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The preservation of pancreatic islet ß-cells is crucial in diabetes mellitus, encompassing both type 1 and type 2 diabetes. ß-cell dysfunction, reduced mass, and apoptosis are central to insufficient insulin secretion in both types. Research is focused on understanding ß-cell characteristics and the factors regulating their function to develop novel therapeutic approaches. In type 1 diabetes (T1D), ß-cell destruction by the immune system calls for exploring immunosuppressive therapies, non-steroidal anti-inflammatory drugs, and leukotriene antagonists. Islet transplantation, stem cell therapy, and xenogeneic transplantation offer promising strategies for type 1 diabetes treatment. For type 2 diabetes (T2D), lifestyle changes like weight loss and exercise enhance insulin sensitivity and maintain ß-cell function. Additionally, various pharmacological approaches, such as cytokine inhibitors and protein kinase inhibitors, are being investigated to protect ß-cells from inflammation and glucotoxicity. Bariatric surgery emerges as an effective treatment for obesity and T2D by promoting ß-cell survival and function. It improves insulin sensitivity, modulates gut hormones, and expands ß-cell mass, leading to diabetes remission and better glycemic control. In conclusion, preserving ß-cells offers a promising approach to managing both types of diabetes. By combining lifestyle modifications, targeted pharmacological interventions, and advanced therapies like stem cell transplantation and bariatric surgery, we have a significant chance to preserve ß-cell function and enhance glucose regulation in diabetic patients.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Células Secretoras de Insulina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , Glucosa/metabolismo , Insulina/metabolismoRESUMEN
Dear Readers,Currently, there is a myriad of new developments in the field of endocrinology. In particular, significant strides have been made in the development of poly-agonists for the treatment of type 2 diabetes and obesity 1 2. Poly-agonists represent a novel therapeutic approach by combining multiple actions within a single molecule, targeting multiple receptors simultaneously to achieve enhanced efficacy. These innovative compounds aim to address the complex interplay of hormonal pathways involved in glucose regulation and metabolism, offering potential breakthroughs in the management of diabetes and obesity.
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Diabetes Mellitus Tipo 2 , Endocrinología , Enfermedades Metabólicas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Enfermedades Metabólicas/terapia , Glucosa/metabolismo , Obesidad/tratamiento farmacológicoRESUMEN
Breast cancer poses a significant health risk worldwide. However, the effectiveness of current chemotherapy is limited due to increasing drug resistance and side effects, making it crucial to develop new compounds with novel mechanism of action that can surpass these limitations. As a consequence of their reversible and targeted mechanism, DNA minor groove binders (MGBs) are considered as a relatively safer and more effective alternative. In this study, transcriptomic analysis was conducted to reveal the dysregulated genes and signaling pathways in MCF7 cancer cells following treatment with novel MGB ligands to gain insights into the mechanism of action of MGBs at the molecular level. The transcriptomic results were validated using real-time PCR. The findings of this study indicate that the investigated MGBs primarily inhibit the genes associated with the estrogen receptor. Remarkably, ligand 5 showed downregulation of 34 out of the 35 genes regulated by estrogen receptor, highlighting its potential as a promising candidate for breast cancer therapy.
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Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual kinase that can phosphorylate its own activation loop on tyrosine residue and phosphorylate its substrates on threonine and serine residues. It is the most studied member of DYRK kinases, because its gene maps to human chromosome 21 within the Down syndrome critical region (DSCR). DYRK1A overexpression was found to be responsible for the phenotypic features observed in Down syndrome such as mental retardation, early onset neurodegenerative, and developmental heart defects. Besides its dual activity in phosphorylation, DYRK1A carries the characteristic of duality in tumorigenesis. Many studies indicate its possible role as a tumor suppressor gene; however, others prove its pro-oncogenic activity. In this review, we will focus on its multifaceted role in tumorigenesis by explaining its participation in some cancer hallmarks pathways such as proliferative signaling, transcription, stress, DNA damage repair, apoptosis, and angiogenesis, and finally, we will discuss targeting DYRK1A as a potential strategy for management of cancer and neurodegenerative disorders.
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Carcinogénesis/metabolismo , Síndrome de Down/metabolismo , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Apoptosis , Carcinogénesis/genética , Daño del ADN , Reparación del ADN , Síndrome de Down/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Transducción de Señal , Regulación hacia Arriba , Quinasas DyrKRESUMEN
The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight the most common cytochrome P450 isoenzymes associated with the metabolism of psychotropic medications (antidepressants, antipsychotics, and mood stabilizers), their variations among different populations, their impact on endogenous neurotransmitters (dopamine and serotonin), and the effect of nongenetic factors, particularly smoking, age, and pregnancy, on their metabolic activity. Furthermore, the adverse effects of psychiatric medications may be associated with certain human leukocytic antigen (HLA) genotypes. We also highlight the gene variants that may potentially increase susceptibility to obesity and metabolic syndrome, as the adverse effects of some psychiatry medications. Collectively, the literature revealed that variation of CYP450 activity is mostly investigated in relation to genetic polymorphism, and is directly correlated with individualized clinical outcomes; whereas adverse effects are associated with HLA variants, projecting the value of pharmacogenetics implementation in psychiatry clinics. Only a few previous studies have discussed the impact of such genetic variations on the metabolism of endogenous neuropeptides. In this review, we also report on the prevalence of key variants in different ethnicities, by demonstrating publicly available data from the 1000 Genomes Project and others. Finally, we highlight the future direction of further investigations to enhance the predictability of the individual gene variants to achieve precision therapies for psychiatric patients.
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Farmacogenética , Psiquiatría , Humanos , Citocromo P-450 CYP2D6/genética , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Psicotrópicos/efectos adversos , Psicotrópicos/metabolismoRESUMEN
Background: Breast cancer currently affects more than two million women worldwide, and its incidence is steadily increasing. One of the most essential factors of invasion and metastasis of breast cancer cells is angiogenesis and non-angiogenic vascularization. Lenvatinib and Regorafenib share the same anti-angiogenic effect by inhibiting vascular endothelial growth factor receptors (VEGFRs subtypes 1 to 3) and have been approved for treating different types of cancer. Methods: We investigated Lenvatinib and Regorafenib effects on a well-established in-vitro model of breast cancer using MCF-7 (estrogen, progesterone receptor-positive, and HER2-negative), MDA-MB-231 (triple negative), as well as Human Umbilical Vascular Endothelial Cell line (HUVEC) cell lines. We performed the cell viability assay on four groups of cells, which included a control group, a Lenvatinib treated only group, a Regorafenib treated only group, and a group treated with a combination of both drugs at 24, 48, and 72 h. Data were analyzed as means ± standard deviation, and the drug−drug interactions with Compusyn software. Cellular migration assay, tube formation assay, and Western blots were conducted to determine the functional and the protein expression of downstream signals such as Caspase-9, anti-apoptotic Survivin, P-ERK, and total-ERK in the control and treatment groups. Results: MCF-7 cells showed a reduction in cell survival rates with higher dosing and longer incubation periods with each drug and with the combination of drugs. A synergistic interaction was identified (CI < 1) with both drugs on MCF7 at different dose combinations and at a higher dose in MDA-MB-231 cells. Furthermore, there was a marked decrease in the anti-angiogenic effect of both drugs in tube formation assay using MDA-MB-231 cells and survivin protein expression in MCF-7, and those antitumor markers showed a better outcome in drug combination than the use of each drug alone. Conclusion: Our result is the first to report the synergistic anti-angiogenic potential of combination therapy of Lenvatinib and Regorafenib. Therefore, it shows their therapeutic potential in breast cancer, including the aggressive types. Further studies are warranted to confirm and explore this therapeutic approach.
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Neoplasias de la Mama , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Neovascularización Patológica/tratamiento farmacológico , Compuestos de Fenilurea , Piridinas , Quinolinas , Survivin , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: High-quality patient care is a complex phenomenon that requires collaboration among healthcare professionals. Research has shown that Interprofessional Education (IPE) carries promise to improve collaborative work and patient care. So far, collaboration among various health professionals remains a challenge. Very few focus group discussions to determine the medical students' readiness and positive attitudes towards IPE have been reported from the Arabian context. METHODS: A two-staged sequential mixed methods study was conducted among medical, dental, pharmacy, and health sciences students of the University of Sharjah United Arab Emirates. The perspectives of students toward IPE and collaborative practice were first gathered by administering a validated instrument, Readiness for Interprofessional Learning Scale (RIPLS). This was followed by focused group discussions. A quantitative as well as a qualitative data analysis was performed. RESULTS: This study cohort included 282 students. All respondents showed readiness to adopt IPE as all statements of the RIPLS inventory scored high median scores. All participants showed positive attitudes and readiness towards IPE. Three main domains of themes were generated from focus group discussions; prior knowledge, need for IPE framework and its implementation. Information workload, lack of clarity and less focused teaching pedagogies of IPE were considered as perceived barriers. CONCLUSION: This study demonstrated a substantial agreement of medical and health sciences students towards readiness and perceived effectiveness of IPE. Educators are urged to embed new IPE programs into existing curricular frameworks, which can potentially enhance collaborative learning and improve quality of patient care.
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Prácticas Interdisciplinarias , Estudiantes de Medicina , Actitud del Personal de Salud , Humanos , Educación Interprofesional , Relaciones Interprofesionales , Emiratos Árabes UnidosRESUMEN
The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.
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Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Animales , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/inmunología , Complicaciones de la Diabetes/genética , Humanos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/inmunología , Microambiente TumoralRESUMEN
Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Epigénesis Genética , Código de Histonas , Histonas/metabolismo , Terapia Molecular Dirigida , Animales , Carcinoma de Pulmón de Células no Pequeñas/terapia , HumanosRESUMEN
As a therapeutic approach, epigenetic modifiers have the potential to enhance the efficacy of chemotherapeutic agents. Protein arginine methyltransferase 5 (PRMT5), highly expressed in lung adenocarcinoma, was identified to be involved in tumorigenesis. In the current study, we examined the potential antineoplastic activity of PRMT5 inhibitor, arginine methyltransferase inhibitor 1 (AMI-1), and cisplatin on lung adenocarcinoma. Bioinformatic analyses identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5-associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival in lung adenocarcinoma. Combined AMI-1 and cisplatin treatment significantly reduced cell viability and induced apoptosis. Cell cycle arrest in A549 and DMS 53 cells was evident after AMI-1, and was reinforced after combination treatment. Western blot analysis showed a reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While the combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on HBEpC (normal epithelial cells). The survival of normal bronchial epithelial cells was not affected by using AMI-1. This study highlights evidence of novel selective antitumor activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Naftalenosulfonatos/farmacología , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Urea/análogos & derivados , Apoptosis , Ciclo Celular , Proliferación Celular , Inhibidores Enzimáticos/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Células Tumorales Cultivadas , Urea/farmacologíaRESUMEN
This study aimed to analyze the expression of microRNAs in relation to p53 status in breast cancer cells and to delineate the role of Moesin in this axis. We used three isogenic breast carcinoma cell lines MCF7 (with wild-type p53), 1001 (MCF7 with mutated p53), and MCF7-E6 (MCF7 in which p53 function was disrupted). MicroRNA expression was analyzed using microarray analysis and confirmed by real-time polymerase chain reaction. The 1001 clone with mutant p53 showed 22 upregulated and 25 downregulated microRNAs. The predicted targets of these 47 microRNAs were >700 human genes belonging to interesting functional groups such as stem cell development and maintenance. The most significantly downregulated microRNAs in the p53-mutant cell line were from the miR-200 family. We focused on miR-200c which targets many transcripts involved in epithelial-to-mesenchymal transition including Moesin. We found that Moesin was expressed in 1001 but not in its p53 wild-type parental MCF7 consistent with the observed mesenchymal features in the 1001, such as vimentin positivity, E-cadherin negativity, and ZEB1 positivity in addition to the morphological changes. After Moesin silencing, the p53-mutant cells 1001 reverted from mesenchymal-to-epithelial phenotype and showed subtle reduction in migration and invasion and loss of ZEB1 and SNAIL expression. Interestingly, Moesin silencing restored the 1001 sensitivity to Doxorubicin. These results indicate that loss of miR-200c, as a consequence of p53 mutation, can upregulate Moesin oncogene and thus promote carcinogenesis. Moesin may play a role in metastasis and drug resistance of breast cancer.
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Neoplasias de la Mama/patología , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Proteínas de Microfilamentos/genética , Proteína p53 Supresora de Tumor/genética , Western Blotting , Transición Epitelial-Mesenquimal/genética , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Proteínas de Microfilamentos/biosíntesis , Microscopía Confocal , Invasividad Neoplásica/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The CYP2C19 gene is frequently included in different pharmacogenomic panels tested in clinical practice, due to its involvement in the metabolism of a myriad of frequently prescribed medications. Accordingly, CYP2C19 genotyping can promote precise therapeutic decisions and avoid the occurrence of significant drug-drug-gene interactions in the clinical setting. A comprehensive examination of the role of the CYP2C19 gene in real-world medical settings is presented in this review. This review summarizes the most recent information on how genetic variants in CYP2C19 affect drug metabolism and therapeutic outcomes. It goes into the wide range of CYP2C19 phenotypes, with different degrees of metabolizing activity, and their implications for customized medication response through a review of the literature. The review also analyzes the clinical significance of CYP2C19 in several medical specialties, including cardiology, psychiatry, and gastro-enterology clinics, and illuminates how it affects pharmacological efficacy, safety, and adverse effects. Finally, CYP2C19-supported clinical decision-making is outlined, highlighting the possibility of improving therapeutic outcomes and achieving more affordable treatment options, a step towards optimizing healthcare provision through precision medicine.
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AIMS: In this study, we investigated the role of the FTO gene in pancreatic ß-cell biology and its association with type 2 diabetes (T2D). To address this issue, human pancreatic islets and rat INS-1 (832/13) cells were used to perform gene silencing, overexpression, and functional analysis of FTO expression; levels of FTO were also measured in serum samples obtained from diabetic and obese individuals. RESULTS: The findings revealed that FTO expression was reduced in islets from hyperglycemic/diabetic donors compared to normal donors. This reduction correlated with decreased INS and GLUT1 expression and increased PDX1, GCK, and SNAP25 expression. Silencing of Fto in INS-1 cells impaired insulin release and mitochondrial ATP production and increased apoptosis in pro-apoptotic cytokine-treated cells. However, glucose uptake and reactive oxygen species production rates remained unaffected. Downregulation of key ß-cell genes was observed following Fto-silencing, while Glut2 and Gck were unaffected. RNA-seq analysis identified several dysregulated genes involved in metal ion binding, calcium ion binding, and protein serine/threonine kinase activity. Furthermore, our findings showed that Pdx1 or Mafa-silencing did not influence FTO protein expression. Overexpression of FTO in human islets promoted insulin secretion and upregulated INS, PDX1, MAFA, and GLUT1 expression. Serum FTO levels did not significantly differ between individuals with diabetes or obesity and their healthy counterparts. CONCLUSION: These findings suggest that FTO plays a crucial role in ß-cell survival, metabolism, and function and point to a potential therapeutic utility of FTO in T2D patients.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Humanos , Ratas , Animales , Secreción de Insulina/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Islotes Pancreáticos/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidad/genética , Obesidad/metabolismo , Glucosa/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismoRESUMEN
Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key ß-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in ß-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.
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Diabetes Mellitus Tipo 2 , Secreción de Insulina , Interleucina-6 , Islotes Pancreáticos , Humanos , Interleucina-6/metabolismo , Interleucina-6/sangre , Secreción de Insulina/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/sangre , Masculino , Persona de Mediana Edad , Femenino , Adulto , Glucosa/metabolismo , Insulina/metabolismo , Insulina/sangre , Ratas , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Animales , Línea Celular , Anciano , Apoptosis/efectos de los fármacosRESUMEN
Metastatic cancer remains incurable as patients eventually loose sensitivity to targeted therapies and chemotherapies, further leading to poor clinical outcome. Thus, there is a clear medical gap and urgent need to develop efficient and improved targeted therapies for cancer patients. In this study, we investigated the role of DYRK1A kinase in regulating cancer progression and evaluated the therapeutic potential of DYRK1A inhibition in invasive solid tumors, including colon and triple-negative breast cancers. We uncovered new roles played by the DYRK1A kinase. We found that blocking DYRK1A gene expression or pharmacological inhibition of its kinase activity via harmine efficiently blocked primary tumor formation and the metastatic tumor spread in preclinical models of breast and colon cancers. Further assessing the underlying molecular mechanisms, we found that DYRK1A inhibition resulted in increased expression of the G1/S cell cycle regulators while decreasing expression of the G2/M regulators. Combined, these effects release cancer cells from quiescence, leading to their accumulation in G1/S and further delaying/preventing their progression toward G2/M, ultimately leading to growth arrest and tumor growth inhibition. Furthermore, we show that accumulation of cancer cells in G1/S upon DYRK1A inhibition led to significant potentiation of G1/S targeting chemotherapy drug responses in vitro and in vivo. This study underscores the potential for developing novel DYRK1A-targeting therapies in colon and breast cancers and, at the same time, further defines DYRK1A pharmacological inhibition as a viable and powerful combinatorial treatment approach for improving G1/S targeting chemotherapy drugs treatments in solid tumors.
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Pharmacogenomics (PGx) is a rapidly changing field of genomics in which healthcare professionals play an important role in its implementation in the clinical setting, however PGx level of adoption remains low. This study aims to investigate the attitude, self-confidence, level of knowledge, and their impact on health sciences undergraduate students' intentions to adopt PGx in clinical practice using a questionnaire developed based on the Theory of Planned Behavior (TPB). A model was proposed and a questionnaire was developed that was distributed to 467 undergraduate students of all academic years from four different departments of the University of Sharjah (UoS) including medical, dental, nursing, and pharmacy students from September 2022 to November 2022. Descriptive statistics along with factor analysis and regression analysis were conducted. The proposed model had a good internal consistency and fit. Attitude was the factor with the greatest impact on student's intentions followed by self-confidence and barriers. The level of knowledge had a meaningless impact. The majority of students shared a positive attitude and were aware of PGx benefits. Almost 60% of the respondents showed a high level of knowledge, while 50% of them were confident of implementing PGx in their clinical practice. Many students were prone to adopt PGx in their future careers. PGx testing cost and the lack of reimbursement were the most important barriers. Overall, students shared a positive intention and were prone to adopt PGx. In the future, it would be important to investigate the differences between gender, year of studies, and area of studies studies and their impact on students' intentions.
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The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.
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Introduction: The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. Methods: We compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. Results: Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1ß, IL-2, IL-15, and IL-17A in COVID-19 patients. Conclusion: Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.
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Enzima Convertidora de Angiotensina 2 , COVID-19 , Citocinas , Polimorfismo de Nucleótido Simple , SARS-CoV-2 , Serina Endopeptidasas , Humanos , COVID-19/genética , Enzima Convertidora de Angiotensina 2/genética , Femenino , Masculino , SARS-CoV-2/fisiología , Citocinas/sangre , Citocinas/genética , Serina Endopeptidasas/genética , Emiratos Árabes Unidos/epidemiología , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , AncianoRESUMEN
Liver injury occurs frequently as a consequence of SARS-CoV-2 infection. Direct infection of the liver leads to hepatic impairment with elevated transaminases. In addition, severe COVID-19 is characterized by cytokine release syndrome, which may initiate or exacerbate liver injury. In patients with cirrhosis, SARS-CoV-2 infection is associated with acute-on-chronic liver failure. The Middle East and North Africa (MENA) region is one of the world's regions characterized by a high prevalence of chronic liver diseases. Both parenchymal and vascular types of injury contribute to liver failure in COVID-19, with a myriad of pro-inflammatory cytokines playing a major role in perpetuating liver injury. Additionally, hypoxia and coagulopathy complicate such a condition. This review discusses the risk factors, and the underlying causes of impaired liver functions in COVID-19, with a focus on key players in the pathogenesis of liver injury. It also highlights the histopathological changes encountered in postmortem liver tissues as well as potential predictors and prognostic factors of such injury, in addition to the management strategies to ameliorate liver damage.
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Diabetes mellitus (DM) represents a major health problem in Egypt and worldwide, with increasing numbers of patients with prediabetes every year. Numerous factors, such as obesity, hyperlipidemia, and hypertension, which have recently become serious concerns, affect the complex pathophysiology of diabetes. These metabolic syndrome diseases are highly linked to genetic variability that drives certain populations, such as Egypt, to be more susceptible to developing DM. Here we conduct a comprehensive analysis to pinpoint the similarities and uniqueness among the Egyptian genome reference and the 1000-genome subpopulations (Europeans, Ad-Mixed Americans, South Asians, East Asians, and Africans), aiming at defining the potential genetic risk of metabolic syndromes. Selected approaches incorporated the analysis of the allele frequency of the different populations' variations, supported by genotypes' principal component analysis. Results show that the Egyptian's reference metabolic genes were clustered together with the Europeans', Ad-Mixed Americans', and South-Asians'. Additionally, 8563 variants were uniquely identified in the Egyptian cohort, from those, two were predicted to cause structural damage, namely, CDKAL1: 6_21065070 (A > T) and PPARG: 3_12351660 (C > T) utilizing the Missense3D database. The former is a protein coding gene associated with Type 2 DM while the latter is a key regulator of adipocyte differentiation and glucose homeostasis. Both variants were detected heterozygous in two different Egyptian individuals from overall 110 sample. This analysis sheds light on the unique genetic traits of the Egyptian population that play a role in the DM high prevalence in Egypt. The proposed analysis pipeline -available through GitHub- could be used to conduct similar analysis for other diseases across populations.