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Increased glycolytic metabolism recently emerged as an essential process driving host defense against Brucella, but little is known about how this process is regulated during infection. We have identified a critical role for nuclear factor kappa B (NF-κB) transcription factor regulation in glycolytic switching during Brucella infection for the first time. Chromatin immunoprecipitation with next-generation sequencing for NF-κB and DNA Pull-Down revealed two novel NF-κB-binding sites in the enhancer region of the Nitric oxide (NO)production-response regulator gene glucose-6-phosphate dehydrogenase (G6PD), which is important for the switch to glycolysis during a Brucella infection. These findings demonstrate that Brucella drives metabolic reprogramming by inhibiting host oxidative phosphorylation (OXPHOS) and enhancing its glycolysis via the NF-κB-G6PD-NO-pathway. These studies provide a theoretical basis for investigating drugs or vaccines to control Brucella colonization and induction of undulant by manipulating host metabolic patterns.
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Plasmodium vivax is a major cause of malaria, which poses an increased health burden on approximately one third of the world's population due to climate change. Primaquine, the preferred treatment for P. vivax malaria, is contraindicated in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common genetic cause of hemolytic anemia, that affects â¼2.5% of the world's population and â¼8% of the population in areas of the world where P. vivax malaria is endemic. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) conducted a structure-function analysis of P. vivax N-myristoyltransferase (PvNMT) as part of efforts to develop alternative malaria drugs. PvNMT catalyzes the attachment of myristate to the N-terminal glycine of many proteins, and this critical post-translational modification is required for the survival of P. vivax. The first step is the formation of a PvNMT-myristoyl-CoA binary complex that can bind to peptides. Understanding how inhibitors prevent protein binding will facilitate the development of PvNMT as a viable drug target. NMTs are secreted in all life stages of malarial parasites, making them attractive targets, unlike current antimalarials that are only effective during the plasmodial erythrocytic stages. The 2.3â Å resolution crystal structure of the ternary complex of PvNMT with myristoyl-CoA and a novel inhibitor is reported. One asymmetric unit contains two monomers. The structure reveals notable differences between the PvNMT and human enzymes and similarities to other plasmodial NMTs that can be exploited to develop new antimalarials.
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G6PD deficiency results from mutations in the X-linked G6PD gene. More than 200 variants are associated with enzyme deficiency: each one of them may either cause predisposition to haemolytic anaemia triggered by exogenous agents (class B variants), or may cause a chronic haemolytic disorder (class A variants). Genotype-phenotype correlations are subtle. We report a rare G6PD variant, discovered in a baby presenting with severe jaundice and haemolytic anaemia since birth: the mutation of this class A variant was found to be p.(Arg454Pro). Two variants affecting the same codon were already known: G6PD Union, p.(Arg454Cys), and G6PD Andalus, p.(Arg454His). Both these class B variants and our class A variant exhibit severe G6PD deficiency. By molecular dynamics simulations, we performed a comparative analysis of the three mutants and of the wild-type G6PD. We found that the tetrameric structure of the enzyme is not perturbed in any of the variants; instead, loss of the positively charged Arg residue causes marked variant-specific rearrangement of hydrogen bonds, and it influences interactions with the substrates G6P and NADP. These findings explain severe deficiency of enzyme activity and may account for p.(Arg454Pro) expressing a more severe clinical phenotype.
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Glucose-6-Phosphate Dehydrogenase (G6PD) is a crucial enzyme that executes the pentose phosphate pathway. Due to its critical nodal position in the metabolic network, it is associated with different forms of cancer tumorigeneses and progression. Nonetheless, its functional role and molecular mechanism in lung cancer remain unknown. The present study provides intricate information associated with G6PD and Lung Cancer. Varieties of public datasets were retrieved by us, including UALCAN, TCGA, cBioPortal, and the UCSC Xena browser. The data obtained were used to assess the expression of G6PD, its clinical features, epigenetic regulation, relationship with tumour infiltration, tumour mutation burden, microsatellite instability, tumour microenvironment, immune checkpoint genes, genomic alteration, and patient's overall survival rate. The present study revealed that the G6PD expression was correlated with the clinical features of lung cancer including disease stage, race, sex, age, smoking habits, and lymph node metastasis. Moreover, the expression profile of G6PD also imparts epigenetic changes by modulating the DNA promoter methylation activity. Methylation of promoters changes the expression of various transcription factors, genes leading to an influence on the immune system. These events linked with G6PD-related mutational gene alterations (FAM3A, LAG3, p53, KRAS). The entire circumstance influences the patient's overall survival rate and poor prognosis. Functional investigation using STRING, GO, and KEGG found that G6PD primarily engages in hallmark functions (metabolism, immunological responses, proliferation, apoptosis, p53, HIF-1, FOXO, PI3K-AKT signaling). This work provides a wide knowledge of G6PD's function in lung cancer, as well as a theoretical foundation for possible prognostic therapeutic markers.
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BACKGROUND: Testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important consideration regarding treatment for malaria. G6PD deficiency may lead to haemolytic anaemia during malaria treatment and, therefore, determining G6PD deficiency in malaria treatment strategies is extremely important. METHODS: This report presents the results of a scoping review and evidence and gap map for consideration by the Guideline Development Group for G6PD near patient tests to support radical cure of Plasmodium vivax. This scoping review has investigated common diagnostic tests for G6PD deficiency and important contextual and additional factors for decision-making. These factors include six of the considerations recommended by the World Health Organization (WHO) handbook for guideline development as important to determining the direction and strength of a recommendation, and included 'acceptability', 'feasibility,' 'equity,' 'valuation of outcomes,' 'gender' and 'human rights'. The aim of this scoping review is to inform the direction of future systematic reviews and evidence syntheses, which can then better inform the development of WHO recommendations regarding the use of G6PD deficiency testing as part of malaria treatment strategies. RESULTS: A comprehensive search was performed, including published, peer-reviewed literature for any article, of any study design and methodology that investigated G6PD diagnostic tests and the factors of 'acceptability', 'feasibility,' 'equity,' 'valuation of outcomes,' 'gender' and 'human rights'. There were 1152 studies identified from the search, of which 14 were determined to be eligible for inclusion into this review. The studies contained data from over 21 unique countries that had considered G6PD diagnostic testing as part of a malaria treatment strategy. The relationship between contextual and additional factors, diagnostic tests for G6PD deficiency and study methodology is presented in an overall evidence and gap, which showed that majority of the evidence was for the contextual factors for diagnostic tests, and the 'Standard G6PD (SD Biosensor)' test. CONCLUSIONS: This scoping review has produced a dynamic evidence and gap map that is reactive to emerging evidence within the field of G6PD diagnostic testing. The evidence and gap map has provided a comprehensive depiction of all the available literature that address the contextual and additional factors important for decision-making, regarding specific G6PD diagnostic tests. The majority of data available investigating the contextual factors of interest relates to quantitative G6PD diagnostic tests. While a formal qualitative synthesis of this data as part of a systematic review is possible, the data may be too heterogenous for this to be appropriate. These results can now be used to inform future direction of WHO Guideline Development Groups for G6PD near patient tests to support radical cure of P. vivax malaria.
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Pruebas Diagnósticas de Rutina , Deficiencia de Glucosafosfato Deshidrogenasa , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Humanos , Pruebas Diagnósticas de Rutina/métodos , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Malaria Vivax/diagnóstico , Malaria Vivax/tratamiento farmacológico , Malaria/diagnóstico , Malaria/tratamiento farmacológicoRESUMEN
Approximately 400 million individuals globally experience glucose-6-phosphate dehydrogenase (G6PD) insufficiency, an enzymatic condition that may be hazardous. Because of mutations in the G6PD gene, which result in functional variants alongside a variety of biochemical and clinical symptoms, this condition is an X-linked hereditary genetic disorder. Our case is that of a 12-year-old male child who presented with acute liver failure and later on, exhibited signs of hemolysis as well. We had to rule out the possibilities of acetaminophen toxicity and hepatitis A before reaching the conclusion that an underlying G6PD deficiency was being exacerbated by viral infection and simultaneous ingestion of non-steroidal anti-inflammatory drugs (NSAIDs).
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Possible protective and therapeutic effects of nobiletin on kidney in a cisplatin-induced nephrotoxicity rat model were investigated. Forty male albino rats were divided into four groups: control, cisplatin (CIS), cisplatin+nobiletin (CIS+NOB), and nobiletin+cisplatin (NOB+CIS). At the end of the study, the rats were subjected to biochemical, histological and immunohistochemical analyzes. Compared to the control group, tGSH (p < 0.05) levels, and G6PD (p < 0.05) and GPx (p < 0.001) activities, were increased in the CIS group; while significant (p < 0.05) decreases occurred in the MDA and TOC levels. Histopathologically, the kidneys of the groups administered nobiletin (CIS+NOB, NOB+CIS) were significantly different from the CIS group, being closer to control group in terms of degeneration and hyaline cylinder formation in the tubules (p < 0.05). While dilatation in the tubules, protein-rich fluid and hyaline cylinder formation in the lumen were most common in the CIS group, a significant decrease (p < 0.05) of these parameters was seen in the nobiletin groups (CIS+NOB, NOB+CIS). This study suggests that nobiletin can be effective in preventing and ameliorating toxic effects of cisplatin on the kidney.
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Consumption of fava beans in a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency, also called favism, can lead to a haemolytic crisis. We report the case of a 69-year-old patient of Iranian origin admitted to the emergency department following syncope. The patient's comprehensive interview and blood analysis revealed that the patient presented a haemolytic crisis triggered by fava beans consumption, due to previously undiagnosed G6PD deficiency. The pathophysiology of favism is complex and clinical presentations of G6PD deficiency are numerous due to multiple genetic variants. Indirect signs, such as the presence of methemoglobinaemia and hemighosts on the blood smear, can aid in the diagnosis. This case highlights the importance of considering G6PD deficiency as a potential diagnosis in case of haemolytic crisis, even in elderly patients.
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INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzyme disorder in red blood cell (RBC). Due to the importance of G6PD enzyme as an antioxidant in RBC, we tried to investigate the oxidative damage in red cell concentrates (RCCs) prepared from donors with G6PD enzyme deficiency in comparison with healthy donors. MATERIAL METHOD: This cross-sectional study was conducted on 20 male donors. Ten of the donors had G6PD deficiency (as a case) and the others had normal enzyme activity (as a control). Biochemical and oxidative damage parameters were examined in RCCs prepared from two groups on days 0, 7, 14, 21, 28 and 35 of RCCs storage; data comparison was analyzed by SPSS statistical software. RESULTS: According to the result, lactate concentration increased significantly from the 7th day to the 35th day of RCC storage in G6PD-deficient donors compared to the control (P < 0.05). In addition, malondialdehyde (MDA) concentration in G6PD-deficient RCC showed a significant increase compared to the control in all days of storage (P < 0.05). Among the hematological parameters, mean corpuscular volume (MCV) and mean cell hemoglobin (MCH) increased significantly in all days of RCC storage in G6PD-deficient donors compared to the control (P < 0.05). CONCLUSION: Our study showed that oxidative changes in G6PD-deficient donors were significantly increased compared to the healthy donors, which probably leads to RCC storage lesion and an increase in blood transfusion complications. Due to the high prevalence of G6PD enzyme deficiency in pandemic areas, it seems that enzyme screening should be included in donor screening programs.
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Studies have shown that decreased expression of glucose-6-phosphate dehydrogenase (G6PD) play an important role in DKD. However, the upstream and downstream pathways of G6PD downregulation leading to DKD have not been elucidated.We conducted a series of studies including clinical study, animal studies, and in vitro studies to explore this. Firstly, a total of 90 subjects were evaluated. The urinary G6PD activity and its association with the clinical markers were analyzed. Then, urine differentially microRNAs that can bind and degrade G6PD were screened and verified in DKD patients. After that, high glucose (HG)-cultured Human kidney cells (HK-2) and Zucker diabetic fatty (ZDF) rats were used to test the roles of miR-7977/G6PD/albumin-induced autophagy in DKD. The plasma and urinary G6PD activity were decreased significantly in patients with DKD, accompanied by increased urinary mir-7977 level. The fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and urinary albumin excretion were independent predictors of urinary G6PD activity by multiple linear regression analysis.The increased expression of miR-7977 and decreased expression of G6PD were also found in the kidney of ZDF rats with early renal tubular damage.In HK-2 cells cultured with normal situation, low level of albumin could induce autophagy along with the stimulation of G6PD although this was impaired under high glucose. Overexpression of G6PD reversed albumin-induced autophagy in HK2 cells under high glucose.Inhibition mir-7977 expression led to significantly increased expression of G6PD and reversed the effects of high glucose on albumin induced autophagy.Our study supports a new mechanism of G6PD downregulation in DKD.
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Metformin is a first-line medication used in the treatment of type 2 diabetes mellitus along with other conditions such as insulin resistance and polycystic ovarian syndrome. Overall, metformin appears to be well tolerated with a low incidence of side effects; however, in certain high-risk populations, it can trigger a hemolytic crisis. This case report describes a middle-aged man who was initiated on metformin for new-onset diabetes, following which he had an acute hemoglobin drop and was diagnosed to be having a hemolytic crisis requiring hospitalization. He was diagnosed with a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) on admission. Extensive workup was done to rule out other causes of hemolysis, all of which came back to be negative. The offending agent was stopped and the patient received supportive care after which he improved. This case highlights a rare, yet important, side effect of metformin that needs to be observed in certain individuals, especially patients with G6PD deficiency. Routine testing of high-risk populations known to be G6PD deficient should be considered before initiating metformin.
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BACKGROUND: Sirtuin 7 (SIRT7) is pivotal in diverse diseases progression. Importantly, SIRT7 is associated with melanin production. However, whether SIRT7 regulates vitiligo is unclear. Therefore, we aimed to investigate the effects of SIRT7 on pigmentation and the modification of glucose 6-phosphate dehydrogenase (G6PD). METHODS: After knockdown SIRT7 and G6PD, pigmentation of melanocytes was evaluated using commercial kits, immunofluorescence, and Western blot analysis. The succinylation of G6PD mediated by SIRT7 was analyzed using co-immunoprecipitation, immunofluorescence, Western blot analysis, and cycloheximide-chase experiment. RESULTS: We found that SIRT7 was highly expressed in vitiligo skin lesions. Knockdown of SIRT7 increased tyrosinase activity, melanin content, and the levels of α-melanocyte-stimulating hormone, MITF, TYR, TRP1, and TRP2. Additionally, SIRT7 directly interacted with G6PD. Silenced SIRT7 promoted the succinylation of G6PD and enhanced its protein stability. G6PD knockdown reversed the effect of reduced SIRT7 expression on melanin production. CONCLSUION: Silencing of SIRT7 promotes pigmentation of melanocytes by succinylating G6PD, suggesting that SIRT7-mediated G6PD desuccinylation may promote vitiligo progression.
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Progresión de la Enfermedad , Glucosafosfato Deshidrogenasa , Melaninas , Melanocitos , Sirtuinas , Vitíligo , Vitíligo/metabolismo , Vitíligo/patología , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Sirtuinas/metabolismo , Sirtuinas/genética , Glucosafosfato Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/genética , Melaninas/metabolismo , Melaninas/biosíntesisRESUMEN
Tumor lysis syndrome (TLS) presents significant challenges in oncology, primarily due to metabolic complications such as hyperuricemia, which can lead to acute kidney injury. Rasburicase, a recombinant urate oxidase, is frequently employed to manage hyperuricemia in TLS patients. However, its use is an absolute contraindication in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolysis. In this case, the patient developed hemolytic anemia post-rasburicase administration even though she had normal G6PD activity, which was confirmed on two separate occasions, including during an acute episode and 3 months later. This case is unique as it documents hemolytic anemia induced by rasburicase in a patient without G6PD deficiency, challenging current understandings of the drug's safety profile. It suggests the need for caution and thorough screening before rasburicase use, even in patients considered low risk for G6PD deficiency. The report highlights the importance of close monitoring for adverse effects and the potential for alternative mechanisms of rasburicase-induced hemolysis.
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BACKGROUND: Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluate the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM). METHODS: Between 2014 and 2017, children aged six months to <4 years hospitalized with SM and community children (CC) were recruited at two hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and post-discharge outcomes and evaluated effect mediation through G6PD deficiency. RESULTS: 557 children with SM and 101 CC were enrolled. The mean age of children was 2.1 years. Children with SM had higher cIC levels than CC, p<0.001. After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF (adjusted odds ratio, 95% confidence interval: 7.33 (3.45, 15.58), p<0.0001; 4.31 (1.68, 11.08), p=0.002; and 5.21 (2.06, 13.18), p<0.0001), respectively. cIC predicted readmissions for SM, severe anemia, and BWF (adjusted incidence rate ratios (95% confidence interval): 2.11 (1.33, 3.34), p=0.001; 8.62 (2.80, 26.59), p<0.0001; and 7.66 (2.62, 22.45), p<0.0001), respectively. The relationship was most evident in males where the frequency of the G6PD African allele (A-) was 16.8%. G6PD deficiency was associated with increases in cIC in males (p=0.01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC. CONCLUSIONS: Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors.
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PURPOSE: Primaquine (PQ) is recommended for radical cure of Plasmodium vivax (Pv) malaria, but its utilization is still limited due to high risk of severe haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-d). The aim of the present study is to assess the different genotypic variants leading to G6PD-d in Delhi and Goa regions of India. METHODS: A total of 46 samples (34 retrospective Pv-mono-infected samples and 12 Pv-uninfected samples) were included in the study. Various genetic variants leading to G6PD-d were analysed by PCR amplification and DNA sequencing of different targeted exons of G6PD gene. RESULTS: Molecular analysis showed presence of four mutations in study population viz. 1311 C > T, 34.1% & IVSXI 93T > C, 45.5% and two novel mutations 1388G > T, 2.3% and 1398 C > T, 2.3% (silent mutation). The bioinformatics and computational analysis demonstrate that the slight conformational changes caused by R643L mutation in protein are deleterious in nature. CONCLUSION: The observed mutations do not clarify the role or association between G6PD-d and Pv-infected cases. Further investigation is required in order to fully comprehend and analyse the precise role of these mutations with context to malaria infections.
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Deficiencia de Glucosafosfato Deshidrogenasa , Glucosafosfato Deshidrogenasa , Malaria Vivax , Plasmodium vivax , Humanos , Malaria Vivax/parasitología , India/epidemiología , Glucosafosfato Deshidrogenasa/genética , Plasmodium vivax/genética , Plasmodium vivax/enzimología , Deficiencia de Glucosafosfato Deshidrogenasa/genética , Estudios Retrospectivos , Genotipo , Mutación , Masculino , Variación Genética , Femenino , AdultoRESUMEN
Chondrocytes, known for their metabolic adaptability in response to varying stimuli, play a significant role in osteoarthritis (OA) progression. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, has recently been found to upregulate in OA chondrocyte. However, the exact role of G6PD in temporomandibular joint osteoarthritis (TMJOA) and its effect on chondrocyte function remains unclear. In present study, we induced OA-like conditions in the rat temporomandibular joint via occlusal disharmony (OD), noting a marked increase in G6PD expression in the condylar cartilage. Our data show that G6PD knockdown in mandibular condylar chondrocytes (MCCs) reduces the expression of catabolic enzymes (e.g., MMP3, MMP13) and inflammatory cytokines (e.g., IL6) induced by IL-1ß. G6PD knockdown also mitigates IL-1ß-induced upregulation of ERK, JNK, and p38 phosphorylation and reduces reactive oxygen species (ROS) levels by decreasing the nicotinamide adenine dinucleotide phosphate (NADPH) and NADPH oxidases 4 (NOX4) mRNA expression. In summary, G6PD appears to regulate the inflammatory state of condylar chondrocytes via the NOX-ROS-MAPK axis, highlighting its potential as a therapeutic target for TMJOA.
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Condrocitos , Glucosafosfato Deshidrogenasa , NADPH Oxidasa 4 , Osteoartritis , Especies Reactivas de Oxígeno , Animales , NADPH Oxidasa 4/metabolismo , NADPH Oxidasa 4/genética , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Osteoartritis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Glucosafosfato Deshidrogenasa/genética , Masculino , Ratas , Ratas Sprague-Dawley , Interleucina-1beta/metabolismo , Articulación Temporomandibular/patología , Articulación Temporomandibular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Cartílago Articular/patología , Cartílago Articular/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inflamación/metabolismo , Transducción de Señal , Modelos Animales de Enfermedad , HumanosRESUMEN
Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aß deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.
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Enfermedad de Alzheimer , Glucosafosfato Deshidrogenasa , Nanopartículas , Enfermedad de Alzheimer/metabolismo , Humanos , Animales , Glucosafosfato Deshidrogenasa/metabolismo , Microfluídica/métodosRESUMEN
The glucose-6-phosphate dehydrogenase (G6PD) deficiency is X-linked and is the most common enzymatic deficiency disorder globally. It is a crucial enzyme for the pentose phosphate pathway and produces NADPH, which plays a vital role in regulating the oxidative stress of many cell types. The deficiency of G6PD primarily causes hemolytic anemia under oxidative stress triggered by food, drugs, or infection. G6PD-deficient patients infected with SARS-CoV-2 showed an increase in hemolysis and thrombosis. Patients also exhibited prolonged COVID-19 symptoms, ventilation support, neurological impacts, and high mortality. However, the mechanism of COVID-19 severity in G6PD deficient patients and its neurological manifestation is still ambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, we observed a significant reduction in NADPH level and an increase in basal reactive oxygen species (ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impairs induced nitric oxide synthase (iNOS) mediated nitric oxide (NO) production, which plays a fundamental role in inhibiting viral replication. Surprisingly, we also observed that the deficiency of the G6PD-NADPH axis reduced lysosomal acidification and free radical production, further abrogating the lysosomal clearance of viral particles. Thus, impairment of NO production, lysosomal functions, and redox dysregulation in G6PD deficient microglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis.