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1.
Front Nutr ; 11: 1445484, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39391681

RESUMO

Dietary lipids play a major role in many diseases, particularly cardiovascular diseases. Recently, the health value of plant oils, particularly heart health, has been recognized. Despite these facts, limited information is available on the potential nutritional and anti-arteriolosclerosis effects of chufa oil, olive oil, and anhydrous milk fat in C57BL/6N mice. In the present study, the effects of olive oil (OO), chufa oil (CO), and anhydrous milk fat (AMF) on 4-week-old C57BL/6N male mice, a model for studies of diet-induced atherosclerosis, were investigated. The AIN-93G-based diet was supplemented with 15% of either OO, CO, or AMF. The final mixture of the diets contained 15% fat, approximately 1.25% cholesterol, and 0.5% sodium cholate. The data obtained showed that most mice had gallstone disease. The highest percentage of the gallstones formed were found in AMF groups (approximately 85.7% of the mice). However, the lowest one was found in the chufa oil group (42.9%), followed by the olive oil group (57.1%). Although the mice's food intake significantly differed, their body weights did not change during the feeding period. The diet supplemented with CO resulted in a significant reduction in serum cholesterol compared with the other groups. Livers from the CO-fed group showed higher triglyceride levels than those from the AMF group. No significant differences were found in atherosclerotic lesions in the aortic valve between the groups. Collectively, our results show no deleterious nutritional effects of the fats used on C57BL/6N mice fed cholesterol-rich diets. Chufa oil improved cholesterol metabolism and atherogenic index in mice. However, the major issue is the formation of gallstones in all mice, which is most prominent in AMF, followed by olive oil and chufa oil diets.

2.
J Infect Chemother ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39293717

RESUMO

BACKGROUND: Acute gastroenteritis is a major health concern for all age groups and accounts for more than 2.5 million deaths annually in children under five years old. Human Aichi virus causes acute gastroenteritis and is associated with foodborne outbreaks. Little is known about its pathogenicity, evolution, and geographical distribution. OBJECTIVE: This study aimed to describe the global seroprevalence of AiV-1 and its genotype distribution, track outbreaks, and estimate co-infection rates with other viral gastroenteritis. METHODS: A comprehensive systematic search of the epidemiological aspects of AiV-1 was conducted using peer-reviewed English original articles indexed in several scientific database libraries since its first detection in Japan until October 2022. A total of 55 published studies were included in the final analysis based on the inclusion criteria. RESULT: The global prevalence of AiV-1 was 1.45 %. To date, nine AiV-1 outbreaks were reported following the first oyster-associated outbreak in Japan between 1987 and 1991. AiV-1 genotype A has a worldwide distribution, whereas genotypes B and C have a pattern of geo-localization. The gradual and significant increase of AiV-1 seroprevalence with age was reported in all studies. The most predominant viruses causing viral coinfection among AiV-1-infected patients were Norovirus (36.55 %), Rotavirus (18.91 %), and Sapovirus (15.13 %). Coinfections with Norovirus (p-value 0.003), Rotavirus (p = 0.007), and Human Astrovirus (p = 0.032) were significantly correlated with AiV-1 coinfection. CONCLUSION: This was the first comprehensive systematic review of AiV-1. Although AiV-1 has a low global prevalence, it can be considered a health concern due to its association with childhood gastroenteritis.

3.
J Enzyme Inhib Med Chem ; 39(1): 2395985, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39311475

RESUMO

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.


A small, focused library comprising 8 novel compounds was synthesised using a series of substituted quinoxaline sulfonohydrazide derivatives.All synthesised compounds were tested against phospholipase A2 (sPLA2) and α-glucosidase enzymes.The compounds exhibited activities against α-glucosidase and were potent at nanomolar concentrations against sPLA2 isozymes.Structure-based molecular modelling was employed to rationalise the SAR of the compounds.


Assuntos
Diabetes Mellitus Tipo 2 , Relação Dose-Resposta a Droga , Hipoglicemiantes , Quinoxalinas , alfa-Glucosidases , Quinoxalinas/farmacologia , Quinoxalinas/química , Quinoxalinas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Relação Estrutura-Atividade , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Estrutura Molecular , alfa-Glucosidases/metabolismo , Modelos Moleculares , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Simulação de Acoplamento Molecular
4.
RSC Med Chem ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39246752

RESUMO

Cancer patients undergoing chemotherapy are highly susceptible to infections owing to their compromised immune system, which also promotes cancer progression through inflammation. Thus, this study aimed to develop novel chemotherapeutic agents with both anticancer and antimicrobial properties. A series of diarylurea derivatives based on pyridazinone scaffolds were designed, synthesized, and characterized as surrogates for sorafenib. The synthesized compounds were tested for their antimicrobial activity and screened against 60 cancer cell lines at the National Cancer Institute (NCI). Compound 10h exhibited potent antibacterial activity against Staphylococcus aureus (MIC = 16 µg mL-1), whereas compound 8g showed significant antifungal activity against Candida albicans (MIC = 16 µg mL-1). Additionally, ten compounds were further evaluated for VEGFR-2 inhibition, with compound 17a showing the best inhibitory activity. Compounds 8f, 10l, and 17a demonstrated significant anticancer activity against melanoma, NSCLC, prostate cancer, and colon cancer, with growth inhibition percentages (GI%) ranging from 62.21% to 100.14%. Compounds 10l and 17a were selected for five-dose screening, displaying GI50 values of 1.66-100 µM. Compound 10l induced G0-G1 phase cell cycle arrest in the A549/ATCC cell line, increasing the cell population from 85.41% to 90.86%. Gene expression analysis showed that compound 10l upregulated pro-apoptotic genes p53 and Bax and downregulated the anti-apoptotic gene Bcl-2. Molecular docking studies provided insights into the binding modes of the compounds to the VEGFR-2 enzyme. In conclusion, the pyridazinone-based diarylurea derivatives developed in this study show promise as dual-function antimicrobial and anticancer agents, warranting further investigation.

6.
Eur J Med Chem ; 277: 116717, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39094274

RESUMO

The urgent and unmet medical demand of acute myeloid leukemia (AML) patients has driven the drug discovery process for expansion of the landscape of AML treatment. Despite the several agents developed for treatment of AML, more than 60 % of treated patients undergo relapse again after re-emission, thus, no complete cure for this complex disease has been reached yet. Targeted oncoprotein degradation is a new paradigm that can be employed to solve drug resistance, disease relapse, and treatment failure in complex diseases as AML, the most lethal hematological malignancy. AML is an aggressive blood cancer form and the most common type of acute leukemia, with bad outcomes and a very poor 5-year survival rate. FLT3 mutations occur in about 30 % of AML cases and FLT3-ITD is associated with poor prognosis of this disease. Prevalent FLT3 mutations include internal tandem duplication and point mutations (e.g., D835) in the tyrosine kinase domain, which induce FLT3 kinase activation and result in survival and proliferation of AML cells again. Currently approved FLT3 inhibitors suffer from limited clinical efficacy due to FLT3 reactivation by mutations, therefore, alternative new treatments are highly needed. Proteolysis-targeting chimera (PROTAC) is a bi-functional molecule that consists of a ligand of the protein of interest, FLT3 inhibitor in our case, that is covalently linked to an E3 ubiquitin ligase ligand. Upon FLT3-specific PROTAC binding to FLT3, the PROTAC can recruit E3 for FLT3 ubiquitination, which is subsequently subjected to proteasome-mediated degradation. In this review we tried to address the question if PROTAC technology has succeeded in tackling the disease relapse and treatment failure of AML. Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Estrutura Molecular , Quimera de Direcionamento de Proteólise
7.
Artigo em Inglês | MEDLINE | ID: mdl-39014044

RESUMO

PURPOSE: Suicidal thoughts are common among patients with first episode psychosis (FEP). The impact of symptoms' severity and social cognition on suicidal risk should be a focus of attention. This study aimed at assessment of the severity of suicidal ideation in patients with FEP and its potential association with the theory of mind (ToM) impairment and symptoms' severity. METHODS: Ninety-six participants were recruited consecutively and subdivided into three equal groups: FEP, schizophrenia, and healthy controls (HC). The symptoms' severity was assessed using Positive and Negative Syndrome Scale (PANSS) and Beck Depression Inventory (BDI). Suicidal ideation was evaluated using Beck Scale for Suicidal Ideation (BSSI). Reading the Mind in the Eyes revised version (RMET) was used to assess ToM. RESULTS: Suicidal ideation was significantly higher only in FEP compared to HC (p = 0.001). Both FEP and schizophrenia had substantially lower performance than HC on RMET (p < 0.001). Higher depression (ß = 0.452, p = 0.007) and negative symptoms (ß = 0.433, p = 0.027) appeared to be significantly associated with increased suicidal ideation severity in FEP while RMET did not. CONCLUSION: Patients with FEP and chronic schizophrenia have comparable deficits in theory of mind dimension of social cognition. The severity of negative and depressive symptoms potentially contributes to the increased risk of suicide in FEP.

8.
Front Genet ; 15: 1396797, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39045318

RESUMO

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families.

9.
PLoS One ; 19(7): e0306143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38954716

RESUMO

INTRODUCTION: Previous evidence suggests an individual variation in the preferred oral processing behavior. Individuals can be classified as firm processing(FPL) or soft processing likers(SPL). FPL(crunchers and chewers) prefer using their teeth while SPL(smooshers and suckers) prefer using the tongue and the palate when processing different food items. Variation in the preferred oral processing behavior has been associated with differences in food texture preference and eating time. Time is one of the factors directly related to the development of dental caries(tooth decay). Oral retention and eating times are associated with greater caries experience. This study aims to explore if a relationship exists between the preferred oral processing behavior and the individual's caries experience. MATERIALS AND METHODS: This was a cross-sectional, dental center-based study conducted at Jordan University of Science and Technology. Five hundred participants consented to fill out the preferred oral processing behavior(POPB) questionnaire. Anthropometric measurements (including weight, height, and waist circumference) were recorded. A single trained and calibrated dentist registered each participant's caries experience and plaque levels using the DMFS index and plaque index of Silness and Loe. RESULTS: A total of 351(70.2%) and 149(29.8%) participants were typed as FPL and SPL, respectively. SPL demonstrated higher levels of dental caries experience compared to FPL. The mean DMFS score for SPL was 28.8(±25.43) while for FPL was 18.71(± 18.34). This difference remained significant after adjustment for confounders(P<0.001). SPL exhibited a significantly higher mean score for the "M" component(P <0.001) while no significant difference in the mean score of the "D"(P = 0.076) and "F"(P = 0.272) components was observed when compared to FPL. CONCLUSION: The current findings provide new insight into a possible relationship between the preferred oral processing behavior and an individual's caries experience. A relationship in which the preferred oral processing behavior can potentially affect and/or be affected by the dental caries experience.


Assuntos
Cárie Dentária , Humanos , Masculino , Feminino , Adulto , Estudos Transversais , Inquéritos e Questionários , Adulto Jovem , Pessoa de Meia-Idade , Comportamento Alimentar/fisiologia , Comportamento Alimentar/psicologia , Preferências Alimentares , Jordânia/epidemiologia
10.
J Multidiscip Healthc ; 17: 3101-3108, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38974369

RESUMO

Objective:  Supracondylar humeral fractures are among the most common pediatric fractures that require surgical intervention when displaced. Recent attention has been directed towards the utilization of serial radiographs in the post-operative period and their effect on decision-making. This study aimed to determine the usefulness of postoperative radiographs early post-operatively, with the goal of determining the optimal frequency for these radiographs. Methods: Pediatric patients who sustained a supracondylar humeral fracture and underwent operative intervention over a 15-year period were included in this study. Data were collected, including the baseline characteristics of the patients, fractures, and operative interventions. In addition, the time until healing, the total number of X-rays before K-wire removal, and postoperative function were evaluated. Results: A total of 122 pediatric patients were included, with a mean age of 5.33 ± 2.93 years. Most fractures were Gartland Type III (74.6%). Most fractures healed at 4 (36.1%) and 3 weeks (35.2%) after surgery. Of the cohort, 94.3% underwent four different x-rays before wire removal, with 4.9% requiring revision surgery. All revision cases were Gartland type 3, and for all cases, the decision to revise was made within three weeks of surgery. Conclusion: Routine post-fixation radiography should not be performed for surgically treated supracondylar humeral fractures before healing. An exception is the Gartland type 3 fracture, for which earlier imaging may be indicated.

11.
Heliyon ; 10(10): e30774, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38765040

RESUMO

This study was aimed to investigate the learning experiences' facilitators and barriers that is encountered by the physically disabled female students during their higher education. Twenty semi-structured interviews were conducted with female students with physical disabilities aged between 19 and 33 years. Interviews were transcribed, confirmed, and analyzed after being recorded. The average age of the sample was 22.15 ± 3.48 years and one-fourth of the participants' disability was due to cerebral palsy and 35% participants used wheelchairs. All the factors promoted inclusive education and equal opportunities for both disabled and nondisabled students. This study reveals that in order to improve the learning experiences of students with disabilities (SwD) and to give them more opportunities for success, it is important to consider all the barriers discussed in this study. It can be concluded that high effort is required to transform the higher educational institutions to be more accommodating for students with disabilities.

12.
Drug Dev Res ; 85(4): e22197, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38751223

RESUMO

Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti-tubulin tetrabromophthalimide hybrids (3-17) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound 16 displayed the lowest IC50 values (11.46 µM) at the FaDu cancer cell lines, whereas compound 17 exhibited the lowest IC50 value (13.62 µM) at the PC3 cancer cell line. However, compound 7b exhibited the lowest IC50 value (11.45 µM) at the MDA-MB-468 cancer cell line. Moreover, compound 17 was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA-MB-468, PC3, and FaDu) with IC50 values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound 17 showed a well-established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound 17 induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL-2). Furthermore, the colchicine binding site inhibition assay showed that compounds 15a and 17 exhibited particularly significant inhibitory potentials, with IC50 values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC50 value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound 17 could prompt cell cycle arrest at both the G0-G1 and G2-M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the ß-tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity.


Assuntos
Antineoplásicos , Apoptose , Desenho de Fármacos , Ftalimidas , Moduladores de Tubulina , Humanos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Ftalimidas/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia
13.
Cureus ; 16(3): e57009, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38681351

RESUMO

Trichodynia is a common symptom, which is characterized by a painful, burning or stinging sensation of the scalp, often in patients presenting with hair loss. It is typically associated with co-morbid psychiatric conditions and remains challenging to treat, with no Food and Drug Administration (FDA) treatments currently available. We herein report the successful use of off-label onabotulinumtoxin-A in treating a patient with trichodynia who has failed conventional therapies.

14.
JBMR Plus ; 8(5): ziae026, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38562913

RESUMO

Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by COL1A1 and COL1A2, respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth, and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI. In this study a multiplex consanguineous family of two affected males with OI was recruited for genetic screening. To determine the causative, pathogenic variant(s), genomic DNA from two affected family members were analyzed using whole exome sequencing, autozygosity mapping, and then validated with Sanger sequencing. The analysis led to the mapping of a homozygous variant previously reported in SP7/OSX, a gene encoding for Osterix, a transcription factor that activates a repertoire of genes involved in osteoblast and osteocyte differentiation and function. The identified variant (c.946C > T; p.Arg316Cys) in exon 2 of SP7/OSX results in a pathogenic amino acid change in two affected male siblings and develops OI, dentinogenesis imperfecta, and craniofacial anomaly. On the basis of the findings of the present study, SP7/OSX:c. 946C > T is a rare homozygous variant causing OI with extra-skeletal features in inbred Arab populations.

15.
J Oral Implantol ; 50(1): 18-23, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38579115

RESUMO

Bone augmentation is often required before the installation of dental implants. Here, we report a case for a patient who previously received bone augmentation at the upper right jaw using a xenogenic graft, followed by successful implant installation. Seven years later, the patient presented with mucosal fenestration with bone exposure at the area and gave a history of a recent diagnosis of cutaneous lichen planus. Several attempts were made to manage the situation, and finally, we resorted to connective tissue graft placement at the site. A piece of bone was sent for histologic evaluation, where the results indicated the presence of un-resorbed graft material surrounded by inflammatory cells, with no evidence of bone formation in the area. The case presents histologic evidence for the lack of new bone formation using xenograft over the evaluation period. The case also shows lichen planus, a possible cause for oral complication for patients undergoing augmentation and implant installation.


Assuntos
Aumento do Rebordo Alveolar , Implantes Dentários , Humanos , Implantação Dentária Endóssea/métodos , Xenoenxertos , Aumento do Rebordo Alveolar/métodos , Osteogênese , Transplante Ósseo/métodos
16.
Int J Mol Sci ; 25(6)2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38542393

RESUMO

Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein's structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3. Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Simulação de Acoplamento Molecular , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Sorafenibe/farmacologia , Mutação , Proteínas Tirosina Quinases/genética
17.
Int J Environ Health Res ; : 1-11, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461375

RESUMO

The strategy for controlling the existence of radionuclides in drinking water depends upon an individual dose criterion (IDC) of 0.1 mSv/y, which represents a very low level of risk that is not expected to cause any identified adverse health effects. Radon gas, considered a carcinogenic radionuclide, can dissolve and accumulate in drinking water. Non-alcoholic carbonated beverages (NACBs), which mainly contain drinking water, phosphoric acid, citric acid, caffeine, and sugar, represent one of the most consumed groups worldwide and in Türkiye. In this study, the radon activity concentration and some physicochemical characteristics of 45 NACB samples from 24 most preferred commercial brands in Türkiye were determined to assess the radiological health risk associated with the ingestion of these samples. Radon activity concentrations measured in NACB samples using the AlphaGUARD radon analyzer ranged from 22.8 ± 0.7 to 54.9 ± 1.7 mBq/L. The pH, conductivity, total dissolved solids, and brix values in NACB samples ranged from 2.31 to 7.29, 401 to 3281 µSv/cm, 355 to 2453 mg/L, and 0.10 to 12.95%, respectively. Total (ingestion and inhalation) annual effective doses and the corresponding excess lifetime cancer risks estimated for adults to assess the radiological health risk are significantly below the IDC and advised safety limit (10-3), respectively.

18.
Pharmaceuticals (Basel) ; 17(3)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38543160

RESUMO

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 µg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

19.
Eur J Med Chem ; 268: 116255, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38401190

RESUMO

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 µM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Aurora Quinase B , Oxindóis/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Apoptose , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Proliferação de Células
20.
Saudi Med J ; 45(2): 188-193, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38309732

RESUMO

OBJECTIVES: To determine the incidence of Clostridioides difficile infection (CDI) and the frequency of known risk factors. METHODS: A prospective hospital-based surveillance for CDI, according to the Centers for Disease Control and Prevention criteria, was carried out from July 2019 to March 2022 for all inpatients aged more than one year in Prince Sultan Military Medical City, Riyadh, Saudi Arabia. RESULTS: A total of 139 cases of CDI were identified during the survey among 130 patients admitted in the hospital. Most cases were incident (n=130; 93.5%), and almost three-quarters (n=102; 73.4%) were hospital-onset (HO) CDI, with an incidence rate of 1.62 per 10,000 patient days (PD). The highest rates were noted in intensive care units with an incidence rate of 3 per 10,000 PD and wards for immunocompromised patients with an incidence rate of 2.72 per 10,000 PD. The most prevalent risk factor for CDI was acid-reducing drugs (72.6%). Vancomycin (48%) and ciprofloxacin (25%) were the most frequently prescribed antibiotics for patients with CDI. Clostridioides difficile infection complications were identified in 5.7% of the cases, with a reported 28-day mortality rate of 3.8%. CONCLUSION: In our hospital, HO-CDI incidence rate is lower than that in high-income countries. National multicenter surveillance is needed to evaluate the actual burden of CDI in Saudi Arabia.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Infecção Hospitalar , Humanos , Arábia Saudita/epidemiologia , Estudos Prospectivos , Atenção Terciária à Saúde , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/prevenção & controle , Infecção Hospitalar/epidemiologia
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