Insight into selenium biofortification and the selenite metabolic mechanism of Monascus ruber M7.

Monascus species are functional fermentation fungi with great potential for selenium (Se) supplementation. This study investigated the effects of Se bio-fortification on the growth, morphology, and biosynthesis of Monascus ruber M7. The results demonstrated a significant increase in the yield of orange and red Monascus pigments (MPs) in red yeast rice (RYR) by 38.52% and 36.57%, respectively, under 20 µg/mL of selenite pressure. Meanwhile, the production of citrinin (CIT), a mycotoxin, decreased from 244.47 µg/g to 175.01 µg/g. Transcriptome analysis revealed significant upregulation of twelve genes involved in MPs biosynthesis, specifically MpigE, MpigF, and MpigN, and downregulation of four genes (mrr3, mrr4, mrr7, and mrr8) associated with CIT biosynthesis. Additionally, three genes encoding cysteine synthase cysK (Log2FC = 1.6), methionine synthase metH (Log2FC = 2.2), and methionyl-tRNA synthetase metG (Log2FC = 1.8) in selenocompound metabolism showed significantly upregulated. These findings provide insights into Se biotransformation and metabolism in filamentous fungi.

Green Extraction of Polyphenols from Elaeagnus angustifolia L. Using Natural Deep Eutectic Solvents and Evaluation of Bioactivity.

In the study, natural deep eutectic solvents (NADESs) were used as alternatives to traditional chemical solvents for the extraction of polyphenols from Elaeagnus angustifolia L. Nine NADESs were tested for the first time and compared with ethanol and water (traditional solvents) regarding the extraction of phenolic compounds from E. angustifolia L. These solvents were particularly effective at extracting polyphenols, whose low water solubility usually requires high amounts of organic solvents. The solvent based on choline chloride and malonic acid provided optimal results and was selected for further optimization. The effects of material-to-liquid ratio, ultrasound time, and ultrasound temperature on the extraction efficiency were studied through single-factor experiments. These parameters were optimized by Box-Behnken design using response surface methodology. The optimal conditions identified were 49.86 g/mL of material-to-liquid ratio, 31.10 min of ultrasound time, and 62.35 °C of ultrasound temperature, resulting in a high yield of 140.30 ± 0.19 mg/g. The results indicated that the NADES extraction technique provided a higher yield than the conventional extraction process. The antioxidant activity of the extract of polyphenols from E. angustifolia L. was determined, and UPLC-IMS-QTOF-MS was used to analyze the phenolic compounds in it. The results revealed that the scavenging ability of 1,1-diphenyl-2-picryl-hydrazil and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) extracted by NADES was higher than that of polyphenols extracted by water and ethanol. Furthermore, a total of 24 phenolic compounds were identified in the extract. To the best of our knowledge, this is the first study in which a green and efficient NADES extraction method has been used to extract bioactive polyphenols from E. angustifolia L., which could provide potential value in pharmaceuticals, cosmetics, and food additives.

Bimetallic MOF-derived three-dimensional nanoflowers PdCoOx as peroxidase mimic activity for determining total antioxidant capacity.

Bimetallic MOF derivatives have shown excellent performance as nano-enzymes in the field of catalysis. Herein, PdCo oxide nanoflowers with three-dimensional flower were prepared by a simple pyrolysis method on a precursor of bimetallic PdCo-MOF. PdCoOx showed excellent peroxidase mimic activity, which could significantly promote the oxidation of TMB by H2O2. Compared with CoOx, the peroxidase mimic activity of the optimized PdCoOx-300 increased by 2.41-fold. PdCoOx-300 has high affinity for TMB and H2O2 with Km values of 0.16 mM and 2.11 mM, which are only 57.03% and 36.87% of HRP, respectively. The highly specific peroxidase mimic activity is conducive to the sensitive detection of H2O2, glucose and ascorbic acid with limit of detection of 10, 100 and 10 nM, respectively. Furthermore, the total antioxidant capacity in the actual beverage samples was conducted, which showed good anti-interference ability and recovery rate.

Zein/fucoidan-coated phytol nanoliposome: preparation, characterization, physicochemical stability, in vitro release, and antioxidant activity.

BACKGROUND: To improve phytol bioavailability, a novel method of magnetic stirring and high-pressure homogenization (HPH) combination was used to prepare zein/fucoidan-coated phytol nanoliposomes (P-NL-ZF). The characterization, the simulated in vitro digestion, and the antioxidant activity of these phytol nanoliposomes from the different processes have been studied. RESULTS: Based on the results of dynamic light scattering (DLS) and gas chromatography-mass spectrometer (GC-MS) analysis, P-NL-ZF prepared through the combination of magnetic stirring and HPH exhibited superior encapsulation efficiency at 76.19% and demonstrated exceptional physicochemical stability under a series of conditions, including storage, pH, and ionic in comparison to single method. It was further confirmed that P-NL-ZF by magnetic stirring and HPH displayed a uniform distribution and regular shape through transmission electron microscopy (TEM). Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) analysis showed that electrostatic interactions and hydrogen bonding were the primary driving forces for the formation of composite nanoliposomes. Additionally, an in vitro digestion study revealed that multilayer composite nanoliposomes displayed significant and favorable slow-release properties (58.21%) under gastrointestinal conditions compared with traditional nanoliposomes (82.36%) and free phytol (89.73%). The assessments of chemical and cell-based antioxidant activities demonstrated that the coating of zein/fucoidan on phytol nanoliposomes resulted in enhanced effectiveness in scavenging activity of ABTS free radical and hydroxyl radical and mitigating oxidative damage to HepG2 cells. CONCLUSION: Based on our studies, the promising delivery carrier of zein/fucoidan-coated nanoliposomes is contributed to the encapsulation of hydrophobic natural products and enhancement of their biological activity. © 2024 Society of Chemical Industry.

Interleukin-10: a novel metabolic inducer of macrophage differentiation and subsequently contributing to improved pregnancy outcomes of mice by orchestrating oxidative phosphorylation metabolism.

Metabolism regulates the phenotype and function of macrophages. After recruitment to local tissues, monocytes are influenced by the local microenvironment and differentiate into various macrophages depending on different metabolic pathways. However, the metabolic mechanisms underlying decidual macrophage differentiation remain unknown. Interleukin-10 (IL-10) is an important decidual macrophage inducer and promotes oxidative phosphorylation (OXPHOS) of bone marrow-derived macrophages. In this study, we mainly investigate the metabolic changes involved in IL-10 generated macrophages from monocytes using in vitro models. We demonstrate that exposure of monocytes (either peripheral or THP-1) to IL-10 altered the phenotype and function of resultant macrophages that is linked with OXPHOS changes. IL-10 enhanced the mitochondrial complex I and III activity of THP-1 cell-differentiated macrophages and increased the mitochondrial membrane potential, intracellular adenosine triphosphate, and reactive oxygen species levels. OXPHOS blockage with oligomycin changed the cell morphology of IL-10-generated macrophages and the expression levels of cytokines, such as transforming growth factor beta, tumor necrosis factor-alpha, interferon gamma, and IL-10, apart from changes in the expression level of the surface markers CD206, CD209, and CD163. Moreover, in vivo IL-10 administration reduced the lipopolysaccharide (LPS)-induced embryo resorption rate, and this effect was diminished when OXPHOS was inhibited, demonstrating that OXPHOS is important for the improved pregnancy outcomes of IL-10 in LPS-induced abortion-prone mice. Our findings provide deep insights into the roles of IL-10 in macrophage biology and pregnancy maintenance. Nevertheless, the direct evidence that OXPHOS is involved in decidual macrophage differentiation or not needs further investigations.

Cascade Co8FeS8@Co1-xS nano-enzymes trigger efficiently apoptosis-ferroptosis combination tumor therapy.

This study involved the preparation of Metal Organic Frameworks (MOF)-derived Co8FeS8@Co1-xS nanoenzymes with strong interfacial interactions. The nanoenzymes presented the peroxidase (POD)-like activity and the oxidation activity of reduced glutathione (GSH). Accordingly, the dual activities of Co8FeS8@Co1-xS provided a self-cascading platform for producing significant amounts of hydroxyl radical (•OH) and depleting reduced glutathione, thereby inducing tumor cell apoptosis and ferroptosis. More importantly, the Co8FeS8@Co1-xS inhibited the anti-apoptosis protein B-cell lymphoma-2 (Bcl-2) and activated caspase family proteins, which caused tumor cell apoptosis. Simultaneously, Co8FeS8@Co1-xS affected the iron metabolism-related genes such as Heme oxygenase-1 (Hmox-1), amplifying the Fenton response and promoting apoptosis and ferroptosis. Therefore, the nanoenzyme synergistically killed anti-apoptotic tumor cells carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Furthermore, Co8FeS8@Co1-xS demonstrated good biocompatibility, which paved the way for constructing a synergistic catalytic nanoplatform for an efficient tumor treatment.

Multi-Enzyme Activity of MIL-101 (Fe)-Derived Cascade Nano-Enzymes for Antitumor and Antimicrobial Therapy.

The clinical application of oncology therapy is hampered by high glutathione concentrations, hypoxia, and inefficient activation of cell death mechanisms in cancer cells. In this study, Fe and Mo bimetallic sulfide nanomaterial (FeS2@MoS2) based on metal-organic framework structure is rationally prepared with peroxidase (POD)-, catalase (CAT)-, superoxide dismutase (SOD)-like activities and glutathione depletion ability, which can confer versatility for treating tumors and mending wounds. In the lesion area, FeS2@MoS2 with SOD-like activity can facilitate the transformation of superoxide anions (O2 -) to hydrogen peroxide (H2O2), and then the resulting H2O2 serves as a substrate for the Fenton reaction with FMS to produce highly toxic hydroxyl radicals (∙OH). Simultaneously, FeS2@MoS2 has an ability to deplete glutathione (GSH) and catalyze the decomposition of nicotinamide adenine dinucleotide phosphate (NADPH) to curb the regeneration of GSH from the source. Thus it can realize effective tumor elimination through synergistic apoptosis-ferroptosis strategy. Based on the alteration of the H2O2 system, free radical production, glutathione depletion and the alleviation of hypoxia in the tumor microenvironment, FeS2@MoS2 NPS can not only significantly inhibit tumors in vivo and in vitro, but also inhibit multidrug-resistant bacteria and hasten wound healing. It may open the door to the development of cascade nanoplatforms for effective tumor treatment and overcoming wound infection.

Metabolic Regulation of Two pksCT Gene Transcripts in Monascus ruber Impacts Citrinin Biosynthesis.

Citrinin (CIT), a secondary metabolite produced by the filamentous fungi Monascus species, exhibits nephrotoxic, hepatotoxic, and carcinogenic effects in mammals, remarkably restricting the utilization of Monascus-derived products. CIT synthesis is mediated through the pksCT gene and modified by multiple genetic factors. Here, the regulatory effects of two pksCT transcripts, pksCTα, and pksCTß, generated via pre-mRNA alternative splicing (AS), were investigated using hairpin RNA (ihpRNA) interference, and their impact on CIT biosynthesis and the underlying mechanisms were assessed through chemical biology and transcriptome analyses. The CIT yield in ihpRNA-pksCTα and ihpRNA-pksCT (α + ß) transformants decreased from 7.2 µg/mL in the wild-type strain to 3.8 µg/mL and 0.08 µg/mL, respectively. Notably, several genes in the CIT biosynthetic gene cluster, specifically mrl3, mrl5, mrr1, and mrr5 in the ihpRNA-pksCT (α + ß) transformant, were downregulated. Transcriptome results revealed that silencing pksCT has a great impact on carbohydrate metabolism, amino acid metabolism, lipid metabolism, and AS events. The key enzymes in the citrate cycle (TCA cycle) and glycolysis were significantly inhibited in the transformants, leading to a decrease in the production of biosynthetic precursors, such as acetyl-coenzyme-A (acetyl-coA) and malonyl-coenzyme-A (malonyl-coA). Furthermore, the reduction of CIT has a regulatory effect on lipid metabolism via redirecting acetyl-coA from CIT biosynthesis towards lipid biosynthesis. These findings offer insights into the mechanisms underlying CIT biosynthesis and AS in Monascus, thus providing a foundation for future research.

Monascus Red Pigment Liposomes: Microstructural Characteristics, Stability, and Anticancer Activity.

Monascus red pigments (MRPs), which are a kind of natural colorant produced by Monascus spp., are widely used in the food and health supplements industry but are not very stable during processing and storage. Thus, MRPs were embedded into liposome membranes using a thin-film ultrasonic method to improve stability in this study. Monascus red pigments liposomes (MRPL) exhibited spherical unilamellar vesicles (UV) with particle size, polydispersity indexes (PDI), and zeta potential of 20-200 nm, 0.362 ± 0.023, and -42.37 ± 0.21 mV, respectively. pH, thermal, light, metal ion, storage, and in vitro simulated gastrointestinal digestion stability revealed that, compared with free MRPs, liposomes embedding significantly enhanced the stability of MRPs when exposed to adverse environmental conditions. Furthermore, anticancer assay suggested that MRPL exhibited a stronger inhibitory effect on MKN-28 cells by damaging the integrity of cells, with the IC50 value at 0.57 mg/mL. Overall, MRPLs possess stronger stability in external environment and in vitro simulated digestion with greater anticancer activity, indicating that MRPLs have the potential for promising application in the functional foods and pharmaceutical industries.

The value of pulmonary artery acceleration time in evaluating pulmonary vascular disease in preterm infants with bronchopulmonary dysplasia.

OBJECTIVES: Early screening and dynamic monitoring of pulmonary vascular disease (PVD) in bronchopulmonary dysplasia (BPD) high-risk infants is of great clinical significance. Pulmonary artery acceleration time (PAAT) is a reliable and non-invasive method for assessing PVD in children over 1 year, but to date, few studies have used PAAT to assess pulmonary hemodynamics of preterm infants, especially those with BPD. Through dynamic monitoring the main hemodynamic indicators reflected PVD after birth, this study aimed to assess the value of PAAT in evaluating early PVD in BPD infants. METHODS: All 81 preterm infants at risk of BPD were divided into BPD and non-BPD groups according to whether BPD occurred. Clinical characteristics, PAAT, right ventricular ejection time (RVET) and other main hemodynamic indicators at four different time points after birth were studied and compared. RESULTS: PAAT and PAAT/RVET increased gradually within 72 h after birth in the BPD group (p < .05), but the curve tended to be flat over time after 72 h (p > .05). At PMA32 and 36 weeks, the PAAT (49.7 ± 4.8 vs. 54.8 ± 5.7, p = .001; 50.0 ± 5.3 vs. 57.0 ± 5.3, p = .001) and PAAT/RVET (.33 ± .04 vs. .35 ± .03, p = .001; .34 ± .03 vs. .37 ± .04, p = .001) in BPD group were significantly lower than those in the non-BPD group. CONCLUSIONS: PAAT and PAAT/RVET in the BPD group infants showed different change patterns compared to non-BPD group infants. PAAT can be used as a noninvasive and reliable screening method for screening and dynamic monitoring of PVD in BPD high-risk infants.

Gelsemine Exerts Neuroprotective Effects on Neonatal Mice with Hypoxic-Ischemic Brain Injury by Suppressing Inflammation and Oxidative Stress via Nrf2/HO-1 Pathway.

Given that the role of Gelsemine in neuroinflammation has been demonstrated, this research aimed to investigate the effect of Gelsemine on neonatal hypoxic-ischemic (HI) brain injury. An in vivo HI brain injury neonatal mouse model and an in vitro oxygen-glucose deprivation (OGD) cell model were established and pretreated with Gelsemine. The brain infarct volume, neuronal loss and apoptosis, as well as spatial learning and memory were examined by TTC staining, Nissl's staining, TUNEL staining and Morris water maze test. Immunohistochemical staining was applied to detect the microglia cells and astrocytes in the mouse brain tissue. The cell viability was analyzed by CCK-8 assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), TNF-α, IL-1ß, and IL-6 were determined via ELISA. The lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) level in OGD-treated cells were detected by colorimetry and DCFH-DA staining. Nrf2, HO-1, and inflammation-related factors were analyzed by immunofluorescence, qRT-PCR, or western blot. Gelsemine reduced the infarct volume and neuronal loss and apoptosis, yet improved spatial learning and memory impairment of HI-injured mice. Gelsemine inhibited the elevated MDA, TNF-α, IL-1ß, IL-6, LDH and ROS levels, promoted the reduced SOD level and viability, and strengthened the up-regulation of HO-1 and Nrf2 in brain tissues and OGD-treated cells. However, Nrf2 silencing reversed the effects of Gelsemine on the Nrf2/HO-1 pathway, inflammation, and oxidative stress in OGD-treated cells. Gelsemine produces neuroprotective effects on neonatal mice with HI brain injury by suppressing inflammation and oxidative stress via Nrf2/HO-1 pathway.

Decorin promotes decidual M1-like macrophage polarization via mitochondrial dysfunction resulting in recurrent pregnancy loss.

Rationale: Recurrent pregnancy loss (RPL) is a distressing disorder that seriously affects the physical and psychological health of women. RPL is also a sentinel risk marker for future obstetric complications and warrants in-depth investigation. Abnormal polarization and functions of decidual macrophages are associated with RPL; however, the underlying mechanisms remain poorly understood. Methods: Decorin expression, localization, and content in the decidua of women with normal pregnancy (NP) and those with RPL were measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting, immunofluorescence, and enzyme-linked immunosorbent assay. The profiles of decidual macrophage subsets were determined using flow cytometry and immunofluorescence in both groups. The correlation between decorin content and the proportion of decidual macrophage subsets in the decidua of early NP women was determined using Pearson analysis. The effects of decorin on the polarization and functions of macrophages were assessed in an in-vitro model of Raw264.7 cells via flow cytometry, western blotting, and RT-qPCR. Moreover, the mitochondrial metabolism in Raw264.7 cells under decorin administration was measured via flow cytometry, western blotting, and immunofluorescence. Thirty-three pregnant mice were included in the in vivo model and underwent different treatments. The embryo abortion rate, macrophage phenotype in the spleen and uteri, and placental development were evaluated using flow cytometry and hematoxylin-eosin staining. Results: Decorin, derived from decidual stromal cells, was highly expressed in the decidua of women with RPL. A positive correlation between decorin content and the proportion of M1-like macrophages was also observed in the decidua of early NP women. In vitro studies showed that decorin treatment inhibited macrophage polarization to M2-like subsets and boosted the inflammatory response, which was related to enhanced anaerobic glycolysis, increased mitochondrial membrane potential and intracellular reactive oxygen species levels, reduced mitochondrial mass, and activation of the myeloid differentiation primary response 88-nuclear factor-κB signaling pathway. Adoptive transfer of decorin-treated bone marrow-derived macrophages in pregnant C57BL/6 mice increased the embryo absorption, accompanied by impaired fetal vascularization. Conclusions: Decidual stromal cell-derived decorin can polarize decidual macrophages toward the M1 phenotype by regulating mitochondrial metabolism, resulting in the occurrence of RPL.

Knockdown of circ_0026579 ameliorates lipopolysaccharide (bacterial origin)-induced inflammatory injury in bronchial epithelium cells by targeting miR-338-3p/TBL1XR1 axis.

BACKGROUND: Circular RNAs (circRNAs) play an important regulatory role in human diseases including organ allograft rejection. The aim of this study is to clarify the functional role and molecular mechanism of circ_0026579 RNA in lipopolysaccharide (LPS)-induced bronchopneumonia injury. MATERIALS AND METHODS: Bronchial epithelial BEAS-2B cells were treated with LPS to mimic an in vitro model for bronchopneumonia. Cell viability and proliferation were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay. Flow cytometry assay was used to assess cell apoptosis. Caspase-3 activity was analyzed by Caspase-3 activity assay kit. The expression levels of circ_0026579 RNA, miR-338-3p, and transducin ß-like 1× related protein 1 (TBL1XR1) RNA were determined by RT-qPCR. The protein level was quantified by western blot assay. The correlation between miR-338-3p and circ_0026579 or TBL1XR1 was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. RESULTS: LPS treatment repressed proliferation but induced apoptosis and inflammatory response in BEAS-2B cells. Circ_0026579 RNA was highly expressed in patients with pneumonia. Besides, the expression levels of circ_0026579 RNA and TBL1XR1 RNA/protein were upregulated, while miR-338-3p level was decreased in LPS-treated BEAS-2B cells. Knockdown of circ_0026579 RNA or TBL1XR1 protein could abolish LPS-induced cell injury in BEAS-2B cells. Furthermore, we found that circ_0026579 RNA functioned as a "sponge" for miR-338-3p to regulate TBL1XR1 expression. Additionally, silencing circ_0026579 RNA protected BEAS-2B cells from LPS-induced bronchopneumonia injury by regulating TBL1XR1 expression. CONCLUSION: Circ_0026579 RNA knockdown promoted cell proliferation but inhibited apoptosis and inflammation in LPS-induced BEAS-2B cells through regulating miR-338-3p RNA/TBL1XR1 protein axis.

Cutting edge: the regulatory mechanisms of macrophage polarization and function during pregnancy.

Macrophages are highly diverse cells and represent the major antigen-presenting cell at the maternal-fetal interface. Except for protecting the embryo with half of the paternal antigens from attack by the maternal immune system, decidua macrophages also have a critical role in implantation, trophoblast invasion, spiral artery remodeling, angiogenesis, and pathogen clearance. The classically activated (M1) and alternatively activated (M2) macrophages are the simplified classifications of macrophages, often applied to differentiate decidual macrophages. Particular phenotypes and functions of macrophages corresponding to each phase of the menstrual cycle and pregnancy are critical for establishing and maintaining pregnancy. Aberrant dynamics of decidual macrophages are associated with multiple pregnancy complications, such as recurrent pregnancy loss, preeclampsia, and preterm birth. Although various factors are related to decidual macrophage polarization, including cytokines, growth factors, hormones, and transcription factors, the potential regulatory mechanisms underlying decidual macrophage polarization are still unclear. Therefore, a thorough understanding of macrophage function and regulatory mechanism during pregnancy is critical to clarify the pathogenesis of pregnancy complications. In this review, we first describe an overview of the origin, phenotype, and function of macrophages in the uterus. Secondly, we propose emerging concepts explaining how macrophage polarization and functions are regulated, including immunometabolism, epigenetics, immune checkpoint, and microorganisms. Finally, we review the potential relationship among these novel factors in regulating the function of the immune system.

UHRF1 shapes both the trophoblast invasion and decidual macrophage differentiation in early pregnancy.

Trophoblasts play critical roles in establishment and maintenance of a normal pregnancy. Their dysfunction in early pregnancy is closely related to pregnancy-related diseases, including recurrent pregnancy loss (RPL). Epigenetic modifications dynamically change during pregnancy; however, the role of the epigenetic modifier UHRF1 in trophoblast regulation remains unknown. This is the first study to show that UHRF1 expression was localized in the cytoplasm of cytotrophoblasts, syncytiotrophoblasts, and villi columns, and decreased in the villi of patients with RPL. The invasion and cell viability in a UHRF1 knockdown trophoblast cell line were significantly decreased. In addition, the mRNA expression profiles of Swan71 cells were partially altered by UHRF1 knockdown. The altered immune-related genes were screened out and the pro-inflammatory TH1-type chemokine/cytokines CXCL2 and IL-1ß were identified as the most promising targets of UHRF1 in the trophoblasts, which were significantly increased in the UHRF1 knockdown Swan71 cells, villi, and serum from patients with RPL. The macrophages treated with the supernatants of UHRF1 knockdown Swan71 cells were polarized to the M1 phenotype and secreted high levels of pro-inflammatory cytokines, which might be driven by the activated MyD88/NF-κB signaling pathway and mediated by the increased expression of CXCR2 and IL-1R1 (CXCL2 and IL-1ß receptors, respectively). In addition, the supernatants of UHRF1 knockdown Swan71 cells showed stronger chemotaxis to macrophages than those from the controls. Our findings highlight the previously unknown roles of UHRF1 as one of the key regulators on the trophoblasts and their cross-talk with local immune cells, and demonstrate a potential approach for RPL intervention.

Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy.

Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.

A newly intervention strategy in preeclampsia: Targeting PD-1/Tim-3 signaling pathways to modulate the polarization of decidual macrophages.

Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) are important immune checkpoint receptors that prevent an overreacted maternal immune response to fetal antigens during pregnancy. Disruption of complex immune regulation mechanisms is associated with adverse pregnancy outcomes, including preeclampsia (PE). Our recent study showed that the Tim-3 pathway was involved in the regulation of decidual macrophage polarization. Decidual macrophages polarized to the M1 phenotype may impair uterine vessel remodeling during placentation, accounting for the occurrence of PE. Co-blockade of the PD-1/Tim-3 pathway was shown to successfully control tumor growth in preclinical cancer models. However, the effects of activating both PD-1 and Tim-3 pathways as a combined intervention strategy in PE are never reported. Herein, we observed the skew of decidual macrophage polarization toward the M1 phenotype in patients with PE and lipopolysaccharide (LPS)-induced PE-like rat model. Moreover, we found that the activation of PD-1/Tim-3 pathway by using PD-L1 and Gal-9 fusion proteins could alleviate the manifestation of the LPS-induced PE-like rats and protect their offspring. Compared with the single intervention, the combination of PD-L1and Gal-9 fusion proteins exhibited obvious advantages in the relief of PE-like symptoms, trophoblast invasion, and fetal vascular development, indicating a synergistic effect of the activated PD-1/Tim-3 pathway. The in vitro study also revealed that the combined intervention using PD-L1 and Gal-9 fusion proteins inhibited the LPS-induced M1 macrophage polarization via the synergic activation of the ERK/GSK3ß/ß-catenin signaling pathway. Together, our findings provide the first evidence that simultaneous activation of PD-1/Tim-3 signaling pathways may have an optimal protective effect and serve as a new potential target for PE intervention.

Chronic Hepatitis Virus Infection Are Associated With High Risk of Gastric Cancer: A Systematic Review and Cumulative Analysis.

Mounting studies demonstrated both chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection might be associated not only with an increased risk of hepatocellular carcinoma but also extrahepatic malignancies, i.e., gastric cancer (GC). However, a quantitative result addressing the association between HBV/HCV infection and GC development is scarce. A systematic search to identify the eligible studies was performed in four databases, including MEDLINE, EMBASE, Cochrane Library, and the PsychINFO. The relationship between HBV/HCV infection and the risk of GC was quantified by calculating the hazard ratio (HR) with a 95% confidence interval (CI). More methodologies of this study were available in the PROSPERO (ID: CRD42021243719). Thirteen included studies involving 7,027,546 individuals (mean age, 42.6-71.9 years) were enrolled in the pooled analyses. Two articles provided the clinical data of both HBV and HCV infections. The proportion of high methodological quality studies was 76.9% (10/13). Synthetic results from 10 eligible studies of HBV showed that HBV infection was associated with a significantly higher risk of GC when compared with the healthy controls without HBV infection (pooled HR, 1.26; 95% CI, 1.08-1.47; P = 0.003; heterogeneity, I2 = 89.3%; P< 0.001). In line with this finding, the combined effect derived from five included studies of HCV also supported a significant positive association between chronic HBV infection and GC development (pooled HR, 1.88; 95% CI, 1.28-2.76; P = 0.001; heterogeneity, I 2 = 74.7%; P = 0.003). In conclusion, both chronic HBV and HCV infections were related to a high risk of GC. The plausible mechanisms underlying such association might be correlated to HBV/HCV infection-induced persistent inflammation, immune dysfunction, and cirrhosis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (http://www.crd.york.ac.uk/PROSPERO), identifier (CRD42021243719).

Systematic Chromatin Accessibility Analysis Based on Different Immunological Subtypes of Clear Cell Renal Cell Carcinoma.

BACKGROUND: Recent research of clear cell renal cell carcinoma (ccRCC) is focused on the tumor immune microenvironment (TIME). Chromatin accessibility is critical for regulation of gene expression. However, its role in different immunological subtypes of ccRCC based on immune cell infiltration has not been systematically studied. METHODS: Five hundred thirty patient data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) were adopted to estimate immune cell infiltration. Twenty-four types of immune cells were evaluated with single-sample Gene Set Enrichment Analysis (ssGSEA). Patients were divided into two clusters based on immune cell infiltration. Systematic chromatin accessibility analysis was conducted based on the two clusters. RESULTS: We compared the relative expression of the immune gene signatures among 530 patients of TCGA-KIRC using ssGSEA. Overall survival (OS) analysis revealed 10 types of immune cells were significantly associated with prognosis. Patients were divided into two clusters based on 24 types of immune cell infiltration. Immune cell signals as well as PD-1/PD-L1 signal were higher in cluster 1. Among the two clusters, 2,400 differential peaks were found in TCGA-KIRC Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) data. The distribution of differential peaks and prognosis-related immune cells in 23 chromosomes are essentially the same. There is no peak distribution downstream. The proportion of peaks upstream of the 5' transcription start site decreases, and both sides of binding regions of the TSS 0.1-1 kb becomes smaller. Enrichment analysis of GO and KEGG of these differential peaks showed that they are remarkably related to the immune regulation in tumor microenvironment. Known motifs and de novo motifs were found by linking motif annotations to different peaks. Survival analysis of related motif transcription factors were prognostic. The GSEA enrichment analysis showed that high SP1 expression positively correlates with TGF-beta signaling and inflammatory response, while negatively correlates with TNF-alpha signaling via NFKB. High KLF12 expression negatively correlates with interferon gamma response, IL2-STAT5 signaling, TNF-alpha signaling via NFKB, IL6-JAK-STAT3 signaling. CONCLUSION: The abnormality of chromatin accessibility may play an important regulatory role in ccRCC immunity.

Recent insights into the impact of immune dysfunction on reproduction in autoimmune thyroiditis.

Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with a high incidence among women of childbearing age. Recent studies have reported that women with AIT are more susceptible to infertility, miscarriage and preterm birth. It has been investigated that abnormal changes in maternal immune system and maternal-fetal interface can dampen the immune tolerance between mother and fetus, which underlie the pathogenesis of adverse pregnancy outcomes. Hence, we summarize the immunological changes related to adverse reproductive outcomes in AIT and highlight the respective contributions of both humoral and cellular immune dysfunctions to pregnancy failures. Moreover, the direct impacts of AIT on maternal-fetal immune activation and biological influences to trophoblasts are discussed as well. All these associations require confirmation in larger studies, and the pathogenic mechanisms need to be better understood, which might provide useful information for clinical diagnosis and therapy of AIT.