-
International Journal of Molecular... Jun 2024We present a case involving a patient whose clinical phenotype aligns with oculocutaneous albinism (OCA), yet exhibits a complex genotype primarily characterized by...
We present a case involving a patient whose clinical phenotype aligns with oculocutaneous albinism (OCA), yet exhibits a complex genotype primarily characterized by variants of unknown significance (VUS). An 11-year-old boy manifested iris hypopigmentation and translucency, pronounced photophobia, diminished visual acuity and stereopsis, nystagmus, reduced pigmentation of the retina, and foveal hypoplasia. Genetic testing was performed. A heterozygous missense VUS c.230A>G, p.(Gln77Arg), a heterozygous missense VUS c.1307G>C, p.(Gly436Ala), and a heterozygous missense variant c.1205G>A, p.(Arg402Gln) which was classified as a risk factor, were identified. We hypothesized that the c.1307G>C, p.(Gly436Ala) variant is in genetic disequilibrium with the c.1205G>A, p.(Arg402Gln) variant leading to deficient expression of melanogenic enzymes in retinal cells, resulting in the manifestation of mild OCA. Additionally, this study represents the case where we did not detect chiasmal misrouting in visual evoked potentials, nor did we observe a shift in the distribution of ganglion cell thickness from a temporal to a central position. Moreover, our patient's case supports the probable benign nature of the c.230A>G, p.(Gln77Arg) variant.
Topics: Humans; Male; Child; Calpain; Monophenol Monooxygenase; Mutation, Missense; Vitreoretinopathy, Proliferative; Albinism, Oculocutaneous; Phenotype; Pedigree
PubMed: 38928147
DOI: 10.3390/ijms25126442 -
International Journal of Molecular... Jun 2024Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic...
Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (), suppressor of cytokine signaling 3 (), sterol regulatory element-binding transcription factor 1 (), stearoyl-CoA desaturase-1 (), and patatin-like phospholipase domain-containing protein 2 (), were determined from liver and adipose tissue. Higher serum leptin and levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, was positively correlated with leptin expression in adipose tissue, and was correlated with . In OAT, was correlated with insulin resistance and transaminase enzymes ( < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.
Topics: Humans; Leptin; Female; Male; Liver; Middle Aged; Omentum; Adipose Tissue; Adult; Fatty Liver; Receptors, Leptin; Suppressor of Cytokine Signaling 3 Protein; Insulin Resistance; Sterol Regulatory Element Binding Protein 1; Stearoyl-CoA Desaturase
PubMed: 38928125
DOI: 10.3390/ijms25126420 -
International Journal of Molecular... Jun 2024and , bacterial degraders of the herbicide glyphosate, were found to induce phosphonatase (phosphonoacetaldehyde hydrolase, EC 3.11.1.1) when grown on minimal media...
and , bacterial degraders of the herbicide glyphosate, were found to induce phosphonatase (phosphonoacetaldehyde hydrolase, EC 3.11.1.1) when grown on minimal media with glyphosate as the sole source of phosphorus. The phosphonatases of the strains were purified to an electrophoretically homogeneous state and characterized. The enzymes differed in their kinetic characteristics and some other parameters from the previously described phosphonatases. The phosphonatase of was first revealed to separate into two stable forms, which had similar kinetic characteristics but interacted differently with affinity and ion-exchange resins. The genomes of the investigated bacteria were sequenced. The phosphonatase genes were identified, and their context was determined: the bacteria were shown to have gene clusters, which, besides the phosphonatase operon, included genes for LysR-type transcription activator (substrate sensor) and putative iron-containing oxygenase PhnHD homologous to monooxygenases PhnY and TmpB of marine organophosphonate degraders. Genes of 2-aminoethylphosphonate aminotransferase (PhnW, EC 2.6.1.37) were absent in the achromobacterial phosphonatase operons; instead, we revealed the presence of genes encoding the putative flavin oxidase HpnW. In silico simulation showed 1-hydroxy-2-aminoethylphosphonate to be the most likely substrate of the new monooxygenase, and a number of glycine derivatives structurally similar to glyphosate to be substrates of flavin oxidase.
Topics: Glyphosate; Glycine; Achromobacter; Operon; Soil Microbiology; Bacterial Proteins; Herbicides; Multigene Family; Kinetics; Gene Expression Regulation, Bacterial
PubMed: 38928116
DOI: 10.3390/ijms25126409 -
International Journal of Molecular... Jun 2024Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients...
Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients suffering from SSD are at risk of developing life-threatening complications. Pharmacogenetic studies have shown promising results on personalized treatment of psychosis. In the current study, 103 patients diagnosed with SSD treated with risperidone as antipsychotic monotherapy were enrolled. Socio-demographics and clinical data were recorded, and laboratory tests and genotyping standard procedure for cytochrome P450 (CYP) 2D6*4 were performed. Patients were evaluated by the Positive and Negative Syndrome Scale (PANSS) on admission and at discharge. Based on the reduction in the PANSS total score, subjects were divided into non-responders, partial responders and full responders. Only 11 subjects had a full response to risperidone (10.67%), 53 subjects (51.45%) had a partial response, and 39 participants (37.86%) were non-responders. Patients at first episode psychosis showed significantly higher levels of blood glucose and prolactin levels, while chronic patients showed significantly higher LDL levels. Adverse drug reactions (ADR) such as tremor and stiffness significantly correlated with genetic phenotypes ( = 0.0145). While CYP2D6 showed no impact on treatment response, ADR were significantly more frequent among poor and intermediate metabolizers.
Topics: Humans; Cytochrome P-450 CYP2D6; Risperidone; Male; Female; Schizophrenia; Adult; Antipsychotic Agents; Middle Aged; Genotype; Young Adult
PubMed: 38928058
DOI: 10.3390/ijms25126350 -
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