The cAMP-responsive transcription factor CREB functions in adipose tissue and liver to regulate glycogen and lipid metabolism in mammals. While Drosophila has a homolog of mammalian CREB, dCREB2, its role in energy metabolism is not fully understood. Using tissue-specific expression of a dominant-negative form of CREB (DN-CREB), we have examined the effect of blocking CREB activity in neurons and in the fat body, the primary energy storage depot with functions of adipose tissue and the liver in flies, on energy balance, stress resistance and feeding behavior. We found that disruption of CREB function in neurons reduced glycogen and lipid stores and increased sensitivity to starvation. Expression of DN-CREB in the fat body also reduced glycogen levels, while it did not affect starvation sensitivity, presumably due to increased lipid levels in these flies. Interestingly, blocking CREB activity in the fat body increased food intake. These flies did not show a significant change in overall body size, suggesting that disruption of CREB activity in the fat body caused an obese-like phenotype. Using a transgenic CRE-luciferase reporter, we further demonstrated that disruption of the adipokinetic hormone receptor, which is functionally related to mammalian glucagon and beta-adrenergic signaling, in the fat body reduced CRE-mediated transcription in flies. This study demonstrates that CREB activity in either neuronal or peripheral tissues regulates energy balance in Drosophila, and that the key signaling pathway regulating CREB activity in peripheral tissue is evolutionarily conserved.
Abstract Aim: The c‐myc proto‐oncogene is over‐expressed in synoviocytes from patients with rheumatoid arthritis (RA). For improving the inhibition of c‐myc antisense oligodeoxynucleotides (AS ODN) on RA synoviocytes proliferation, we used two antisense sequences: one (antimyc‐AUG AS ODN) targeting the initiation codon (AUG) and the next four codons on c‐myc mRNA; another (antimyc‐CRD AS ODN) targeting the coding region determinant (CRD) on c‐myc mRNA to investigate if there was a difference on inhibiting synoviocytes proliferation. Methods: Cultured human synoviocytes from patients with RA. The sequences were modified by phosphorothioates. Lipofectin was used as carrier. MTT assay was used to examine the inhibition of cell proliferation. Results: Antimyc‐AUG AS ODN and antimyc‐CRD AS ODN both can inhibit synoviocytes proliferation dose‐dependently. The maximum decrement of cell number was 40% at 2.5 µM and 48 h, 41.4% at 5 µM and 48 h, respectively. The action time of antimyc‐AUG AS ODN inhibiting synoviocytes proliferation was earlier than that of antimyc‐CRD AS ODN. ODN at high levels had non‐sequence‐specific cytotoxicity. Conclusions: Both c‐myc AS ODN are useful in inhibiting synoviocytes proliferation.
Background. Functional constipation (FC) is one of the prevalent gastrointestinal disorders that affect people of all ages. Long-term FC has significant effects on the quality of life of patients. Although commonly used drugs have reliable short-term effects, they are easily addictive and have side effects. Therefore, pursuing a convenient drug-food homogenous program is critical for FC patients. Maxing Xianchang Su is a functional food based on traditional Chinese medicine. To investigate the efficacy and safety of Maxing Xianchang Su in FC treatment, we conducted a randomized controlled trial. Methods. We carried out a prospective multicenter randomized parallel controlled study in three hospitals in Jiangsu Province, China, from January 2020 to March 2021, which included 206 FC patients. All patients were arbitrarily assigned into a treatment group and a control group at a ratio of 1 : 1; 103 cases in each group. The treatment group was given oral Maxing Xianchang Su, whereas the control group was treated with lactulose oral solution. The course of treatment was two weeks. The two groups of patients were evaluated after six weeks for symptom improvement before and after taking the drug. Furthermore, the safety of Maxing Xianchang Su was assessed. Results. Both groups of patients successfully completed the study without shedding cases. The effective rates of the treatment group and control group after two weeks were 90.6% and 67.0%, respectively. The treatment group had a better curative effect than the control group ( ). The symptom score of the two groups improved compared with that before the treatment. The difference between the two groups was statistically significant ( ). During the treatment process, neither group experienced abnormal changes in blood lipid, blood glucose, routine hematuria, or liver and kidney functions. There were no adverse reactions in both groups. Conclusion. Maxing Xianchang Su has a positive effect on FC treatment with reliable mid-term effect and a high level of safety.
Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide each year. Our previous research demonstrated that heme oxygenase-1 (HO-1) can suppress PRRSV replication via an unknown molecular mechanism. In this study, inhibition of PRRSV replication was demonstrated to be mediated by carbon monoxide (CO), a downstream metabolite of HO-1. Using several approaches, we demonstrate that CO significantly inhibited PRRSV replication in both a PRRSV permissive cell line, MARC-145, and the predominant cell type targeted during in vivo PRRSV infection, porcine alveolar macrophages (PAMs). Our results showed that CO inhibited intercellular spread of PRRSV; however, it did not affect PRRSV entry into host cells. Furthermore, CO was found to suppress PRRSV replication via the activation of the cyclic GMP/protein kinase G (cGMP/PKG) signaling pathway. CO significantly inhibits PRRSV-induced NF-κB activation, a required step for PRRSV replication. Moreover, CO significantly reduced PRRSV-induced proinflammatory cytokine mRNA levels. In conclusion, the present study demonstrates that CO exerts its anti-PRRSV effect by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.PRRSV causes great economic losses each year to the swine industry worldwide. Carbon monoxide (CO), a metabolite of HO-1, has been shown to have antimicrobial and antiviral activities in infected cells. Our previous research demonstrated that HO-1 can suppress PRRSV replication. Here we show that endogenous CO produced through HO-1 catalysis mediates the antiviral effect of HO-1. CO inhibits PRRSV replication by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.
Abstract Objective Endometrial carcinoma (EC) is one of the most prevalent types of gynecologic cancer. The purpose of this work was to identify the metabolic-related biological characteristics of endometrial cancer and to investigate the immune-related molecular pathways of carcinogenesis in endometrial cancer. Methods Data from The Cancer Genome Atlas (TCGA) were utilized to identify lipid metabolism-related genes (LMRGs) with significant correlations to the prognosis of EC patients. Enrichment of functional pathways within the LMRGs was studied. LASSO and Cox regression analysis were conducted to identify LMRGs that were significantly associated with the prognosis of EC patients. We created a prognostic signature and proved its effectiveness in both training and validation groups. In addition, we constructed a complete nomogram consisting of risk models and clinical variables to estimate the survival probability of EC patients. Results ACOT11, CYP1A2, GDPD5, MOGAT3, OLAH, PIASS4, PIP5K1C, PLPP2, and SRD5A1 were discovered to be strongly associated with the clinical outcomes of EC patients. On the basis of these nine LMRGs, we generated and validated our predictive signature using the training and validation cohorts. In addition to being independent of other clinical factors, the nine-LMRG signature distinguished between patients at high- and low-risk for EC and predict EC patient's probability of survival. Statistically, the nomogram exhibited a high correlation between survival forecasts and observations. In the high-risk group, immune/stromal scores were lower and there was a higher density of several kinds of immune cells. Conclusions The LMRG's prognostic model and comprehensive nomogram could guide therapeutic choices in clinical practice, and explore the underlying mechanisms involved in EC progression.
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