Role In Metabolism Research Articles

The Molecular Mechanism Underlying the Therapeutic Effect of Dihydromyricetin on Type 2 Diabetes Mellitus Based on Network Pharmacology, Molecular Docking, and Transcriptomics.

Type 2 diabetes mellitus (T2DM) is a chronic and complex disease, and traditional drugs have many side effects. The active compound dihydromyricetin (DHM), derived from natural plants, has been shown in our previous study to possess the potential for reducing blood glucose levels; however, its precise molecular mechanism remains unclear. In the present study, network pharmacology and transcriptomics were performed to screen the molecular targets and signaling pathways of DHM disturbed associated with T2DM, and the results were partially verified by molecular docking, RT-PCR, and Western blotting at in vivo levels. Firstly, the effect of DHM on blood glucose, lipid profile, and liver oxidative stress in db/db mice was explored and the results showed that DHM could reduce blood glucose and improve oxidative stress in the liver. Secondly, GO analysis based on network pharmacology and transcriptomics results showed that DHM mainly played a significant role in anti-inflammatory, antioxidant, and fatty acid metabolism in biological processes, on lipoprotein and respiratory chain on cell components, and on redox-related enzyme activity, iron ion binding, and glutathione transferase on molecular functional processes. KEGG system analysis results showed that the PI3K-Akt signaling pathway, IL17 signaling pathway, HIF signaling pathway, MAPK signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway were typical signaling pathways disturbed by DHM in T2DM. Thirdly, molecular docking results showed that VEGFA, SRC, HIF1A, ESR1, KDR, MMP9, PPARG, and MAPK14 are key target genes, five genes of which were verified by RT-PCR in a dose-dependent manner. Finally, Western blotting results revealed that DHM effectively upregulated the expression of AKT protein and downregulated the expression of MEK protein in the liver of db/db mice. Therefore, our study found that DHM played a therapeutic effect partially by activation of the PI3K/AKT/MAPK signaling pathway. This study establishes the foundation for DHM as a novel therapeutic agent for T2DM. Additionally, it presents a fresh approach to utilizing natural plant extracts for chemoprevention and treatment of T2DM.

Inhibition of Hyperglycemia and Hyperlipidemia by Blocking Toll-like Receptor 4: Comparison of Wild-Type and Toll-like Receptor 4 Gene Knockout Mice on Obesity and Diabetes Modeling.

Innate immune receptor TLR4 plays an important role in glycolipid metabolism. The objective of this study is to investigate the inhibitory effects of blocking TLR4 on hyperglycemia and hyperlipidemia by comparing WT and TLR4-/- mice in obesity and diabetes modeling. The knockout of the TLR4 gene could prevent weight gain induced by a high-fat diet (HFD)/high-sugar and high-fat diet (HSHFD), and the differences in the responses existed between the sexes. It extends the time required to reach the obesity criteria. However, when mice were injected with intraperitoneal streptozotocin (STZ) after being fed by HSHFD for two months, TLR4-/- mice exhibited less weight loss than WT. Blocking TLR4 alleviated the changes in body weight and blood glucose, consequently reducing the efficiency of diabetes modeling, especially for male mice. Additionally, male TLR4-/- obese mice exhibit lower total cholesterol (TC) and low-density lipoprotein (LDL) levels in serum and less formation of fat droplets in the liver compared to WT. On the other hand, the knockout of TLR4 significantly increased the high-density lipoprotein (HDL) of male mice. This study should provide new insights into the role of TLR4, as well as opportunities to target novel approaches to the prevention and treatment of metabolic diseases like obesity and diabetes.

THE SYSTEMATIC REVIEW OF ADIPOCYTES IN ACUTE LEUKEMIA

Background: Adipose tissue, a major cell type in the bone marrow microenvironment, plays a crucial role in the development and progression of cancer. Adipocytes, which make up the majority of cells in adipose tissue, exhibit distinct metabolic roles, replication and development abilities, cytokine production, and reactions to external stimuli. Adipocytes are abundant in bone marrow, a key site of metastasis for solid tumors and a crucial microenvironment for hematological malignancies. The aim: This study aims to determine the association of adipocytes in acute leukemia. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like PubMed and ScienceDirect, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Results: In the PubMed database, the results of our search brought up 27 articles, whereas the results of our search on ScienceDirect brought up 281 articles. The results of the search conducted by title screening yielded a total 14 articles for PubMed and 3 articles for ScienceDirect. We compiled a total of 12 papers, 10 of which came from PubMed and 2 of which came from ScienceDirect. We excluded 4 review articles, 2 articles having ineligible subjects, and 1 article having insufficient outcomes. In the end, we included five research that met the criteria. Conclusion: Acute leukemia cells have various effects on adipocytes which alter adipogenic differentiation capacities or adipocyte lipolysis and promote bone marrow adipocyte remodeling. Adipocytes play a crucial role in acute leukemia cell survival and their treatment.

D-amino acids metabolism reflects the evolutionary origin of higher plants and their adaptation to the environment.

d-amino acids are the d stereoisomers of the common l-amino acids found in proteins. Over the past two decades, the occurrence of d-amino acids in plants has been reported and circumstantial evidence for a role in various processes, including interaction with soil microorganisms or interference with cellular signalling, has been provided. However, examples are not numerous and d-amino acids can also be detrimental, some of them inhibiting growth and development. Thus, the persistence of d-amino acid metabolism in plants is rather surprising, and the evolutionary origins of d-amino acid metabolism are currently unclear. Systemic analysis of sequences associated with d-amino acid metabolism enzymes shows that they are not simply inherited from cyanobacterial metabolism. In fact, the history of plant d-amino acid metabolism enzymes likely involves multiple steps, cellular compartments, gene transfersand losses. Regardless of evolutionary steps, enzymes of d-amino acid metabolism, such as d-amino acid transferases or racemases, have been retained by higher plants and have not simply been eliminated, so it is likely that they fulfil important metabolic roles such as serine, folateor plastid peptidoglycan metabolism. We suggest that d-amino acid metabolism may have been critical to support metabolic functions required during the evolution of land plants.

Elevated plasma apolipoprotein E levels in people living with HIV: Associations with biomarkers and HIV-specific risk factors

Background and aimsApolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. MethodsWe included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. ResultsMean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. ConclusionsPWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.

Ophthalmic acid is a glutathione regulating tripeptide.

Since its discovery in 1958 in the lens of cows, ophthalmic acid (OPH) has stood in the shadow of its anti-oxidant analog: glutathione (GSH). Lacking the thiol group that gives GSH many of its important properties, ophthalmic acid's function has remained elusive, and it has been widely presumed to be an accidental product of the same enzymes. In this review, we compile evidence demonstrating that OPH is a ubiquitous metabolite found in bacteria, plants, fungi, and animals, produced through several layers of metabolic regulation. We discuss the limitations of the oft-repeated suggestions that aberrations in OPH levels should solely indicate GSH deficiency or oxidative stress. Finally, we discuss the available literature and suggest OPH's role in metabolism as a GSH-regulating tripeptide; controlling both cellular and organelle influx and efflux of GSH, as well as modulating GSH-dependent reactions and signaling. Ultimately, we hope that this review reinvigorates and directs more research into this versatile metabolite.

Advance in Multi-omics Research Strategies on Cholesterol Metabolism in Psoriasis.

The skin is a complex and dynamic organ where homeostasis is maintained through the intricate interplay between the immune system and metabolism, particularly cholesterol metabolism. Various factors such as cytokines, inflammatory mediators, cholesterol metabolites, and metabolic enzymes play crucial roles in facilitating these interactions. Dysregulation of this delicate balance contributes to the pathogenic pathways of inflammatory skin conditions, notably psoriasis. In this article, we provide an overview of omics biomarkers associated with psoriasis in relation to cholesterol metabolism. We explore multi-omics approaches that reveal the communication between immunometabolism and psoriatic inflammation. Additionally, we summarize the use of multi-omics strategies to uncover the complexities of multifactorial and heterogeneous inflammatory diseases. Finally, we highlight potential future perspectives related to targeted drug therapies and research areas that can advance precise medicine. This review aims to serve as a valuable resource for those investigating the role of cholesterol metabolism in psoriasis.

Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis

Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.

Folate supports IL-25-induced tuft cell expansion following enteroviral infections.

Intestinal tuft cells, a kind of epithelial immune cells, rapidly expand in response to pathogenic infections, which is associated with infection-induced interleukin 25 (IL-25) upregulation. However, the metabolic mechanism of IL-25-induced tuft cell expansion is largely unknown. Folate metabolism provides essential purine and methyl substrates for cell proliferation and differentiation. Thus, we aim to investigate the roles of folate metabolism playing in IL-25-induced tuft cell expansion by enteroviral infection and recombinant murine IL-25 (rmIL-25) protein-stimulated mouse models. At present, enteroviruses, such as EV71, CVA16, CVB3, and CVB4, upregulated IL-25 expression and induced tuft cell expansion in the intestinal tissues of mice. However, EV71 did not induce intestinal tuft cell expansion in IL-25-/- mice. Interestingly, compared to the mock group, folate was enriched in the intestinal tissues of both the EV71-infected group and the rmIL-25 protein-stimulated group. Moreover, folate metabolism supported IL-25-induced tuft cell expansion since both folate-depletion and anti-folate MTX-treated mice had a disrupted tuft cell expansion in response to rmIL-25 protein stimulation. In summary, our data suggested that folate metabolism supported intestinal tuft cell expansion in response to enterovirus-induced IL-25 expression, which provided a new insight into the mechanisms of tuft cell expansion from the perspective of folate metabolism.

The mechanistic study of cancer-associated adipocytes promoting colorectal cancer peritoneal metastasis via FKBP5/UCP1-mediated lipid metabolism reprogramming.

178 Background: Colorectal cancer (CRC) is a prevalent malignant tumor globally, with peritoneal metastasis as a significant late-stage dissemination pathway, severely impacting patient prognosis. Recent research increasingly suggests the critical role of lipid metabolism within the tumor microenvironment in tumor progression. Cancer associated adipocytes (CAAs), a vital component, contribute to tumor progression, yet the exact molecular mechanisms remain unclear. We aim to explore the role of CAAs in CRC peritoneal metastasis and their specific regulatory mechanisms. Methods: In this study, we analyzed clinical samples from 312 CRC patients to assess the expression levels of FKBP5 and UCP1 proteins in tumor-adjacent tissues. Purified exosomes from co-cultured adipocytes and tumor cells, along with exosomes from ordinary tumor cells, underwent miRNA profiling via sequencing to evaluate exosomal miR-200a-3p expression. We established FKBP5 stable knockdown (FKBP5-/-) transgenic mouse models, organotypic co-culture models, and patient-derived xenograft (PDX) models. Through experiments involving metabolomics, mass spectrometry, immunoprecipitation, western blotting, and qPCR, we investigated the role of the miR-200a-3p/FKBP5/PPARγ/UCP1 signaling pathway in CAAs in CRC peritoneal metastasis. Results: After co-culturing adipocytes and tumor cells, we observed brown adipocyte differentiation, resulting in significant downregulation of FKBP5 protein expression. FKBP5 exhibited a strong association with UCP1 expression. Tumor cells highly expressed miR-200a-3p, released via exosomes into the tumor microenvironment and internalized by adipocytes. Within adipocytes, miR-200a-3p orchestrated metabolic reprogramming via the FKBP5/PPARγ/UCP1 pathway, inducing brown adipocyte differentiation, generating CAAs. CAAs released FFAs, promoting tumor peritoneal metastasis by activating tumor cell surface G-protein coupled receptors (GPCRs). Conversely, miR-200a-3p inhibition in tumor cells yielded opposing effects. In a spontaneous mouse model of colorectal cancer using azoxymethane (AOM)/dextran sulfate sodium salt (DSS), FKBP5-/- mice exhibited increased brown adipocyte content in the tumor microenvironment, along with notably higher spontaneous colorectal tumor numbers and sizes compared to wild-type mice. Conclusions: This study elucidates the pivotal role of CAAs in the peritoneal metastasis of CRC, confirming the regulatory role of the FKBP5/UCP1 pathway-mediated lipid metabolism reprogramming in this process. These findings offer a fresh perspective for further exploration of the molecular mechanisms underlying CRC peritoneal metastasis, and provide a theoretical foundation for the identification of novel therapeutic targets.

Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase

Pseudorabies virus (PRV) is an alpha-herpesvirus capable of infecting a range of animal species, particularly its natural host, pigs, resulting in substantial economic losses for the swine industry. Recent research has shed light on the significant role of cholesterol metabolism in the replication of various viruses. However, the specific role of cholesterol metabolism in PRV infection remains unknown. Here, we demonstrated that the expression of 7-dehydrocholesterol reductase (DHCR7) is upregulated following PRV infection, as evidenced by the proteomic analysis. Subsequently, we showed that DHCR7 plays a crucial role in promoting PRV replication by converting 7-dehydrocholesterol (7-DHC) into cholesterol, leading to increased cellular cholesterol levels. Importantly, DHCR7 inhibits the phosphorylation of interferon regulatory factor 3 (IRF3), resulting in reduced levels of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs). Finally, we revealed that the DHCR7 inhibitor, trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (AY9944), significantly suppresses PRV replication both in vitro and in vivo. Taken together, the study has established a connection between cholesterol metabolism and PRV replication, offering novel insights that may guide future approaches to the prevention and treatment of PRV infections.

Predictive value of serum TBA for 2-year MACEs in ACS patients undergoing PCI: a prospective cohort study

Bile acids play important roles in lipid metabolism and glucose homeostasis. Limited research exist on the association between serum total bile acid (TBA) levels and major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS), particularly those with comorbid type 2 diabetes mellitus (T2DM). This study was conducted to examine the relationship between baseline serum TBA level and T2DM status in patients with ACS after percutaneous coronary intervention (PCI) and to identify the predictive value of TBA levels for a 2-year risk of MACEs. 425 ACS patients underwent PCI were recruited and divided into three groups based on baseline serum TBA concentration. An analysis of the association between the T2DM status and baseline serum TBA levels was conducted using univariate linear regression and multivariate linear regression. The predictive relevance of serum TBA levels was evaluated using the receiver operating characteristic (ROC) curve and Cox regression. Kaplan–Meier curves were employed to analyze the differences among groups in predicting MACEs over a 2-year follow-up period. Baseline serum TBA levels were higher in ACS patients who were diagnosed with T2DM (the median 3.6 µmol/L) than those without T2DM (the median 3.0 µmol/L). T2DM status in ACS patients was positively correlated with baseline serum TBA concentrations (β: 1.7, 95% confidence interval [CI] 0.3–3.0), particularly in the male (β: 2.0, 95% CI 0.3–3.6) and 50–69-year-old (β: 2.5, 95% CI 0.6–4.4) populations. The areas under the ROC curve of baseline serum TBA levels predicted MACEs in ACS and ACS-T2DM patients following PCI were 0.649 (95% CI 0.595–0.703) and 0.783 (95% CI 0.685–0.881), respectively. Furthermore, Cox regression analysis showed that baseline serum TBA level was associated with the occurrence of MACEs in patients with ACS after PCI over a 2-year follow-up period, especially in those diagnosed with T2DM, whose baseline TBA concentration was lower than 10.0 µmol/L. ACS Patients with T2DM had higher serum TBA levels. TBA level at baseline was an independent predictor of MACEs in ACS patients who underwent PCI, especially with comorbid T2DM.

Metabolic Flexibility of the Heart: The Role of Fatty Acid Metabolism in Health, Heart Failure, and Cardiometabolic Diseases.

This comprehensive review explores the critical role of fatty acid (FA) metabolism in cardiac diseases, particularly heart failure (HF), and the implications for therapeutic strategies. The heart's reliance on ATP, primarily sourced from mitochondrial oxidative metabolism, underscores the significance of metabolic flexibility, with fatty acid oxidation (FAO) being a dominant source. In HF, metabolic shifts occur with an altered FA uptake and FAO, impacting mitochondrial function and contributing to disease progression. Conditions like obesity and diabetes also lead to metabolic disturbances, resulting in cardiomyopathy marked by an over-reliance on FAO, mitochondrial dysfunction, and lipotoxicity. Therapeutic approaches targeting FA metabolism in cardiac diseases have evolved, focusing on inhibiting or stimulating FAO to optimize cardiac energetics. Strategies include using CPT1A inhibitors, using PPARα agonists, and enhancing mitochondrial biogenesis and function. However, the effectiveness varies, reflecting the complexity of metabolic remodeling in HF. Hence, treatment strategies should be individualized, considering that cardiac energy metabolism is intricate and tightly regulated. The therapeutic aim is to optimize overall metabolic function, recognizing the pivotal role of FAs and the need for further research to develop effective therapies, with promising new approaches targeting mitochondrial oxidative metabolism and FAO that improve cardiac function.

Impact of glucose metabolism on PD-L1 expression in sorafenib-resistant hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC.

Swine Gastrointestinal Microbiota and the Effects of Dietary Amino Acids on Its Composition and Metabolism.

Many researchers consider gut microbiota (trillions of microorganisms) an endogenous organ of its animal host, which confers a vast genetic diversity in providing the host with essential biological functions. Particularly, the gut microbiota regulates not only gut tissue structure but also gut health and gut functionality. This paper first summarized those common bacterial species (dominated by the Firmicutes, Bacteroidota, and Proteobacteria phyla) in swine gut and then briefly discussed their roles in swine nutrition and health, which include roles in nutrient metabolism, pathogen exclusion, and immunity modulation. Secondly, the current knowledge on how dietary nutrients and feed additives affect the gut bacterial composition and nutrient metabolism in pigs was discussed. Finally, how dietary amino acids affect the relative abundances and metabolism of bacteria in the swine gut was reviewed. Tryptophan supplementation promotes the growth of beneficial bacteria and suppresses pathogens, while arginine metabolism affects nitrogen recycling, impacting gut immune response and health. Glutamate and glutamine supplementations elevate the levels of beneficial bacteria and mitigate pathogenic ones. It was concluded that nutritional strategies to manipulate gut microbial ecosystems are useful measures to optimize gut health and gut functions. For example, providing pigs with nutrients that promote the growth of Lactobacillus and Bifidobacterium can lead to better gut health and growth performance, especially when dietary protein is limited. Further research to establish the mechanistic cause-and-effect relationships between amino acids and the dynamics of gut microbiota will allow swine producers to reap the greatest return on their feed investment.

Investigating the transcriptomic variances in two phases Ecytonucleospora hepatopenaei (EHP) in Litopenaeus vannamei

This study explores the transcriptomic differences in two distinct phases of Ecytonucleospora hepatopenaei (EHP) in Litopenaeus vannamei, a crucial aspect in shrimp health management. We employed high-throughput sequencing to categorize samples into two phases, 'Phase A' and 'Phase B', defined by the differential expression of PTP2 and TPS1 genes. Our analysis identified 2057 genes, with 78 exhibiting significant variances, including 62 upregulated and 16 downregulated genes. Enrichment analyses via GO and KEGG pathways highlighted these genes' roles in cellular metabolism, signal transduction, and immune responses. Notably, genes like IQGAP2, Rhob, Pim1, and PCM1 emerged as potentially crucial in EHP's infection process and lifecycle. We hypothesize that these genes may influence trehalose metabolism and glucose provision, impacting the biological activities within EHP during different phases. Interestingly, a lower transcript count in 'Phase A' EHP suggests a reduction in biological activities, likely preparing for host cell invasion. This research provides a foundational understanding of EHP infection mechanisms, offering vital insights for future studies and therapeutic interventions.

Protein 4.1R regulates M1 macrophages polarization via glycolysis, alleviating sepsis-induced liver injury in mice

Acute liver injury (ALI) is a common clinical disease caused by sepsis, metabolic syndrome, hepatitis virus. Macrophage plays an important role in the development of ALI, which is characterized by polarization and inflammatory regulation. The polarization process of macrophages is related to membrane binding proteins and adaptors. Protein 4.1R acts as an adaptor, linking membrane proteins to the cytoskeleton, and is involved in cell activation and cytokine secretion. However, whether protein 4.1R is involved in regulating macrophage polarization and inflammation-induced liver injury remains unknown. In this study, protein 4.1R is identified with the special effect on macrophage M1 polarization. And it is further demonstrated that protein 4.1R deficiency significantly enhance glycolytic metabolism. Mechanistically, the regulation of protein 4.1R on pyruvate kinase M2 (PKM2) plays a key role in glycolysis metabolism. In addition, we found that protein 4.1R directly interacts with toll-like receptor 4 (TLR4), inhibits the activation of the AKT/HIF-1α signaling pathway. In conclusion, protein 4.1R targets HIF-1α mediated glycolysis regulates M1 macrophage polarization, indicating that protein 4.1R is a candidate for regulating macrophage mediated inflammatory response. In conclusion, we have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy. We have revealed a novel function of protein 4.1R in macrophage polarization and ALI, providing important insights into the metabolic reprogramming, which is important for ALI therapy.

DoAP2/ERF89 activated the terpene synthase gene DoPAES in Dendrobium officinale and participated in the synthesis of β-patchoulene.

Dendrobium officinale Kimura et Migo is a tonic plant that has both ornamental and medicinal properties. Terpenoids are significant and diverse secondary metabolites in plants, and are one of the important natural active ingredients in D. officinale. The AP2/ERF gene family plays a major role in primary and secondary metabolism. However, the AP2/ERF transcription factor family has not been identified in D. officinale, and it is unclear if it is involved in the regulation of terpenoid biosynthesis. This study identified a sesquiterpene synthetase-β-patchoulene synthase (DoPAES) using transcriptome and terpenic metabolic profile analyses. A total of 111 members of the AP2/ERF family were identified through the whole genome of D. officinale. The tissue-specific expression and gene co-expression pattern of the DoAP2/ERF family members were analyzed. The results showed that the expression of DoPAES was highly correlated with the expression of DoAP2/ERF89 and DoAP2/ERF47. The yeast one-hybrid (Y1H) assays and dual-luciferase experiments demonstrated that DoAP2/ERF89 and DoAP2/ERF47 could regulate the expression of DoPAES. The transcriptional regulatory effects were examined using homologous transient expression of DoAP2/ERF89 in protocorms of D. officinale. DoAP2/ERF89 positively regulated the biosynthesis of β-patchoulene. This study showed that DoAP2/ERF89 can bind to the promoter region of DoPAES to control its expression and further regulate the biosynthesis of β-patchoulene in D. officinale. These results provide new insights on the regulation of terpenoid biosynthesis.

Deciphering the molecular functionality of Cdc45 in replisomal complex

The members of DHH superfamily have been reported with diverse substrate spectrum and play pivotal roles in replication, repair, and RNA metabolism. This family comprises phosphatases, phosphoesterase and bifunctional enzymes having nanoRNase and phosphatase activities. Cell cycle factor Cdc45, a member of this superfamily, is crucial for movement of the replication fork during DNA replication and an important component of the replisome. The specific protein-protein interactions of Cdc45 with other factors along with helicase moderate the faithful DNA replication process. However, the exact biochemical functions of this factor are still unknown and need further investigation. Here, we studied the biochemical roles of Cdc45 and its molecular interactions within the replisomal complex. The alteration in the level of protein, observed when DNA damage is induced in-vivo, suggests its association with DNA replication stress. We analyzed protein Cdc45, providing new insights about the molecular and biochemical functionality of this replisomal factor.

Regulation of sirt1 and foxO1 in glucose metabolism of Megalobrama amblycephala

Both silent information regulator 2 homolog 1 (sirt1) and forkhead box transcription factor 1 (foxO1) are crucial transcription factors involved in glucolipid metabolism and energy regulation. The presnt study aimed to understand their regulatory roles in glucose metabolism. Molecular cloning and sequencing of sirt1 gene of Megalobrama amblycephala (masirt1) was conducted and cellular localization of both the factors were analysed. Their effects and action patterns in the glucose metabolism of Megalobrama amblycephala (M. amblycephala) were investigated through acute and long-term glucose tolerance assays. The results revealed that the full-length masirt1 cDNA sequence was 2350 bp and closely related to Sinocyclocheilus rhinocerous. Sirt1 and foxO1 were found to be mutually dependent and localized in the nucleus. Acute glucose tolerance tests revealed that the expression levels of both factors in the liver of M. amblycephala showed an initial increase followed by a decrease. Plasma glucose levels in M. amblycephala significantly increased at 2 and 12 h (P < 0.05). In a long-term breeding experiment with high-sugar feeding, the expressions of the sirt1 and foxO1 genes in the kidney and intestine of M. amblycephala exhibited synergistic changes. The 51WS groups had significantly higher levels of sirt1 and foxO1 gene expression in the kidney and intestine compared to the 0WS and 17WS groups (P < 0.05). Overall, masirt1 is evolutionarily highly conserved, and the interaction site of sirt1 and foxO1 is located in the nucleus. In long-term hyperglycemic regulation, sirt1 and foxO1 exhibit synergistic regulatory effects in the kidney and intestine of M. amblycephala. This study provides insights into how sirt1 and foxO1 regulate glucose metabolism in M. amblycephala.