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Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.

Golgi protein 73 (GP73), also called Golgi membrane protein 1 (GOLM1), is a resident Golgi type II transmembrane protein and is considered as a serum marker for the detection of a variety of cancers. A recent work revealed the role of the secreted GP73 in stimulating liver glucose production and systemic glucose homeostasis. Since exaggerated hepatic glucose production plays a key role in the pathogenesis of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), GP73 may thus represent a potential therapeutic target for treating diabetic patients with pathologically elevated levels. Here, in this study, we found that the circulating GP73 levels were significantly elevated in T2DM and positively correlated with hemoglobin A1c. Notably, the aberrantly upregulated GP73 levels were indispensable for the enhanced protein kinase A signaling pathway associated with diabetes. In diet-induced obese mouse model, GP73 siRNA primarily targeting liver tissue was potently effective in alleviating abnormal glucose metabolism. Ablation of GP73 from whole animals also exerted a profound glucose-lowering effect. Importantly, neutralizing circulating GP73 improved glucose metabolism in streptozotocin (STZ) and high-fat diet/STZ-induced diabetic mice. We thus concluded that GP73 was a feasible therapeutic target for the treatment of diabetes.

The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention., Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia withoutdenovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF α . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy.Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNFα-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

Surgery can be used to remove tumors from patients with colon cancer, but some patients have recurrence a short time after the tumor is surgically removed, and the disease-free survival (DFS) period is short. Therefore, if these high-risk patients can be identified as early as possible, appropriate treatment strategies can be formulated to reduce their postoperative recurrence rate. Tumor immune scores have been proven to be effective in predicting the prognosis of patients, but the scoring can only be performed after the tumor has been removed from the patient. There is still urgency to find indicators that can predict the prognosis of patients before surgery. We used electrochemiluminescence electrodes modified with nanomaterials to detect the expression of serum markers. After comparison, it was found that the contents of CEA, AFP, CA19-9, and CA125 in patients with CRC were substantially higher than those with benign colonic disease. Pearson correlation analysis showed that CEA, AFP, CA19-9, and CA125 contents are positive correlated to the patient’s tumor immune score. Further investigation found that patients with high expression of CEA, AFP, CA19-9, and CA125 had a three-year DFS rate, which was substantially lower than those with low expression. Therefore, our findings suggest that the use of the composite nano-modified electrode electrochemiluminescence method to detect the content of CEA, AFP, CA19-9, and CA125 in patients with colorectal cancer can predict DFS after surgery to a certain extent. Additionally, the perioperative data plan can be adjusted in time according to the expression of tumor markers before surgery.

Objective. A retrospective cohort study was carried out to research the effect of stent combined with laparoscopy combined with enhanced recovery after surgery (ERAS) in the operation of acute intestinal obstruction and to explore and analyze the prognostic factors. Methods. During February 2019 to April 2021, sixty patients with acute intestinal obstruction cured in our hospital were enrolled. Randomly assigned control group patients ( n = 50 ) were divided into the research group and control group patients. The control group accepted stent combined with laparoscopic therapeutic, and the research group accepted stent combined with laparoscopic therapeutic based on ERAS. The general data, operative index, Short Form 36 (SF-36) score, visual analogue scale (VAS) score, procalcitonin (PCT), CRP, prealbumin (PA) index, curative effect, and incidence of complications were investigated. Results. No difference was found in age, gender, or type of disease among the general population ( P > 0.05 ). A lower amount of blood was lost during the operation, less anal exhaustion was experienced by the research group, and a shorter hospital stay and lower hospitalization cost was experienced in the research group compared to the control group ( P < 0.05 ). There exhibited no remarkable difference in SF-36 score and VAS score before operation, but after operation, the VAS score lessened, the SF-36 score augmented, while the VAS score was lower, and the SF-36 score in the research group was higher ( P < 0.05 ). There exited no remarkable difference in the indexes of PCT, CRP, and PA before operation, but after operation, the levels of PCT and CRP lessened as well as the level of PA augmented, and the levels of PCT and CRP were lower, while the level of PA in the research group was higher. In terms of the clinical efficacy, the effective rate of the research group (98.00%) was higher compared to the control (86.00%) ( P < 0.05 ). The main postoperative complications were pulmonary infection and incision infection. One case of incision infection occurred in the research group, and the probability of postoperative complications was 2.00%. In the control group, there were 3 cases of pulmonary infection, 0 cases of perforation, and 4 cases of incision infection, and the probability of postoperative complications was 14.00%. The prevalence in the research group was remarkably lower ( P < 0.05 ). Conclusion. Compared with the traditional concept of surgical therapeutic, it can more effectively reduce stress reaction, relieve postoperative pain, promote the recovery of postoperative gastrointestinal function as soon as possible, and reduce postoperative complications, which is worth to explore the application in the therapeutic of acute abdomen.

Acyl-CoA:diacylglycerol acyltransferase (DGAT) catalyzes the final committed step in triacylglycerol biosynthesis in eukaryotes. In microalgae, the copy number of DGAT genes is extraordinarily expanded, yet the functions of many DGATs remain largely unknown. This study revealed that microalgal DGAT can function as a lysophosphatidic acyltransferase (LPAAT) both in vitro and in vivo while losing its original function as DGAT. Among the five DGAT-encoding genes identified and cloned from the green microalga Haematococcus pluvialis, four encoded HpDGATs that showed triacylglycerol synthase activities in yeast functional complementation analyses; the exception was one of the type II DGAT encoding genes, HpDGTT2. The hydrophobic recombinant HpDGTT2 protein was purified in soluble form and was found to function as a LPAAT via enzymatic assay. Introducing this gene into the green microalga Chlamydomonas reinhardtii led to retarded cellular growth, enlarged cell size, and enhanced triacylglycerol accumulation, identical to the phenotypes of transgenic strains overexpressing CrLPAAT. This study provides a framework for dissecting uncharacterized DGATs, and could pave the way to decrypting the structure–function relationship of this large group of enzymes that are critical to lipid biosynthesis., One copy of acyl-CoA:diacylglycerol acyltransferase (DGAT) from microalgae can function as a lysophosphatidic acyltransferase both in vitro and in vivo while losing its original function as DGAT.

Overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types and targeting Mps1 for tumor therapy has been shown great promise in multiple preclinical cancer models. However, the role of Mps1 in tamoxifen resistance in breast cancer has never been reported. Here in this study, we report that Mps1 determined the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while Mps1 inhibitor or siMps1 oligos could overcome tamoxifen resistance. Mechanistically, Mps1 interacted with ERα and stimulated its transcriptional activity in kinase activity-dependent manner. Mps1 was responsible for ERα phosphorylation at S559 and T224 sites. Importantly, Mps1 failed to enhance the transcriptional activity of ERα in the presence of ERα S559A or T224A mutant. Collectively, our findings suggest that Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic to overcome tamoxifen resistance in breast cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.

Background Circular RNA 0029803 (circ_0029803) was found to be upregulated in colorectal cancer (CRC) tissues, but its function and underlying molecular mechanism are not studied in CRC. Methods The expression levels of circ_0029803, microRNA-216b-5p (miR-216b-5p), and ski-oncogene-like (SKIL) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R treatment was used to affirm the existence of circ_0029803. Cell proliferation, apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, and Transwell assays, respectively. A glucose and lactate assay kit was used to detect glucose consumption and lactate production. Western blot was applied to analyze the levels of all proteins. Dual-luciferase reporter assay was performed to assess the relationship between miR-216b-5p and circ_0029803 or SKIL. Tumor xenograft models were established to elucidate the effect of circ_0029803 in vivo. Results Circ_0029803 expression was enhanced in CRC tissues and cells, and the 5-year overall survival rate of patients with high circ_0029803 expression was substantially reduced. Circ_0029803 depletion retarded proliferation, migration, invasion, EMT and glycolysis of CRC cells in vitro as well as the tumor growth in vivo. Mechanically, circ_0029803 could serve as miR-216b-5p sponge to regulate its expression, and miR-216b-5p knockdown reversed the inhibition of si-circ_0029803 on the malignant behaviors of CRC cells. Additionally, as the target mRNA of miR-216b-5p, SKIL could counteract the inhibitory effect of miR-216b-5p on the development of CRC cells. Importantly, silencing circ_0029803 reduced SKIL expression via sponging miR-216b-5p. Conclusion Circ_0029803 knockdown hindered proliferation, migration, invasion, EMT, and glycolysis and promoted apoptosis in CRC cells by modulating the miR-216b-5p/SKIL axis.

The plastidial lysophosphatidic acid acyltransferase of the unicellular green alga Chlamydomonas reinhardtii (CrLPAAT1) is a key enzyme involved in triacylglycerol biosynthesis. However, research on the biochemical characteristics of CrLPAAT1 has been impeded by its membrane-bound nature. In this study, the recombinant CrLPAAT1 was purified in a soluble form and was utilized for comprehensive biochemical characterization. The recombinant CrLPAAT1 favors the conditions of pH 6.5–7.5, 30 °C and the presence of magnesium ion in vitro. Similar with the CrLPAAT1 associated with the membranes, the purified CrLPAAT1 prefers to utilize C16:0-CoA over other acyl donors, whereas it showed broader substrate selectivity than the membrane-bound enzyme. By comparing the wild-type CrLPAAT1 and a transmembrane domain-truncated enzyme, it was uncovered in this study that the two transmembrane domains of CrLPAAT1 are involved in shaping its substrate preference for C16:0-CoA. Additionally, CrLPAAT1 was found to be interacting with the water-soluble plastidial glycerol-3-phosphate acyltransferase (CrGAPTcl) via its two transmembrane domains in vitro. The interaction between CrLPAAT1 and CrGPATcl can be negatively regulated by both the acyl-CoAs and lysophosphatidic acid in a dosage-dependent manner. Such a regulation pattern may represent a novel mechanism adopted by algal cells to control lipid metabolism homeostasis under various environmental conditions.