@article{Kumar2024,

title = {Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues},

author = {Kukkala Kiran Kumar and Elhadi Husein Aburawi and Milos Ljubisavljevic and Melvin Khee Shing Leow and Xu Feng and Suraiya Anjum Ansari and Bright Starling Emerald},

url = {https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01692-0},

doi = {10.1186/s13148-024-01692-0},

issn = {1868-7083},

year  = {2024},

date = {2024-06-01},

journal = {Clinical Epigenetics},

volume = {16},

number = {1},

pages = {78},

abstract = {Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the $β$ -cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting $β$ -cells and reducing T2DM-associated complications, among others.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{https://doi.org/10.1002/advs.202401939,

title = {The Long Non-Coding RNA Obesity-Related (Obr) Contributes To Lipid Metabolism Through Epigenetic Regulation},

author = {Suneesh Kaimala and Shareena Saeed Lootah and Neha Mehra and Challagandla Anil Kumar and Saeeda Al Marzooqi and Prabha Sampath and Suraiya Anjum Ansari and Bright Starling Emerald},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202401939},

doi = {https://doi.org/10.1002/advs.202401939},

year  = {2024},

date = {2024-05-05},

journal = {Advanced Science},

volume = {n/a},

number = {n/a},

pages = {2401939},

abstract = {Abstract Obesity is a multifactorial disease that is part of today's epidemic and also increases the risk of other metabolic diseases. Long noncoding RNAs (lncRNAs) provide one tier of regulatory mechanisms to maintain metabolic homeostasis. Although lncRNAs are a significant constituent of the mammalian genome, studies aimed at their metabolic significance, including obesity, are only beginning to be addressed. Here, a developmentally regulated lncRNA, termed as obesity related (Obr), whose expression in metabolically relevant tissues such as skeletal muscle, liver, and pancreas is altered in diet-induced obesity, is identified. The Clone 9 cell line and high-fat diet-induced obese Wistar rats are used as a model system to verify the function of Obr. By using stable expression and antisense oligonucleotide-mediated downregulation of the expression of Obr followed by different molecular biology experiments, its role in lipid metabolism is verified. It is shown that Obr associates with the cAMP response element-binding protein (Creb) and activates different transcription factors involved in lipid metabolism. Its association with the Creb histone acetyltransferase complex, which includes the cAMP response element-binding protein (CBP) and p300, positively regulates the transcription of genes involved in lipid metabolism. In addition, Obr is regulated by Pparγ in response to lipid accumulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PMID:38503745,

title = {The role of RNA-modifying proteins in renal cell carcinoma},

author = {Muna A Alhammadi and Khuloud Bajbouj and Iman M Talaat and Rifat Hamoudi},

url = {https://europepmc.org/articles/PMC10951318},

doi = {10.1038/s41419-024-06479-y},

issn = {2041-4889},

year  = {2024},

date = {2024-03-01},

journal = {Cell death & disease},

volume = {15},

number = {3},

pages = {227},

abstract = {Gene expression is one of the most critical cellular processes. It is controlled by complex mechanisms at the genomic, epigenomic, transcriptomic, and proteomic levels. Any aberration in these mechanisms can lead to dysregulated gene expression. One recently discovered process that controls gene expression includes chemical modifications of RNA molecules by RNA-modifying proteins, a field known as epitranscriptomics. Epitranscriptomics can regulate mRNA splicing, nuclear export, stabilization, translation, or induce degradation of target RNA molecules. Dysregulation in RNA-modifying proteins has been found to contribute to many pathological conditions, such as cancer, diabetes, obesity, cardiovascular diseases, and neurological diseases, among others. This article reviews the role of epitranscriptomics in the pathogenesis and progression of renal cell carcinoma. It summarizes the molecular function of RNA-modifying proteins in the pathogenesis of renal cell carcinoma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Khasawneh2024,

title = {The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population},

author = {Lubna Q. Khasawneh and Habiba Alsafar and Hiba Alblooshi and Mushal Allam and George P. Patrinos and Bassam R. Ali},

url = {https://doi.org/10.1186/s40246-023-00568-3},

doi = {10.1186/s40246-023-00568-3},

issn = {1479-7364},

year  = {2024},

date = {2024-01-03},

journal = {Human Genomics},

volume = {18},

number = {1},

pages = {2},

abstract = {Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{biomedinformatics4020081,

title = {Anomaly Detection and Artificial Intelligence Identified the Pathogenic Role of Apoptosis and RELB Proto-Oncogene, NF-kB Subunit in Diffuse Large B-Cell Lymphoma},

author = {Joaquim Carreras and Rifat Hamoudi},

url = {https://www.mdpi.com/2673-7426/4/2/81},

doi = {10.3390/biomedinformatics4020081},

issn = {2673-7426},

year  = {2024},

date = {2024-01-01},

journal = {BioMedInformatics},

volume = {4},

number = {2},

pages = {1480–1505},

abstract = {Background: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent lymphomas. DLBCL is phenotypically, genetically, and clinically heterogeneous. Aim: We aim to identify new prognostic markers. Methods: We performed anomaly detection analysis, other artificial intelligence techniques, and conventional statistics using gene expression data of 414 patients from the Lymphoma/Leukemia Molecular Profiling Project (GSE10846), and immunohistochemistry in 10 reactive tonsils and 30 DLBCL cases. Results: First, an unsupervised anomaly detection analysis pinpointed outliers (anomalies) in the series, and 12 genes were identified: DPM2, TRAPPC1, HYAL2, TRIM35, NUDT18, TMEM219, CHCHD10, IGFBP7, LAMTOR2, ZNF688, UBL7, and RELB, which belonged to the apoptosis, MAPK, MTOR, and NF-kB pathways. Second, these 12 genes were used to predict overall survival using machine learning, artificial neural networks, and conventional statistics. In a multivariate Cox regression analysis, high expressions of HYAL2 and UBL7 were correlated with poor overall survival, whereas TRAPPC1, IGFBP7, and RELB were correlated with good overall survival (p < 0.01). As a single marker and only in RCHOP-like treated cases, the prognostic value of RELB was confirmed using GSEA analysis and Kaplan–Meier with log-rank test and validated in the TCGA and GSE57611 datasets. Anomaly detection analysis was successfully tested in the GSE31312 and GSE117556 datasets. Using immunohistochemistry, RELB was positive in B-lymphocytes and macrophage/dendritic-like cells, and correlation with HLA DP-DR, SIRPA, CD85A (LILRB3), PD-L1, MARCO, and TOX was explored. Conclusions: Anomaly detection and other bioinformatic techniques successfully predicted the prognosis of DLBCL, and high RELB was associated with a favorable prognosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PMID:37914398,

title = {Identification of a Gag binding site critical for feline immunodeficiency virus (FIV) genomic RNA packaging},

author = {Anjana Krishnan and Lizna M Ali and Suresha G Prabhu and Vineeta N Pillai and Akhil Chameettachal and Valerie Vivet-Boudou and Serena Bernacchi and Farah Mustafa and Roland Marquet and Tahir A Rizvi},

doi = {10.1261/rna.079840.123},

year  = {2024},

date = {2024-01-01},

urldate = {2024-01-01},

journal = {RNA},

volume = {30},

number = {1},

pages = {68-88},

abstract = {The retroviral Gag precursor plays a central role in the selection and packaging of viral genomic RNA (gRNA) by binding to virus-specific packaging signal(s) (psi or ψ). Previously, we have mapped the FIV ψ to two discontinuous regions within the 5' end of the gRNA that assumes a higher order structure harboring several structural motifs. To better define the region and structural elements important for gRNA packaging, we methodically investigated these FIV ψ sequences employing genetic, biochemical, and structure-function relationship approaches. Our mutational analysis revealed that the unpaired U85CUG88 stretch within FIV ψ is crucial for gRNA encapsidation into nascent virions. High-throughput Selective 2' Hydroxyl Acylation analyzed by Primer Extension (hSHAPE) performed on wild type and mutant FIV ψ sequences with substitutions in the U85CUG88 stretch revealed that these mutations had limited structural impact and maintained nucleotides 80 to 92 unpaired, as in the wild type structure. Since these mutations dramatically affected packaging, our data suggests that the single-stranded U85CUG88 sequence is important during FIV RNA packaging. Filter binding assays performed using purified FIV Pr50Gag on wild type and mutant U85CUG88 ψ RNAs led to reduced levels of Pr50Gag binding to mutant U85CUG88 ψ RNAs, indicating that the U85CUG88 stretch is crucial for ψ RNA-Pr50Gag interactions. Delineating sequences important for FIV gRNA encapsidation should enhance our understanding of both gRNA packaging and virion assembly, making them potential targets for novel retroviral therapeutic interventions, as well as development of FIV-based vectors for human gene therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{https://doi.org/10.1111/tra.12928,

title = {Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild type allele},

author = {Nesrin Gariballa and Sally Badawi and Bassam R. Ali},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/tra.12928},

doi = {https://doi.org/10.1111/tra.12928},

year  = {2024},

date = {2024-01-01},

journal = {Traffic},

volume = {25},

number = {1},

pages = {e12928},

abstract = {Abstract Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting 1 in 5000–8000 individuals. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is the most common HHT and manifests as diverse vascular malformations ranging from mild symptoms such as epistaxis and mucosal and cutaneous telangiectases to severe arteriovenous malformations (AVMs) in the lungs, brain or liver. HHT1 is caused by heterozygous mutations in the ENG gene, which encodes endoglin, the TGFβ homodimeric co-receptor. It was previously shown that some endoglin HHT1-causing variants failed to traffic to the plasma membrane due to their retention in the endoplasmic reticulum (ER) and consequent degradation by ER-associated degradation (ERAD). Endoglin is a homodimer formed in the ER, and we therefore hypothesized that mixed heterodimers might form between ER-retained variants and WT protein, thus hampering its maturation and trafficking to the plasma membrane causing dominant negative effects. Indeed, HA-tagged ER-retained mutants formed heterodimers with Myc-tagged WT endoglin. Moreover, variants L32R, V105D, P165L, I271N and C363Y adversely affected the trafficking of WT endoglin by reducing its maturation and plasma membrane localization. These results strongly suggest dominant negative effects exerted by these ER-retained variants aggravating endoglin loss of function in patients expressing them in the heterozygous state with the WT allele. Moreover, this study may help explain some of the variability observed among HHT1 patients due to the additional loss of function exerted by the dominant negative effects in addition to that due to haploinsufficiency. These findings might also have implications for some of the many conditions impacted by ERAD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.3389/fphar.2024.1335058,

title = {Exploring the efficacy and safety of Ambroxol in Gaucher disease: an overview of clinical studies},

author = {Feda E. Mohamed and Fatma Al-Jasmi},

url = {https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1335058},

doi = {10.3389/fphar.2024.1335058},

issn = {1663-9812},

year  = {2024},

date = {2024-01-01},

journal = {Frontiers in Pharmacology},

volume = {15},

abstract = {
Gaucher disease (GD) is mainly caused by glucocerebrosidase (GCase) enzyme deficiency due to genetic variations in the GBA1 gene leading to the toxic accumulation of sphingolipids in various organs, which causes symptoms such as anemia, thrombocytopenia, hepatosplenomegaly, and neurological manifestations. GD is clinically classified into the non-neuronopathic type 1, and the acute and chronic neuronopathic forms, types 2 and 3, respectively. In addition to the current approved GD medications, the repurposing of Ambroxol (ABX) has emerged as a prospective enzyme enhancement therapy option showing its potential to enhance mutated GCase activity and reduce glucosylceramide accumulation in GD-affected tissues of different GBA1 genotypes. The variability in response to ABX varies across different variants, highlighting the diversity in patients’ therapeutic outcomes. Its oral availability and safety profile make it an attractive option, particularly for patients with neurological manifestations. Clinical trials are essential to explore further ABX’s potential as a therapeutic medication for GD to encourage pharmaceutical companies’ investment in its development. This review highlights the potential of ABX as a pharmacological chaperone therapy for GD and stresses the importance of addressing response variability in clinical studies to improve the management of this rare and complex disorder.
},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.3389/fnins.2024.1362497,

title = {Epigenetic alterations in creatine transporter deficiency: a new marker for dodecyl creatine ester therapeutic efficacy monitoring},

author = {Léa Broca-Brisson and Clémence Disdier and Rania Harati and Rifat Hamoudi and Aloïse Mabondzo},

url = {https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1362497},

doi = {10.3389/fnins.2024.1362497},

issn = {1662-453X},

year  = {2024},

date = {2024-01-01},

journal = {Frontiers in Neuroscience},

volume = {18},

abstract = {
Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the Slc6a8 gene. The impaired creatine uptake in the brain leads to developmental delays with intellectual disability. We hypothesized that deficient creatine uptake in CTD cerebral cells impact methylation balance leading to alterations of genes and proteins expression by epigenetic mechanism. In this study, we determined the status of nucleic acid methylation in both Slc6a8 knockout mouse model and brain organoids derived from CTD patients’ cells. We also investigated the effect of dodecyl creatine ester (DCE), a promising prodrug that increases brain creatine content in the mouse model of CTD. The level of nucleic acid methylation was significantly reduced compared to healthy controls in both in vivo and in vitro CTD models. This hypo-methylation tended to be regulated by DCE treatment in vivo. These results suggest that increased brain creatine after DCE treatment restores normal levels of DNA methylation, unveiling the potential of using DNA methylation as a marker to monitor the drug efficacy.
},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.3389/fimmu.2024.1354297,

title = {Oral administration of Manuka honey induces IFNγ-dependent resistance to tumor growth that correlates with beneficial modulation of gut microbiota composition},

author = {Razan J. Masad and Ienas Idriss and Yassir A. Mohamed and Ashraf Al-Sbiei and Ghada Bashir and Farah Al-Marzooq and Abeer Altahrawi and Maria J. Fernandez-Cabezudo and Basel K. Al-Ramadi},

url = {https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1354297},

doi = {10.3389/fimmu.2024.1354297},

issn = {1664-3224},

year  = {2024},

date = {2024-01-01},

journal = {Frontiers in Immunology},

volume = {15},

abstract = {
To investigate the potential of Manuka honey (MH) as an immunomodulatory agent in colorectal cancer (CRC) and dissect the underlying molecular and cellular mechanisms.
MH was administered orally over a 4 week-period. The effect of MH treatment on microbiota composition was studied using 16S rRNA sequencing of fecal pellets collected before and after treatment. Pretreated mice were implanted with CRC cells and followed for tumor growth. Tumors and lymphoid organs were analyzed by flow cytometry (FACS), immunohistochemistry and qRT-PCR. Efficacy of MH was also assessed in a therapeutic setting, with oral treatment initiated after tumor implantation. We utilized IFNγ-deficient mice to determine the importance of interferon signaling in MH-induced immunomodulation.
Pretreatment with MH enhanced anti-tumor responses leading to suppression of tumor growth. Evidence for enhanced tumor immunogenicity included upregulated MHC class-II on intratumoral macrophages, enhanced MHC class-I expression on tumor cells and increased infiltration of effector T cells into the tumor microenvironment. Importantly, oral MH was also effective in retarding tumor growth when given therapeutically. Transcriptomic analysis of tumor tissue highlighted changes in the expression of various chemokines and inflammatory cytokines that drive the observed changes in tumor immunogenicity. The immunomodulatory capacity of MH was abrogated in IFNγ-deficient mice. Finally, bacterial 16S rRNA sequencing demonstrated that oral MH treatment induced unique changes in gut microbiota that may well underlie the IFN-dependent enhancement in tumor immunogenicity.
Our findings highlight the immunostimulatory properties of MH and demonstrate its potential utilization in cancer prevention and treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.1093/braincomms/fcae139,

title = {Tracts in the limbic system show microstructural alterations post COVID-19 recovery},

author = {Sapna S Mishra and Caterina A Pedersini and Rohit Misra and Tapan K Gandhi and Bas Rokers and Bharat B Biswal},

url = {https://doi.org/10.1093/braincomms/fcae139},

doi = {10.1093/braincomms/fcae139},

issn = {2632-1297},

year  = {2024},

date = {2024-01-01},

journal = {Brain Communications},

volume = {6},

number = {3},

pages = {fcae139},

abstract = {Delirium, memory loss, attention deficit and fatigue are frequently reported by COVID survivors, yet the neurological pathways underlying these symptoms are not well understood. To study the possible mechanisms for these long-term sequelae after COVID-19 recovery, we investigated the microstructural properties of white matter in Indian cohorts of COVID-recovered patients and healthy controls. For the cross-sectional study presented here, we recruited 44 COVID-recovered patients and 29 healthy controls in New Delhi, India. Using deterministic whole-brain tractography on the acquired diffusion MRI scans, we traced 20 white matter tracts and compared fractional anisotropy, axial, mean and radial diffusivity between the cohorts. Our results revealed statistically significant differences (PFWE < 0.01) in the uncinate fasciculus, cingulum cingulate, cingulum hippocampus and arcuate fasciculus in COVID survivors, suggesting the presence of microstructural abnormalities. Additionally, in a subsequent subgroup analysis based on infection severity (healthy control, non-hospitalized patients and hospitalized patients), we observed a correlation between tract diffusion measures and COVID-19 infection severity. Although there were significant differences between healthy controls and infected groups, we found no significant differences between hospitalized and non-hospitalized COVID patients. Notably, the identified tracts are part of the limbic system and orbitofrontal cortex, indicating microstructural differences in neural circuits associated with memory and emotion. The observed white matter alterations in the limbic system resonate strongly with the functional deficits reported in Long COVID. Overall, our study provides additional evidence that damage to the limbic system could be a neuroimaging signature of Long COVID. The findings identify targets for follow-up studies investigating the long-term physiological and psychological impact of COVID-19.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.1371/journal.pone.0302818,

title = {Vitamin D regulates COVID-19 associated severity by suppressing the NLRP3 inflammasome pathway},

author = {Bariaa Khalil and Narjes Saheb Sharif-Askari and Shirin Hafezi and Fatemeh Saheb Sharif-Askari and Fatme Al Anouti and Qutayba Hamid and Rabih Halwani},

url = {https://doi.org/10.1371/journal.pone.0302818},

doi = {10.1371/journal.pone.0302818},

year  = {2024},

date = {2024-01-01},

journal = {PLOS ONE},

volume = {19},

number = {5},

pages = {1-19},

publisher = {Public Library of Science},

abstract = {Background The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus disease-2019 (COVID-19) pandemic, the role of VitD3 has been highlighted in many correlational and observational studies. However, the exact mechanisms of action are not well identified. One of the mechanisms via which VitD3 modulates innate immunity is by regulating the NLRP3-inflammasome pathway, being a main underlying cause of SARS-CoV-2-induced hyperinflammation. Aims and main methods Blood specimens of severe COVID-19 patients with or without VitD3 treatment were collected during their stay in the intensive care unit and patients were followed up for 29 days. qPCR, western blot, and ELISA were done to investigate the mechanism of action of VitD3 on the NLRP3 inflammasome activation. Key findings We here report the ability of VitD3 to downregulate the NLRP3-inflammsome pathway in severe COVID-19 patients. Lower inflammasome pathway activation was observed with significantly lower gene and protein expression of NLRP3, cleaved caspase-1, ASC and IL-1β among severe COVID-19 patients treated with VitD3. The reduction of the inflammasome pathway was associated with a reduction in disease severity markers and enhancement of type I IFN pathway. Significance Our data reveals an important anti-inflammatory effect of VitD3 during SARS-CoV-2 infection. Further investigations are warranted to better characterize the ability of VitD3 to control disease pathogenesis and prevent progression to severe states. This will allow for a more efficient use of a low cost and accessible treatment like VitD3.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PMID:37924129,

title = {Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families},

author = {Marwa Al Busaidi and Feda E Mohamed and Eiman Al-Ajmi and Nadia Al Hashmi and Khalid Al-Thihli and Amna Al Futaisi and Watfa Al Mamari and Fathiya Al-Murshedi and Fatma Al-Jasmi},

url = {https://europepmc.org/articles/PMC10625263},

doi = {10.1186/s13023-023-02946-5},

issn = {1750-1172},

year  = {2023},

date = {2023-11-01},

journal = {Orphanet journal of rare diseases},

volume = {18},

number = {1},

pages = {344},

abstract = {
Background
In metabolic stress, the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) enzyme is involved in energy production through the gluconeogenesis pathway. PEPCK-C deficiency is a rare childhood-onset autosomal recessive metabolic disease caused by PCK1 genetic defects. Previous studies showed a broad clinical spectrum ranging from asymptomatic to recurrent hypoglycemia with/without lactic acidosis, encephalopathy, seizures, and liver failure.
Results
In this article, we discuss the occurrence of PEPCK-C deficiency in four families from the United Arab Emirates and Oman. All patients presented with unexplained hypoglycemia as a common feature. Two out of the seven patients presented with episodes of encephalopathy that resulted in seizures and neuroregression leading to global developmental delay and one patient had a neonatal presentation. Observed biochemical abnormalities include elevated lactate, transaminases, and tricarboxylic acid cycle metabolites in most patients. Elevated creatine kinase was documented in two patients. Whole exome sequencing revealed two novel (c.574T > C, and c.1268 C > T) and a previously reported splice site (c.961 + 1G > A) PCK1 variant in the affected families.
Conclusion
Patients become vulnerable during intercurrent illness; thus, prevention and prompt reversal of a catabolic state are crucial to avoid irreversible brain damage. This report will help to expand the clinical understanding of this rare disease and recommends screening for PEPCK-C deficiency in unexplained hypoglycemia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{PMID:37963898,

title = {Node embedding-based graph autoencoder outlier detection for adverse pregnancy outcomes},

author = {Wasif Khan and Nazar Zaki and Amir Ahmad and Mohammad M Masud and Romana Govender and Natalia Rojas-Perilla and Luqman Ali and Nadirah Ghenimi and Luai A Ahmed},

url = {https://europepmc.org/articles/PMC10645849},

doi = {10.1038/s41598-023-46726-4},

issn = {2045-2322},

year  = {2023},

date = {2023-11-01},

journal = {Scientific reports},

volume = {13},

number = {1},

pages = {19817},

abstract = {Adverse pregnancy outcomes, such as low birth weight (LBW) and preterm birth (PTB), can have serious consequences for both the mother and infant. Early prediction of such outcomes is important for their prevention. Previous studies using traditional machine learning (ML) models for predicting PTB and LBW have encountered two important limitations: extreme class imbalance in medical datasets and the inability to account for complex relational structures between entities. To address these limitations, we propose a node embedding-based graph outlier detection algorithm to predict adverse pregnancy outcomes. We developed a knowledge graph using a well-curated representative dataset of the Emirati population and two node embedding algorithms. The graph autoencoder (GAE) was trained by applying a combination of original risk factors and node embedding features. Samples that were difficult to reconstruct at the output of GAE were identified as outliers considered representing PTB and LBW samples. Our experiments using LBW, PTB, and very PTB datasets demonstrated that incorporating node embedding considerably improved performance, achieving a 12% higher AUC-ROC compared to traditional GAE. Our study demonstrates the effectiveness of node embedding and graph outlier detection in improving the prediction performance of adverse pregnancy outcomes in well-curated population datasets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.7554/eLife.88459,

title = {Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency},

author = {Léa Broca-Brisson and Rania Harati and Clémence Disdier and Orsolya Mozner and Romane Gaston-Breton and Auriane Maïza and Narciso Costa and Anne-Cécile Guyot and Balazs Sarkadi and Agota Apati and Matthew R Skelton and Lucie Madrange and Frank Yates and Jean Armengaud and Rifat Hamoudi and Aloïse Mabondzo},

editor = {Yunlei Yang and Mone Zaidi},

url = {https://doi.org/10.7554/eLife.88459},

doi = {10.7554/eLife.88459},

issn = {2050-084X},

year  = {2023},

date = {2023-10-01},

journal = {eLife},

volume = {12},

pages = {RP88459},

publisher = {eLife Sciences Publications, Ltd},

abstract = {Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cimb45040227b,

title = {Molecular Heterogeneity of the Brain Endothelium},

author = {Nada Alnaqbi and Mohammad G. Mohammad and Rifat Hamoudi and Aloïse Mabondzo and Rania Harati},

url = {https://www.mdpi.com/1467-3045/45/4/227},

doi = {10.3390/cimb45040227},

issn = {1467-3045},

year  = {2023},

date = {2023-01-01},

journal = {Current Issues in Molecular Biology},

volume = {45},

number = {4},

pages = {3462–3478},

abstract = {The blood–brain barrier (BBB) is part of a neurovascular structure located in the brain’s micro vessels, that is essential to maintain brain homeostasis, but prevents the brain uptake of most drugs. Because of its importance in neuro-pharmacotherapy, the BBB has been the subject of extensive research since its discovery over 100 years ago. Major advances in understanding the structure and function of the barrier have been made. Drugs are re-designed to cross the BBB. However, despite these efforts, overcoming the BBB efficiently to treat brain diseases safely remains challenging. The majority of BBB research studies focus on the BBB as a homogenous structure throughout the different brain regions. However, this simplification may lead to an inadequate understanding of the BBB function with significant therapeutic consequences. From this perspective, we analyzed the gene and protein expression profiles of the BBB in the micro vessels from the brains of mice that were isolated from two different brain regions, namely the cortex and the hippocampus. The expression profile of the inter-endothelial junctional protein (claudin-5), three ABC transporters (P-glycoprotein, Bcrp and Mrp-1), and three BBB receptors (lrp-1, TRF and GLUT-1) were analyzed. Our gene and protein analysis showed that the brain endothelium in the hippocampus exhibits different expression profiles compared to the brain cortex. Specifically, brain endothelial cells (BECs) of the hippocampus express higher gene levels of abcb1, abcg2, lrp1, and slc2a1 compared to the BECs of the cortex regions with a trend of increase for claudin-5, while BECs of the cortex express higher gene levels of abcc1 and trf compared to the hippocampus. At the protein levels, the P-gp expression was found to be significantly higher in the hippocampus compared to the cortex, while TRF was found to be up-regulated in the cortex. These data suggest that the structure and function of the BBB are not homogeneous, and imply that drugs are not delivered similarly among the different brain regions. Appreciation of the BBB heterogeneity by future research programs is thus critical for efficient drug delivery and the treatment of brain diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ELMOSELHI2023e22067,

title = {Unveiling the molecular Culprit of arterial stiffness in vitamin D deficiency and obesity: Potential for novel therapeutic targets},

author = {Adel B. Elmoselhi and Amal Bouzid and Mohamed Seif Allah and Zeinab Ibrahim and Khuloud Bajbouj and Rebal S. Abou Assaleh and Thenmozhi Venkatachalam and Mohamed Madkour and Ruqaiyyah Siddiqui and Naveed Ahmed Khan and Rifat A. Hamoudi},

url = {https://www.sciencedirect.com/science/article/pii/S2405844023092757},

doi = {https://doi.org/10.1016/j.heliyon.2023.e22067},

issn = {2405-8440},

year  = {2023},

date = {2023-01-01},

journal = {Heliyon},

volume = {9},

number = {11},

pages = {e22067},

abstract = {Cardiovascular diseases (CVDs) are highly associated with both vitamin D deficiency and obesity, two prevalent health conditions worldwide. Arterial stiffness, an independent predictor of CVDs, is particularly elevated in both conditions, yet the molecular mechanisms underlying this phenomenon remain elusive, hindering effective management of CVDs in this population. We recruited 20 middle-aged Emiratis, including 9 individuals with vitamin D deficiency (Vit D level ≤20 ng) and obesity (BMI ≥30) and 11 individuals as control with Vit D level >20 ng and BMI <30. We measured arterial stiffness using pulse wave velocity (PWV) and performed whole transcriptome sequencing to identify differentially expressed genes (DEGs) and enriched pathways. We validated these findings using qRT-PCR, Western blot, and multiplex analysis. PWV was significantly higher in the vitamin D deficient and obese group relative to controls (p ≤ 0.05). The DEG analysis revealed that pathways related to interleukin 1 (IL-1), nitrogen metabolism, HIF-1 signaling, and MAPK signaling were over-activated in the vitamin D deficient and obese group. We found that HIF-1alpha, NOX-I, NOX-II, IL-1b, IL-8, IL-10, and VEGF were significantly upregulated in the vitamin D deficient and obese group (p < 0.05). Our study provides new insights into the molecular mechanisms of arterial stiffness in vitamin D deficiency and obesity, demonstrating the role of oxidative stress and inflammation in this process. Our findings suggest that these biomarkers may serve as potential therapeutic targets for early prevention of CVDs. Further studies are needed to investigate these pathways and biomarkers with larger cohort.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.3389/fcell.2023.1294748,

title = {Unveiling the pathogenic mechanisms of NPR2 missense variants: insights into the genotype-associated severity in acromesomelic dysplasia and short stature},

author = {Sally Badawi and Divya Saro Varghese and Anjana Raj and Anne John and Hamda S. Al-Musafir and Ahmed J. Al-Ghamari and Alreem R. Alshamsi and Sara H. Ouda and Ghayth Al-Dirbashi and Bassam R. Ali},

url = {https://www.frontiersin.org/articles/10.3389/fcell.2023.1294748},

doi = {10.3389/fcell.2023.1294748},

issn = {2296-634X},

year  = {2023},

date = {2023-01-01},

journal = {Frontiers in Cell and Developmental Biology},

volume = {11},

abstract = {Introduction: Natriuretic peptide receptor 2 (NPR2 or NPR-B) plays a central role in growth development and bone morphogenesis and therefore loss-of-function variations in NPR2 gene have been reported to cause Acromesomelic Dysplasia, Maroteaux type 1 and short stature. While several hypotheses have been proposed to underlie the pathogenic mechanisms responsible for these conditions, the exact mechanisms, and functional characteristics of many of those variants and their correlations with the clinical manifestations have not been fully established.Methods: In this study, we examined eight NPR2 genetic missense variants (p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg318Gly, p.Arg388Gln, p.Arg495Cys, p.Arg557His, and p.Arg932Cys) Acromesomelic Dysplasia, Maroteaux type 1 and short stature located on diverse domains and broadly classified as variants of uncertain significance. The evaluated variants are either reported in patients with acromesomelic dysplasia in the homozygous state or short stature in the heterozygous state. Our investigation included the evaluation of their expression, subcellular trafficking and localization, N-glycosylation profiles, and cyclic guanosine monophosphate (cGMP) production activity.Results and Discussion: Our results indicate that variants p.Leu51Pro, p.Gly123Val, p.Leu314Arg, p.Arg388Gln have defective cellular trafficking, being sequestered within the endoplasmic reticulum (ER), and consequently impaired cGMP production ability. Conversely, variants p.Arg318Gly, p.Arg495Cys, and p.Arg557His seem to display a non-statistically significant behavior that is slightly comparable to WT-NPR2. On the other hand, p.Arg932Cys which is located within the guanylyl cyclase active site displayed normal cellular trafficking profile albeit with defective cGMP. Collectively, our data highlights the genotype-phenotype relationship that might be responsible for the milder symptoms observed in short stature compared to acromesomelic dysplasia. This study enhances our understanding of the functional consequences of several NPR2 variants, shedding light on their mechanisms and roles in related genetic disorders which might also help in their pathogenicity re-classification.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nu15235010,

title = {Exploring the Anticancer Potential of Origanum majorana Essential Oil Monoterpenes Alone and in Combination against Non-Small Cell Lung Cancer},

author = {Kholoud Arafat and Aya Mudhafar Al-Azawi and Shahrazad Sulaiman and Samir Attoub},

url = {https://www.mdpi.com/2072-6643/15/23/5010},

doi = {10.3390/nu15235010},

issn = {2072-6643},

year  = {2023},

date = {2023-01-01},

journal = {Nutrients},

volume = {15},

number = {23},

abstract = {Lung cancer is the second most commonly diagnosed cancer and has the highest mortality rate worldwide despite the remarkable advances in its treatment. Origanum majorana Essential Oil (OMEO) has been shown to be effective against non-small cell lung cancer (NSCLC) cells, decreasing their viability and colony growth in vitro, as well as inhibiting tumor growth in chick embryo chorioallantoic membranes (CAM) and nude mice in vivo. OMEO is mainly composed of four monoterpenes, namely terpinen-4-ol, sabinene hydrate, α-terpinene, and γ-terpinene. In this study, we aimed to investigate the potential anticancer effects of these monoterpenes, either alone or in combination, on NSCLC. Our findings indicate that these four monoterpenes significantly decreased NSCLC cell viability in a concentration-dependent manner, reduced their colony growth in vitro, and also downregulated survivin expression in these cells. Moreover, different combined mixtures of these monoterpenes further enhanced their anticancer effects on cellular viability, with a terpinen-4-ol and sabinene hydrate combination being the most potent. We also found that terpinen-4-ol, in combination with sabinene hydrate, markedly enhanced the anticancer effect of the individual monoterpenes on NSCLC viability within a shorter treatment duration through, at least in part, survivin downregulation. Furthermore, this combination enhanced the inhibition of colony growth in vitro and the tumor growth of NSCLC cells xenografted onto chick embryo CAM in vivo. Altogether, our study highlights the potential of these monoterpenes for use in further pre-clinical investigations against various cancer hallmarks.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{masad2023oral,

title = {Oral administration of Manuka honey modulates gut microbiota composition and enhances anti-tumor immunity in a preclinical model of colorectal cancer},

author = {Ashraf Al-Sbiei Ghada Bashir Razan J. Masad},

url = {https://www.researchsquare.com/article/rs-3273451/v2.pdf?c=1692853595000},

doi = {10.21203/rs.3.rs-3273451/v2},

year  = {2023},

date = {2023-01-01},

abstract = {Conclusions: Our findings demonstrate that oral administration of MH induces specific alterations in the gut microbiota and triggers innate and adaptive mucosal immune responses through the activation of type I/II IFN signaling pathways. This culminates in rendering the tumors more immunogenically responsive. Our data highlight the immunostimulatory properties of MH and demonstrate its potential utilization in cancer prevention. 

Background: There is increasing interest in exploring alternative natural products for cancer prevention and treatment. Among these, we recently highlighted the potential utilization of Manuka honey (MH) as an immunomodulatory agent. In the present study, we characterized mechanistically the immunomodulatory properties of MH in a preclinical model of colorectal cancer (CRC). 

Methods: MH was administered orally over a 4 week-period. A solution containing equivalent concentrations of the main sugars in MH was used as a control (SC). Mucosal and systemic lymphoid tissues were examined for alterations in cellular composition and activation status by multi-color flow cytometry (FACS). Fecal pellets were collected before and after treatment and used for bacterial 16S rRNA sequencing. Pretreated mice were implanted with CRC cells and followed for tumor growth. Tumors, lymph nodes, and spleens were analyzed by FACS, immunohistochemistry, and qRT-PCR 3-weeks post-implantation. 

Results: Pretreatment with MH, but not SC solution, induced type I/II IFN response in mucosal and systemic lymphoid tissues, resulting in enhanced expression of IFN-inducible stem cell antigen-1 (Sca-1) and MHC class II proteins. In an implantable model of CRC, tumor growth was significantly retarded in MH-pretreated mice. These tumors had increased infiltration of immune cells, ~2.0-fold increase in the percentage of intratumoral CD4+ and CD8+ T cells, and a 50% decrease in the percentage of Ly6G+ myeloid cells. Immunohistochemical analysis of tumor tissues revealed an increase in CD4+ and CD8+ T cells and granzyme-B-expressing cells following MH treatment. Moreover, FACS analysis showed significantly elevated expression of MHC class I on tumors of MH-treated mice. qRT-PCR analysis of purified tumor-infiltrating leucocytes highlighted changes in the expression of various chemokines and inflammatory cytokines that underlie the increased tumor immunogenicity. Finally, bacterial 16S rRNA sequencing revealed unique enrichment of >20 bacterial genera in MH-treated mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}