognized for its function in bone metabolism regulation, has shown potential in bone repair. However, the underlying mechanism through which Sr2+ guided favorable osteogenesis by modulating macrophages remains unclear, limiting their application in the design of bone biomaterials. Herein, Sr-incorporated bioactive glass (SrBG) was synthesized for further investigation. The release of Sr ions enhanced the immunomodulatory properties and osteogenic potential by modulating the polarization of macrophages toward the M2 phenotype. In vivo, a 3D-printed SrBG scaffold was fabricated and showed consistently improved bone regeneration by creating a prohealing immunological microenvironment. RNA sequencing was performed to explore the underlying mechanisms. It was found that Sr ions might enhance the mitochondrial function of macrophage by activating PI3K/AKT/mTOR signaling, thereby favoring osteogenesis. Our findings demonstrate the relationship between the immunomodulatory role of Sr ions and the mitochondrial function of macrophages. By focusing on the mitochondrial function of macrophages, Sr2+-mediated immunomodulation sheds light on the future design of biomaterials for tissue regenerative engineering.

Regulation of carbohydrate metabolism and insulin secretion in diabetic rats following treatment with Hypericum perforatum L. hairy root aqueous methanol extract

Hairy root (HR) cultures of Hypericum perforatum L. have shown promise in controlling hyperglycemia, regulating blood lipid and enzyme profiles, and improving metabolic function in vivo. These benefits are mainly attributed to the phenolic acids, flavonoids, and xanthones present in HR extracts. However, the specific mechanism underlying these effects remains unclear. This study was performed to elucidate the biochemical and molecular mechanisms driving HR the antihyperglycemic and antidiabetic effects of HR extracts. HR extract (200 mg/kg body weight) was administered daily for 14 days to healthy rats and rats with streptozotocin-induced diabetes, with glibenclamide serving as a positive control. The phenolic composition of the HR extracts was confirmed through high-performance liquid chromatography/diode array detection/electrospray ionization mass spectrometry (HPLC/DAD/ESI-MSn ) analysis. The results showed that HR extract treatment increased the plasma insulin level and pancreatic poly (adenosine diphosphate-ribose) polymerase (PARP) activity in diabetic rats, thus normalizing blood glucose levels. Additionally, it reduced the activity of gluconeogenic enzymes, increased the activity of glycolytic enzymes, and normalized the glycogen content in the liver. HR extract-treated rats also exhibited increased hepatic adenosine monophosphate-activated protein kinase (AMPK) mRNA expression and a decreased protein kinase Cε (PKCε) concentration. In conclusion, HR extract demonstrated insulinotropic effects and effectively regulated hepatic carbohydrate metabolism in diabetic rats by modulating AMPK expression and the PKCε concentration. These findings suggest the potential use of HR extract as an herbal medicine for diabetes treatment and a source of antidiabetic drug development.

Targeting Intrinsic and Extrinsic Pathways of Ferroptosis: A Novel Anticancer Strategy of Curcumin

Background The turmeric rhizome yields a medicinal compound called curcumin. Curcumin’s anticancer methods mostly involve blocking cell invasion and proliferation, controlling gene expression, preventing angiogenesis, triggering apoptosis, and inducing ferroptosis. A brand-new nonapoptotic kind of planned cell death is called ferroptosis. Ferroptosis can be initiated through two major pathways: the extrinsic or transporter-dependent pathway, and the intrinsic or enzyme-regulated pathway. It is unknown, therefore, how curcumin and its derivatives prevent cancer by controlling ferroptosis. Purpose Through this review, we concentrate on the possible anticancer mechanisms of curcumin by means of its effect on ferroptosis; the regulation of iron metabolism, the synthesis of reactive oxygen species, and the targeting of antioxidant pathways represent a few of these processes. Methods Retrieve English literature of curcumin and its derivatives in the treatment of tumor by ferroptosis from databases such as Web of Science, etc. Conclusion This review provides a rationale for the clinical use of curcumin and its derivatives as anticancer agents.

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets

BackgroundInfection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored.ResultsOur results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells.ConclusionsIn conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.Graphical

Metformin-induced changes of the gut microbiota in patients with type 2 diabetes mellitus: results from a prospective cohort study.

The influence of the microbiota on hypoglycemic agents is becoming more apparent. The effects of metformin, a primary anti-diabetes drug, on gut microbiota are still not fully understood. This prospective cohort study aims to investigate the longitudinal effects of metformin on the gut microbiota of 25 treatment-naïve diabetes patients, each receiving a daily dose of 1500 mg. Microbiota compositions were analyzed at baseline, and at 1, 3, and 6 months of medication using 16S rRNA gene sequencing. Prior to the 3-month period of metformin treatment, significant improvements were noted in body mass index (BMI) and glycemic-related parameters, such as fasting blood glucose (FPG) and hemoglobin A1c (HbA1c), alongside homeostasis model assessment indices of insulin resistance (HOMA-IR). At the 3-month mark of medication, a significant reduction in the α-diversity of the gut microbiota was noted, while β-diversity exhibited no marked variances throughout the treatment duration. The Firmicutes to Bacteroidetes ratio. markedly decreased. Metformin treatment consistently increased Escherichia-Shigella and decreased Romboutsia, while Pseudomonas decreased at 3 months. Fuzzy c-means clustering identified three longitudinal trajectory clusters for microbial fluctuations: (i) genera temporarily changing, (ii) genera continuing to decrease (Bacteroides), and (iii) genera continuing to increase(Lachnospiraceae ND3007 group, [Eubacterium] xylanophilum group, Romboutsia, Faecalibacterium and Ruminococcaceae UCG-014). The correlation matrix revealed associations between specific fecal taxa and metformin-related clinical parameters HbA1c, FPG, Uric Acid (UA), high-density lipoproteincholesterol (HDL-C), alanine aminotransferase (ALT), hypersensitive C-reactive protein (hs-CRP), triglyceride (TG) (P < 0.05). Metacyc database showed that metformin significantly altered 17 functional pathways. Amino acid metabolism pathways such as isoleucine biosynthesis predominated in the post-treatment group. Metformin's role in glucose metabolism regulation may primarily involve specific alterations in certain gut microbial species rather than an overall increase in microbial species diversity. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by metformin.

Titanium dioxide nanoparticles alleviates polystyrene nanoplastics induced growth inhibition by modulating carbon and nitrogen metabolism via melatonin signaling in maize.

Nanoplastics, are emerging pollutants, present a potential hazard to food security and human health. Titanium dioxide nanoparticles (Nano-TiO2), serving as nano-fertilizer in agriculture, may be important in alleviating polystyrene nanoplastics (PSNPs) toxicity. Here, we performed transcriptomic, metabolomic and physiological analyzes to identify the role of Nano-TiO2 in regulating the metabolic processes in PSNPs-stressed maize seedlings (Zea mays L.). The growth inhibition by PSNPs stress was partially relieved by Nano-TiO2. Furthermore, when considering the outcomes obtained from RNA-seq, enzyme activity, and metabolite content analyses, it becomes evident that Nano-TiO2 significantly enhance carbon and nitrogen metabolism levels in plants. In comparison to plants that were not subjected to Nano-TiO2, plants exposed to Nano-TiO2 exhibited enhanced capabilities in maintaining higher rates of photosynthesis, sucrose synthesis, nitrogen assimilation, and protein synthesis under stressful conditions. Meanwhile, Nano-TiO2 alleviated the oxidative damage by modulating the antioxidant systems. Interestingly, we also found that Nano-TiO2 significantly enhanced the endogenous melatonin levels in maize seedlings. P-chlorophenylalanine (p-CPA, a melatonin synthesis inhibitor) declined Nano-TiO2-induced PSNPs tolerance. Taken together, our data show that melatonin is involved in Nano-TiO2-induced growth promotion in maize through the regulation of carbon and nitrogen metabolism.

Inducing ferroptosis via nanomaterials: a novel and effective route in cancer therapy

Abstract The use of nanomaterials for cancer ferroptosis presents a promising avenue for research and clinical applications. The unique properties of nanomaterials, such as their small size, large surface area, and ability to be engineered for specific tasks, make them ideal candidates for ferroptosis inducing cancer therapies. Ferroptosis is a new type of cell death mechanism that is distinct from apoptosis and necrosis. It has been shown to be critical in the treatment of various tumors. The ferroptotic mechanism has been mainly linked with the regulation of iron, amino acid, glutathione, and lipid metabolism of cells. The relationship between ferroptosis mechanisms and cancer nanomedicine has attracted considerable interest in recent years. It has been reported that the combination of nanomedicine and ferroptosis can achieve high therapeutic efficacy for the treatment of different cancer types. This review will provide an overview of recent work in ferroptosis-related cancer nanomedicine. First, general information is given about the definition of ferroptosis and its differences from other cell death mechanisms. Later, studies exploring the role of ferroptosis in the cancer nanomedicine field are discussed in detail. Specific focus has been given to the use of combinatorial treatment strategies which combine ferroptosis with chemodynamic therapy, photodynamic therapy, photothermal therapy, immunotherapy and sonodynamic therapy. Considering the fact that ferroptosis inducing nanoparticles have already been introduced into clinical studies, nanoscientists can further accelerate this clinical translation as they tailor the physicochemical characteristics of nanomaterials. This review provides enlightening information for all researchers interested in the molecular characterization and relationship between ferroptosis and cancer-directed nanoparticles.

Regulation of copper uptake by the SWI/SNF chromatin remodeling complex in Candida albicans affects susceptibility to antifungal and oxidative stresses under hypoxia.

Candida albicans is a human colonizer and also an opportunistic yeast occupying different niches that are mostly hypoxic. While hypoxia is the prevalent condition within the host, the machinery that integrates oxygen status to tune the fitness of fungal pathogens remains poorly characterized. Here, we uncovered that, Snf5, a subunit of the chromatin remodeling complex SWI/SNF, is required to tolerate antifungal stress particularly under hypoxia. RNA-seq profiling of snf5 mutant exposed to amphotericin B and fluconazole under hypoxic conditions uncovered a signature that is reminiscent of copper (Cu) starvation. We found that under hypoxic and Cu-starved environments, Snf5 is critical for preserving Cu homeostasis and the transcriptional modulation of the Cu regulon. Furthermore, snf5 exhibits elevated levels of reactive oxygen species and an increased sensitivity to oxidative stress principally under hypoxia. Supplementing growth medium with Cu or increasing gene dosage of the copper transporter CTR1 alleviated snf5 growth defect and attenuated ROS levels in response to antifungal challenge. Genetic interaction analysis suggests that Snf5 and the bona fide Cu homeostasis regulator Mac1, function in separate pathways. Together, our data underlined a unique role of SWI/SNF complex as a potent regulator of copper metabolism and antifungal stress under hypoxia.

Metabolomic analysis reveals the molecular mechanism related to leg abnormality in broilers

AbstractRapid body weight gain in broilers overloads the metabolic system of the organism, resulting in leg abnormalities, which seriously affects animal welfare and industry economics. In this study, broilers with normal and deformed leg bones were examined. Serum biochemical indices showed that the serum calcium to phosphorus ratio was extremely decreased in leg deformed group. In addition, abnormal serum lipid levels suggested a disruption in lipid metabolism. Based on widely targeted metabonomic analysis of serum and cartilage tissues, a total of nine differential metabolites (DMs) significantly associated with leg abnormalities and serum calcium and phosphorus levels were screened, including carnitine C16:0, carnitine C18:1, 3‐hydroxymethyl‐L‐tyrosine, cis‐4‐hydroxy‐D‐proline, cis‐L‐3‐hydroxyproline, trans‐4‐hydroxy‐L‐proline, and so on. Pathway analysis revealed that fatty acid degradation and arachidonic acid metabolism were enriched. Analysis of DMs in these two pathways showed that prostaglandin D2, prostaglandin J2, prostaglandin A2, 15‐keto prostaglandin F2α, and Δ12‐prostaglandin J2 significantly differed between the normal and abnormal groups. It was hypothesized that these important metabolic pathways and metabolites were involved in the metabolic regulation of leg abnormalities.

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species (ROS)-mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals (•OH). Its notable advantages in cancer treatment have been demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine have been devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment. This article is protected by copyright. All rights reserved.

Nuclear export is a limiting factor in eukaryotic mRNA metabolism.

The eukaryotic mRNA life cycle includes transcription, nuclear mRNA export and degradation. To quantify all these processes simultaneously, we perform thiol-linked alkylation after metabolic labeling of RNA with 4-thiouridine (4sU), followed by sequencing of RNA (SLAM-seq) in the nuclear and cytosolic compartments of human cancer cells. We develop a model that reliably quantifies mRNA-specific synthesis, nuclear export, and nuclear and cytosolic degradation rates on a genome-wide scale. We find that nuclear degradation of polyadenylated mRNA is negligible and nuclear mRNA export is slow, while cytosolic mRNA degradation is comparatively fast. Consequently, an mRNA molecule generally spends most of its life in the nucleus. We also observe large differences in the nuclear export rates of different 3'UTR transcript isoforms. Furthermore, we identify genes whose expression is abruptly induced upon metabolic labeling. These transcripts are exported substantially faster than average mRNAs, suggesting the existence of alternative export pathways. Our results highlight nuclear mRNA export as a limiting factor in mRNA metabolism and gene regulation.

Role of T cells in liver metastasis.

The liver is a major metastatic site (organ) for gastrointestinal cancers (such as colorectal, gastric, and pancreatic cancers) as well as non-gastrointestinal cancers (such as lung, breast, and melanoma cancers). Due to the innate anatomical position of the liver, the apoptosis of T cells in the liver, the unique metabolic regulation of hepatocytes and other potential mechanisms, the liver tends to form an immunosuppressive microenvironment and subsequently form a pre-metastatic niche (PMN), which can promote metastasis and colonization by various tumor cells(TCs). As a result, the critical role of immunoresponse in liver based metastasis has become increasingly appreciated. T cells, a centrally important member of adaptive immune response, play a significant role in liver based metastases and clarifying the different roles of the various T cells subsets is important to guide future clinical treatment. In this review, we first introduce the predisposing factors and related mechanisms of liver metastasis (LM) before introducing the PMN and its transition to LM. Finally, we detail the role of different subsets of T cells in LM and advances in the management of LM in order to identify potential therapeutic targets for patients with LM.

Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies.

Diosmetin, a natural occurring flavonoid, is primarily found in citrus fruits, beans, and other plants. Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The process of literature search was done using PubMed, Web of Science and ClinicalTrials databases with search terms containing Diosmetin, content, anticancer, anti-inflammatory, antioxidant, pharmacological activity, pharmacokinetics, in vivo, and in vitro. The aim of this review is to summarize the in vivo, in vitro and clinical studies of Diosmetin over the last decade, focusing on studies related to its anticancer, anti-inflammatory, and antioxidant activities. It is found that DIO has significant therapeutic effects on skin and cardiovascular system diseases, and its research in pharmacokinetics and toxicology is summarized. It provides the latest information for researchers and points out the limitations of current research and areas that should be strengthened in future research, so as to facilitate the relevant scientific research and clinical application of DIO.

RPGRIP1L as a new biomarker for prognosis and tumor immune of breast cancer.

The Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) gene encodes an important protein that performs various physiological functions. Variants of RPGRIP1L are related to a number of diseases. However, it is currently unknown whether RPGRIP1L is correlated with breast invasive carcinoma (BRCA). In BRCA tissue specimens, the expression of RPGRIP1L was found to be elevated in comparison to its levels in normal breast tissue. A notable decline in survival rates was associated with patients exhibiting heightened RPGRIP1L gene expression. Consistent with these findings, our data also show the above results. Furthermore, elevated expression of RPGRIP1L corresponded with a spectrum of unfavorable clinicopathological features, including the presence of human epidermal growth factor receptor 2 (HER2) positive, estrogen receptor (ER) positive, over 60 years old, T2, N0, and N3. At the same time, our research indicated that 50 genes and 15 proteins were positively related to RPGRIP1L, and that these proteins and genes were mostly involved in T cell proliferation, immune response, cytokine activity, and metabolic regulation. In addition, in the present study, there was a significant correlation between RPGRIP1L expression and immune cell infiltration. Finally, we found that four Chemicals could downregulate the expression of RPGRIP1L. Altogether, our results strongly indicated that RPGRIP1L might serve as a new prognostic biomarker for BRCA.

SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P.

SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1PA to mature S1PC form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1PA into its mature S1PC form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRINGKO cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1PA→C and trafficking of S1PC to the Golgi. However, despite reaching the Golgi in SPRINGKO cells, S1PC fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRINGKO cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.

Antiviral Shrimp lncRNA06 Possesses Anti-Tumor Activity by Inducing Apoptosis of Human Gastric Cancer Stem Cells in a Cross-Species Manner

Virus infection causes the metabolic disorder of host cells, whereas the metabolic disorder of cells is one of the major causes of tumorigenesis, suggesting that antiviral molecules might possess anti-tumor activities by regulating cell metabolism. As the key regulators of gene expression, long non-coding RNAs (lncRNAs) play vital roles in the regulation of cell metabolism. However, the influence of antiviral lncRNAs on tumorigenesis has not been explored. To address this issue, the antiviral and anti-tumor capacities of shrimp lncRNAs were characterized in this study. The results revealed that shrimp lncRNA06, having antiviral activity in shrimp, could suppress the tumorigenesis of human gastric cancer stem cells (GCSCs) via triggering apoptosis of GCSCs in a cross-species manner. Shrimp lncRNA06 could sponge human miR-17-5p to suppress the stemness of GCSCs via the miR-17-5p-p21 axis. At the same time, shrimp lncRNA06 could bind to ATP synthase subunit beta (ATP5F1B) to enhance the stability of the ATP5F1B protein in GCSCs, thus suppressing the tumorigenesis of GCSCs. The in vivo data demonstrated that shrimp lncRNA06 promoted apoptosis and inhibited the stemness of GCSCs through interactions with ATP5F1B and miR-17-5p, leading to the suppression of the tumorigenesis of GCSCs. Therefore, our findings highlighted that antiviral lncRNAs possessed anti-tumor capacities and that antiviral lncRNAs could be the anti-tumor reservoir for the treatment of human cancers.