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International Journal of Molecular... Jun 2024Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation...
Endometritis is a common disease in animals, leading to disruption of reproductive processes and economic losses. Noradrenergic control of prostaglandin (PG)I2 formation by inflamed endometrium is unknown. We determined the involvement of α1-, α2- and β-adrenoreceptors (ARs) in noradrenaline-influenced PGI synthase (PGIS) protein abundance and PGI2 release from porcine (1) endometrial explants with ()-induced inflammation in vivo, and (2) lipopolysaccharide (LPS)-treated endometrial epithelial cells. Experiment 1. suspension ( group) or saline (CON group) was injected into the uterine horns. In both groups, noradrenaline increased endometrial PGIS abundance and PGI2 release versus the control values, and it was higher in the group than in the CON group. In the CON group, a noradrenaline stimulating effect on both parameters takes place through α1D-, α2C- and β2-ARs. In the group, noradrenaline increased PGIS abundance and PGI2 release via α1A-, α2(B,C)- and β(1,2)-ARs, and PGI2 release also by α2A-ARs. Experiment 2. LPS and noradrenaline augmented the examined parameters in endometrial epithelial cells versus the control value. In LPS-treated cells, β(1,2)-ARs mediate in noradrenaline excitatory action on PGIS protein abundance and PGI2 release. β3-ARs also contribute to PGI2 release. Under inflammatory conditions, noradrenaline via ARs increases PGI2 synthesis and release from the porcine endometrium, including epithelial cells. Our findings suggest that noradrenaline may indirectly affect processes regulated by PGI2 in the inflamed uterus.
Topics: Animals; Female; Norepinephrine; Endometrium; Swine; Epoprostenol; Receptors, Adrenergic; Lipopolysaccharides; Inflammation; Escherichia coli; Endometritis; Epithelial Cells; Intramolecular Oxidoreductases; Cytochrome P-450 Enzyme System
PubMed: 38928020
DOI: 10.3390/ijms25126313 -
Genes Jun 2024Chilling stress is one of the main abiotic factors affecting rice growth and yield. In rice, chlorophyllide oxygenase encoded by is responsible for converting...
Chilling stress is one of the main abiotic factors affecting rice growth and yield. In rice, chlorophyllide oxygenase encoded by is responsible for converting chlorophyllide to chlorophyllide , playing a crucial role in photosynthesis and thus rice growth. However, little is known about the function of in chilling stress responses. The presence of the -acting element involved in low-temperature responsiveness (LTR) in the promoter implied that probably is a cold-responsive gene. The gene expression level of was usually inhibited by low temperatures during the day and promoted by low temperatures at night. The knockout mutants generated by the CRISPR-Cas9 technology in rice ( L.) exhibited significantly weakened chilling tolerance at the seedling stage. dysfunction led to the accumulation of reactive oxygen species and malondialdehyde, an increase in relative electrolyte leakage, and a reduction in antioxidant gene expression under chilling stress. In addition, the functional deficiency of resulted in more severe damage to chloroplast morphology, such as abnormal grana thylakoid stacking, caused by low temperatures. Moreover, the rice yield was reduced in knockout mutants. Therefore, the elevated expression of probably has the potential to increase both rice yield and chilling tolerance simultaneously, providing a strategy to cultivate chilling-tolerant rice varieties with high yields.
Topics: Oryza; Seedlings; Cold Temperature; Gene Expression Regulation, Plant; Plant Proteins; Oxygenases; Cold-Shock Response; Gene Knockout Techniques; Reactive Oxygen Species; Chlorophyll; Photosynthesis
PubMed: 38927664
DOI: 10.3390/genes15060721 -
Biomolecules Jun 2024Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D [1,25(OH)D]. 1,25(OH)D controls gene...
Vitamin D hydroxylation in the liver/kidney results in conversion to its physiologically active form of 1,25-dihydroxyvitamin D [1,25(OH)D]. 1,25(OH)D controls gene expression through the nuclear vitamin D receptor (VDR) mainly expressed in intestinal epithelial cells. Cytochrome P450 (CYP) 24A1 is a catabolic enzyme expressed in the kidneys. Interestingly, a recently identified mutation in another CYP enzyme, CYP3A4 (gain-of-function), caused type III vitamin D-dependent rickets. CYP3A are also expressed in the intestine, but their hydroxylation activities towards vitamin D substrates are unknown. We evaluated CYP3A or CYP24A1 activities on vitamin D action in cultured cells. In addition, we examined the expression level and regulation of CYP enzymes in intestines from mice. The expression of CYP3A or CYP24A1 significantly reduced 1,25(OH)D-VDRE activity. Moreover, in mice, mRNA was significantly induced by 1,25(OH)D in the intestine, but a mature form (approximately 55 kDa protein) was also expressed in mitochondria and induced by 1,25(OH)D, and this mitochondrial enzyme appears to hydroxylate 25OHD to 24,25(OH)D. Thus, CYP3A or CYP24A1 could locally attenuate 25OHD or 1,25(OH)D action, and we suggest the small intestine is both a vitamin D target tissue, as well as a newly recognized vitamin D-metabolizing tissue.
Topics: Animals; Vitamin D; Humans; Vitamin D3 24-Hydroxylase; Mice; Receptors, Calcitriol; Intestinal Mucosa; Cytochrome P-450 Enzyme System; Cytochrome P-450 CYP3A; Intestines; Calcitriol
PubMed: 38927120
DOI: 10.3390/biom14060717 -
Biomolecules Jun 2024Ginseng ( C. A. Meyer) is an ancient and valuable Chinese herbal medicine, and ginsenoside, as the main active ingredient of ginseng, has received wide attention because...
Ginseng ( C. A. Meyer) is an ancient and valuable Chinese herbal medicine, and ginsenoside, as the main active ingredient of ginseng, has received wide attention because of its various pharmacological active effects. Cytochrome P450 is the largest family of enzymes in plant metabolism and is involved in the biosynthesis of terpenoids, alkaloids, lipids, and other primary and secondary plant metabolites. It is significant to explore more genes with unknown functions and reveal their roles in ginsenoside synthesis. In this study, based on the five genes screened in the pre-laboratory, through the correlation analysis with the content of ginsenosides and the analysis of the interactions network of the key enzyme genes for ginsenoside synthesis, we screened out those highly correlated with ginsenosides, , as the target gene from among the five genes. Methyl jasmonate-induced treatment of ginseng adventitious roots showed that the gene responded to methyl jasmonate induction and was involved in the synthesis of ginsenosides. The gene was cloned and the overexpression vector pBI121-PgCYP309 and the interference vector pART27-PgCYP309 were constructed. Transformation of ginseng adventitious roots by the -mediated method and successful induction of transgenic ginseng hairy roots were achieved. The transformation rate of ginseng hairy roots with overexpression of the gene was 22.7%, and the transformation rate of ginseng hairy roots with interference of the gene was 40%. Analysis of ginseng saponin content and relative gene expression levels in positive ginseng hairy root asexual lines revealed a significant increase in PPD, PPT, and PPT-type monomeric saponins Re and Rg2. The relative expression levels of and genes were also significantly increased. gene promotes the synthesis of ginsenosides, and it was preliminarily verified that gene can promote the synthesis of dammarane-type ginsenosides.
Topics: Panax; Cytochrome P-450 Enzyme System; Ginsenosides; Gene Expression Regulation, Plant; Plant Roots; Plant Proteins; Oxylipins; Acetates; Cyclopentanes
PubMed: 38927118
DOI: 10.3390/biom14060715 -
Biomolecules Jun 2024The active form of vitamin D, 1α,25-dihydroxyvitamin D [1,25(OH)D], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR)....
The active form of vitamin D, 1α,25-dihydroxyvitamin D [1,25(OH)D], is a principal regulator of calcium homeostasis through activation of the vitamin D receptor (VDR). Previous studies have shown that 2α-(3-hydroxypropyl)-1,25D (O1C3) and 2α-(3-hydroxypropoxy)-1,25D (O2C3), vitamin D derivatives resistant to inactivation enzymes, can activate VDR, induce leukemic cell differentiation, and increase blood calcium levels in rats more effectively than 1,25(OH)D. In this study, to further investigate the usefulness of 2α-substituted vitamin D derivatives, we examined the effects of O2C3, O1C3, and their derivatives on VDR activity in cells and mouse tissues and on osteoblast differentiation of dedifferentiated fat (DFAT) cells, a cell type with potential therapeutic application in regenerative medicine. In cell culture experiments using kidney-derived HEK293 cells, intestinal mucosa-derived CaCO cells, and osteoblast-derived MG63 cells, and in mouse experiments, O2C2, O2C3, O1C3, and O1C4 had a weaker effect than or equivalent effect to 1,25(OH)D in VDR transactivation and induction of the VDR target gene , but they enhanced osteoblast differentiation in DFAT cells equally to or more effectively than 1,25(OH)D. In long-term treatment with the compound without the medium change (7 days), the derivatives enhanced osteoblast differentiation more effectively than 1,25(OH)D. O2C3 and O1C3 were more stable than 1,25(OH)D in DFAT cell culture. These results indicate that 2α-substituted vitamin D derivatives, such as inactivation-resistant O2C3 and O1C3, are more effective than 1,25(OH)D in osteoblast differentiation of DFAT cells, suggesting potential roles in regenerative medicine with DFAT cells and other multipotent cells.
Topics: Humans; Osteoblasts; Animals; Receptors, Calcitriol; Cell Differentiation; Mice; HEK293 Cells; Vitamin D; Caco-2 Cells; Adipocytes; Cell Dedifferentiation; Male; Vitamin D3 24-Hydroxylase; Calcitriol
PubMed: 38927109
DOI: 10.3390/biom14060706 -
Biomolecules May 2024Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and...
Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity. Fatty acids caused PPARβ/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 () mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 () mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARβ/δ ligands. The activation of PPARβ/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing -null keratinocytes. HRAS-expressing -null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARβ/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARβ/δ. The results from these studies demonstrate that PPARβ/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components.
Topics: Keratinocytes; PPAR-beta; Animals; Mice; Stearoyl-CoA Desaturase; PPAR delta; Fatty Acids; Angiopoietin-Like Protein 4; Humans; Oleic Acid; Proto-Oncogene Proteins p21(ras); Fatty Acids, Monounsaturated; Skin Neoplasms
PubMed: 38927010
DOI: 10.3390/biom14060606 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
OBJECTIVE
To analyze the DTA (, , ) mutations in patients with myeloproliferative neoplasms (MPN), and preliminarily explore their correlation with thromboembolism.
METHODS
Clinical characteristics of 62 patients diagnosed de novo MPN at Central Hospital Affiliated to Shandong First Medical University from September 2016 to September 2022 were retrospectively analyzed. Next-generation sequencing was used to detect 35 MPN-related genes, and the DTA mutations in MPN patients and their relationship with thromboembolic events were analyzed.
RESULTS
75.8% (47/62) of the patients presented pathogenic non-driver mutations, and the mean number of pathogenic non-driver mutations per patient was 1.08. Among them, the most frequently mutated non-driver genes were (38.7%, 24/62), (9.7%, 6/62) and (6.5%, 4/62). The presence of DTA gene mutations was 50% (31/62) in the total MPN patients, and mainly accompanied by driver mutations. The mutation rate of DTA in patients aged ≥60 years was significantly higher than that in patients <60 years old ( =0.039). The incidence of thromboembolism in patients with DTA mutation was 58.1% (18/31), which was significantly higher than that in patients without DTA mutation (19.4%, 6/31) ( =0.002). The gene mutation rate in MPN patients with thromboembolism was 66.7% (16/24), which was significantly higher than that in patients without thromboembolism (21.1%, 8/38) ( =0.00).
CONCLUSION
Patients with MPN have a higher incidence of DTA mutations, which are mainly accompanied by driver gene mutations. The incidence of thromboembolism in MPN patients with DTA mutations is higher than that in patients without DTA mutations. Especially, the elderly (≥60 years) essential thrombocythemia(ET) and polycythemia vera(PV) patients with mutation should be vigilant for thromboembolic events.
Topics: Humans; Mutation; Dioxygenases; Middle Aged; Myeloproliferative Disorders; Thromboembolism; Retrospective Studies; Proto-Oncogene Proteins; DNA-Binding Proteins; Repressor Proteins; DNA Methyltransferase 3A; DNA (Cytosine-5-)-Methyltransferases; Male; Female; High-Throughput Nucleotide Sequencing
PubMed: 38926973
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.025 -
Cell Death & Disease Jun 2024Advances in functional studies on epigenetic regulators have disclosed the vital roles played by diverse histone lysine demethylases (KDMs), ranging from normal... (Review)
Review
Advances in functional studies on epigenetic regulators have disclosed the vital roles played by diverse histone lysine demethylases (KDMs), ranging from normal development to tumorigenesis. Most of the KDMs are Jumonji C domain-containing (JMJD) proteins. Many of these KDMs remove methyl groups from histone tails to regulate gene transcription. There are more than 30 known KDM proteins, which fall into different subfamilies. Of the many KDM subfamilies, KDM3 (JMJD1) proteins specifically remove dimethyl and monomethyl marks from lysine 9 on histone H3 and other non-histone proteins. Dysregulation of KDM3 proteins leads to infertility, obesity, metabolic syndromes, heart diseases, and cancers. Among the KDM3 proteins, KDM3A has been largely studied in cancers. However, despite a number of studies pointing out their importance in tumorigenesis, KDM3B and KDM3C are relatively overlooked. KDM3B and KDM3C show context-dependent functions, showing pro- or anti-tumorigenic abilities in different cancers. Thus, this review provides a thorough understanding of the involvement of KDM3B and KDMC in oncology that should be helpful in determining the role of KDM3 proteins in preclinical studies for development of novel pharmacological methods to overcome cancer.
Topics: Humans; Jumonji Domain-Containing Histone Demethylases; Epigenesis, Genetic; Carcinogenesis; Animals; Neoplasms
PubMed: 38926399
DOI: 10.1038/s41419-024-06850-z -
Discovery Medicine Jun 2024Genetic mutations play a crucial role in the development and progression of myelodysplastic syndromes (MDS), impacting the immune microenvironment and influencing the...
BACKGROUND
Genetic mutations play a crucial role in the development and progression of myelodysplastic syndromes (MDS), impacting the immune microenvironment and influencing the choice of treatment regimen, as well as the efficacy and prognosis of patients. The objective of this study was to examine variations in hematological and immunological characteristics associated with common gene mutations in MDS patients and establish a foundation for the precise treatment of MDS.
METHODS
The hematological, immunological, and other clinical features of 71 recently diagnosed MDS patients from January 1, 2019, to July 31, 2023, were retrospectively analyzed. These patients were categorized based on their gene mutations, and the variances in hematological and immunological characteristics among distinct groups were compared.
RESULTS
Hematological variances were observed among different gene mutation groups. Specifically, platelet counts in the splicing factor 3B subunit 1 () mutation group were notably higher compared to the wild-type group ( = 0.009). Conversely, in the additional sex combs like 1 () mutation groups, monocyte ratios were significantly elevated in comparison to the wild-type group ( = 0.046), and in the ten-eleven translocation 2 () mutation group, lymphocyte ratios were significantly lower ( = 0.022). Additionally, the leukocyte ( = 0.005), neutrophil ratio ( = 0.002), and lymphocyte ratio ( = 0.001) were significantly higher in the Runt-related transcription factor 1 () mutation group. Regarding immunological distinctions, the Natural Killer (NK) cell ratio demonstrated a significant increase in the mutation group ( = 0.005). Moreover, the mutation group exhibited a significantly higher Interleukin-8 (IL-8) level ( = 0.017). In contrast, the U2 small nuclear RNA auxiliary factor 1 () group displayed significantly lower levels of IL-1β ( = 0.033), IL-10 ( = 0.033), and Tumour Necrosis Factor-α (TNF-α) ( = 0.009).
CONCLUSION
Distinct variations exist in the immune microenvironment of MDS associated with different genetic mutations. Further studies are imperative to delve into the underlying mechanisms that drive these differences.
Topics: Humans; Myelodysplastic Syndromes; Mutation; Female; Male; Middle Aged; Aged; RNA Splicing Factors; Retrospective Studies; Adult; Dioxygenases; Aged, 80 and over; DNA-Binding Proteins; Phosphoproteins; Killer Cells, Natural; Core Binding Factor Alpha 2 Subunit; Platelet Count; Repressor Proteins
PubMed: 38926115
DOI: 10.24976/Discov.Med.202436185.119 -
Trends in Biochemical Sciences Jun 2024Jumonji C domain-containing (JMJD) proteins are found in bacteria, fungi, animals, and plants. They belong to the 2-oxoglutarate-dependent oxygenase superfamily and are... (Review)
Review
Jumonji C domain-containing (JMJD) proteins are found in bacteria, fungi, animals, and plants. They belong to the 2-oxoglutarate-dependent oxygenase superfamily and are endowed with various enzymatic activities, including demethylation of histones and hydroxylation of non-histone proteins. Many JMJD proteins are involved in the epigenetic control of gene expression, yet they also modulate a myriad other cellular processes. In this review we focus on the 33 human JMJD proteins and their established and controversial catalytic properties, survey their epigenetic and non-epigenetic functions, emphasize their contribution to sex-specific disease differences, and highlight how they sense metabolic changes. All this underlines not only their key roles in development and homeostasis, but also that JMJD proteins are destined to become drug targets in multiple diseases.
PubMed: 38926050
DOI: 10.1016/j.tibs.2024.06.009