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International Journal of Molecular... Jun 2024Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In... (Review)
Review
Lung cancer has an unfavorable prognosis with a rate of low overall survival, caused by the difficulty of diagnosis in the early stages and resistance to therapy. In recent years, there have been new therapies that use specific molecular targets and are effective in increasing the survival chances of advanced cancer. Therefore, it is necessary to find more specific biomarkers that can identify early changes in carcinogenesis and allow the earliest possible treatment. Vitamin D (VD) plays an important role in immunity and carcinogenesis. Furthermore, the vitamin D receptor (VDR) regulates the expression of various genes involved in the physiological functions of the human organism. The genes encoding the VDR are extremely polymorphic and vary greatly between human populations. To date, there are significant associations between VDR polymorphism and several types of cancer, but the data on the involvement of VDR polymorphism in lung cancer are still conflicting. Therefore, in this review, our aim was to investigate the relationship between VDR single-nucleotide polymorphisms in humans and the degree of risk for developing lung cancer. The studies showcased different gene polymorphisms to be associated with an increased risk of lung cancer: , , , , and . In addition, there is a strong positive correlation between VD deficiency and lung cancer development. Still, due to a lack of awareness, the assessment of VD status and VDR polymorphism is rarely considered for the prediction of lung cancer evolution and their clinical applicability, despite the fact that studies have shown the highest risk for lung cancer given by TaqI gene polymorphisms and that VDR polymorphisms are associated with more aggressive cancer evolution.
Topics: Humans; Receptors, Calcitriol; Lung Neoplasms; Vitamin D; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Risk Factors
PubMed: 38928369
DOI: 10.3390/ijms25126664 -
International Journal of Molecular... Jun 2024Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the...
Glucocerebrosidase (GCase) is a lysosomal enzyme that catalyzes the breakdown of glucosylceramide in the presence of its activator saposin C (SapC). SapC arises from the proteolytical cleavage of prosaposin (encoded by gene), which gives rise to four saposins. GCase is targeted to the lysosomes by LIMP-2, encoded by gene. GCase deficiency causes Gaucher Disease (GD), which is mainly due to biallelic pathogenetic variants in the GCase-encoding gene, . However, impairment of GCase activity can be rarely caused by SapC or LIMP-2 deficiencies. We report a new case of LIMP-2 deficiency and a new case of SapC deficiency (missing all four saposins, PSAP deficiency), and measured common biomarkers of GD and GCase activity. Glucosylsphingosine and chitotriosidase activity in plasma were increased in GCase deficiencies caused by and mutations, whereas -linked deficiency showed only Glucosylsphingosine elevation. GCase activity was reduced in fibroblasts and leukocytes: the decrease was sharper in - and -mutant fibroblasts than -mutant ones; LIMP-2-deficient leukocytes displayed higher residual GCase activity than -mutant ones. Finally, we demonstrated that GCase mainly undergoes proteasomal degradation in LIMP-2-deficient fibroblasts and lysosomal degradation in PSAP-deficient fibroblasts. Thus, we analyzed the differential biochemical profile of GCase deficiencies due to the ultra-rare and biallelic pathogenic variants in comparison with the profile observed in -linked GCase deficiency.
Topics: Glucosylceramidase; Humans; Gaucher Disease; Saposins; Lysosomal Membrane Proteins; Receptors, Scavenger; Fibroblasts; Mutation; Lysosomes; Hexosaminidases; Male; Female
PubMed: 38928321
DOI: 10.3390/ijms25126615 -
International Journal of Molecular... Jun 2024Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses....
Absent in melanoma 2 (AIM2), a key component of the IFI20X/IFI16 (PYHIN) protein family, is characterized as a DNA sensor to detect cytosolic bacteria and DNA viruses. However, little is known about its immunological role during pathogenic (. ) infection, an extracellular bacterial pathogen. In a pathogenic . gas gangrene model, mice are more susceptible to pathogenic . soft tissue infection, revealing the importance of AIM2 in host protection. Notably, deficiency leads to a defect in bacterial killing and clearance. Our in vivo and in vitro findings further establish that inflammasome signaling is impaired in the absence of in response to pathogenic . . Mechanistically, inflammasome signaling downstream of active AIM2 promotes pathogen control. Importantly, pathogenic . -derived genomic DNA triggers inflammasome signaling activation in an AIM2-dependent manner. Thus, these observations uncover a central role for AIM2 in host defense and triggering innate immunity to combat pathogenic . infections.
Topics: Inflammasomes; Animals; Clostridium perfringens; Mice; Signal Transduction; DNA-Binding Proteins; Mice, Knockout; Immunity, Innate; Mice, Inbred C57BL; Gas Gangrene; Disease Models, Animal; Clostridium Infections; Humans
PubMed: 38928277
DOI: 10.3390/ijms25126571 -
International Journal of Molecular... Jun 2024NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular... (Review)
Review
NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.
Topics: Humans; Neurofibromatoses; Neurofibromin 2; Neurilemmoma; Skin Neoplasms; Animals; Neurofibromatosis 2; Mutation; Signal Transduction; Molecular Targeted Therapy
PubMed: 38928264
DOI: 10.3390/ijms25126558 -
International Journal of Molecular... Jun 2024Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal...
Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na-dependent C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1β treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis.
Topics: Animals; Escherichia coli Infections; Mice; Humans; Intestinal Mucosa; Caco-2 Cells; Plasma Membrane Neurotransmitter Transport Proteins; Inflammation; Escherichia coli; Inflammatory Bowel Diseases; Membrane Transport Proteins; Epithelial Cells; Creatine
PubMed: 38928243
DOI: 10.3390/ijms25126537 -
International Journal of Molecular... Jun 2024Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the...
Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain-including those involving serotonin and dopamine-exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.
Topics: Animals; Serotonin; Mice; Mice, Knockout; Circadian Rhythm; Dopamine; Tyrosine 3-Monooxygenase; Tryptophan Hydroxylase; Ventral Tegmental Area; Cholecystokinin; Dopaminergic Neurons; Male; Substantia Nigra; Mice, Inbred C57BL; Bipolar Disorder
PubMed: 38928178
DOI: 10.3390/ijms25126475 -
International Journal of Molecular... Jun 2024The placenta is a crucial determinant of fetal survival, growth, and development. Deficiency in placental development directly causes intrauterine growth retardation...
The placenta is a crucial determinant of fetal survival, growth, and development. Deficiency in placental development directly causes intrauterine growth retardation (IUGR). IUGR can lead to fetal growth restriction and an increase in the mortality rate. The genetic mechanisms underlying IUGR development, however, remain unclear. In the present study, we integrated whole-genome DNA methylation and transcriptomic analyses to determine distinct gene expression patterns in various placental tissues to identify pivotal genes that are implicated with IUGR development. By performing RNA-sequencing analysis, 1487 differentially expressed genes (DEGs), with 737 upregulated and 750 downregulated genes, were identified in IUGR pigs (H_IUGR) compared with that in normal birth weight pigs (N_IUGR) ( < 0.05); furthermore, 77 miRNAs, 1331 lncRNAs, and 61 circRNAs were differentially expressed. The protein-protein interaction network analysis revealed that among these DEGs, the genes GNGT1, ANXA1, and CDC20 related to cellular developmental processes and blood vessel development were the key genes associated with the development of IUGR. A total of 495,870 differentially methylated regions were identified between the N_IUGR and H_IUGR groups, which included 25,053 differentially methylated genes (DMEs); moreover, the overall methylation level was higher in the H_IUGR group than in the N_IUGR group. Combined analysis showed an inverse correlation between methylation levels and gene expression. A total of 1375 genes involved in developmental processes, tissue development, and immune system regulation exhibited methylation differences in gene expression levels in the promoter regions and gene ontology regions. Five genes, namely, ANXA1, ADM, NRP2, SHH, and SMAD1, with high methylation levels were identified as potential contributors to IUGR development. These findings provide valuable insights that DNA methylation plays a crucial role in the epigenetic regulation of gene expression and mammalian development and that DNA-hypermethylated genes contribute to IUGR development in Rongchang pigs.
Topics: Animals; Fetal Growth Retardation; DNA Methylation; Swine; Female; Pregnancy; Placenta; Gene Expression Profiling; Protein Interaction Maps; Epigenesis, Genetic; MicroRNAs; Transcriptome; Gene Regulatory Networks
PubMed: 38928167
DOI: 10.3390/ijms25126462 -
International Journal of Molecular... Jun 2024Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as...
Nicotinamide adenine dinucleotide (NAD) is involved in renal physiology and is synthesized by nicotinamide mononucleotide adenylyltransferase (NMNAT). NMNAT exists as three isoforms, namely, NMNAT1, NMNAT2, and NMNAT3, encoded by , , and , respectively. In diabetic nephropathy (DN), NAD levels decrease, aggravating renal fibrosis. Conversely, sodium-glucose cotransporter-2 inhibitors increase NAD levels, mitigating renal fibrosis. In this regard, renal NAD synthesis has recently gained attention. However, the renal role of in DN remains uncertain. Therefore, we investigated the role of by establishing genetically engineered mice. Among the three isoforms, NMNAT1 levels were markedly reduced in the proximal tubules (PTs) of db/db mice. We examined the phenotypic changes in PT-specific conditional knockout (CKO) mice. In CKO mice, expression in PTs was downregulated when the tubules exhibited albuminuria, peritubular type IV collagen deposition, and mitochondrial ribosome (mitoribosome) excess. In CKO mice, deficiency-induced mitoribosome excess hindered mitoribosomal translation of mitochondrial inner membrane-associated oxidative phosphorylation complex I (CI), CIII, CIV, and CV proteins and mitoribosomal dysfunction. Furthermore, the expression of hypermethylated in cancer 1, a transcription repressor, was downregulated in CKO mice, causing mitoribosome excess. overexpression preserved mitoribosomal function, suggesting its protective role in DN.
Topics: Animals; Diabetic Nephropathies; Mice; Nicotinamide-Nucleotide Adenylyltransferase; Mice, Knockout; Kidney Tubules, Proximal; Male; Mitochondria; Mice, Inbred C57BL
PubMed: 38928090
DOI: 10.3390/ijms25126384 -
International Journal of Molecular... Jun 2024We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced... (Review)
Review
Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, Gene-Related Tumors, and Insulin Resistance.
We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P ( = 9 studies, N = 1375) involved as a starting point parathyroid NETs ( = 7) or pancreatitis ( = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies ( = 7) included MEN1-related insulinomas ( = 2) or MEN1-associated PHP ( = 2) or analyses of genetic profile ( = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified ( = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome ( = 1). Normocalcemic and mildly symptomatic hyperparathyroidism ( = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.
Topics: Humans; Hyperparathyroidism, Primary; Insulin Resistance; Hypercalcemia; Pancreatitis; Female; Male; Proto-Oncogene Proteins; Pancreatic Neoplasms; Multiple Endocrine Neoplasia Type 1; Parathyroid Neoplasms; Adult; Parathyroidectomy; Neuroendocrine Tumors; Pancreas
PubMed: 38928056
DOI: 10.3390/ijms25126349 -
International Journal of Molecular... Jun 2024Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary...
Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary syndrome (PCOS), where it is strongly related to obesity, insulin resistance (IR) and risk of cardiovascular disease. To determine if the inherent pathophysiology of PCOS or vitamin D levels are linked to dysregulation of cardiovascular risk proteins (CVRPs), a study in non-obese women with PCOS and without IR was undertaken. Our hypothesis was that the levels of vitamin D and its active metabolite would be associated with CVRPs comparably in women with and without PCOS. In women with PCOS ( = 29) and controls ( = 29), 54 CVRPs were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement and correlated to 25-hydroxyvitamin D (25(OH)D) and the active 1,25-dihydroxyvitamin D (1,25(OH)D) measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Women with PCOS had comparable IR and systemic inflammation (normal C-reactive protein) to control women, though had higher free androgen index and anti-Mullerian hormone levels. 25(OH)D and 1,25(OH)D levels did not differ between groups. Nine CVRPs were higher in PCOS ( < 0.05) (Galectin-9, Brother of CDO, C-motif chemokine 3, Interleukin-18 receptor-1, Thrombopoietin, Interleukin-1 receptor antagonist protein, Programmed cell death 1 ligand-2, Low-affinity immunoglobulin gamma Fc-region receptor II-b and human growth hormone), whilst 45 CVRPs did not differ. 25(OH)D correlated with five CVRPs in PCOS and one in controls ( < 0.05). Despite the women with PCOS not exhibiting overt systemic inflammation, 9 of 54 CVRPs were elevated, all relating to inflammation, and 5 of these correlated with 25(OH)D suggesting an ongoing underlying inflammatory process in PCOS even in the absence of obesity/IR.
Topics: Humans; Polycystic Ovary Syndrome; Female; Adult; Cross-Sectional Studies; Biomarkers; Vitamin D; Cardiovascular Diseases; Heart Disease Risk Factors; Vitamin D Deficiency; Insulin Resistance; Obesity; Young Adult
PubMed: 38928037
DOI: 10.3390/ijms25126330