Genetic deficiency of acid a-glucosidase (GAA) results in Pompe disease (PD) encompassing four clinical subtypes of varying severity. Our objective is to develop an innovative and affordable approach for enzyme replacement therapy (ERT) through oral administration (Oral-ERT) to maintain a sustained therapeutic level of enzyme daily to improve treatment efficacy. Tobacco seeds contain the metabolic machinery compatible with mammalian glycosylation-phosphorylation. We have shown that transgenic tobacco seeds expressing human GAA (tobrhGAA) were enzymatically active and can correct the enzyme deficiency in cultured cells and in GAA knockout (GAAKO) mice administered IP. We have extended these studies in PD KO mice with ground tobrhGAA seeds. Briefly, in PD knockout mice, Oral-ERT with ground tobrhGAA seeds showed a significant reversal of fore-limb and hind-limb muscle weakness, increased motor coordination/balance/strength/mobility, improved spontaneous learning, increased GAA activity in tissues, reduced glycogen in tissues and negligible serum titers to GAA. Pharmacokinetics showed maximum serum GAA concentration at 8 - 10 h and peak urine excretion at 10 - 12 h post-administration. The tobrhGAA was taken up in PD fibroblast, lymphoid, and myoblast cells. Enzyme kinetics compared favorably to hGAA, plus alglucosidase alfa or other recombinant human GAAs for Km, Vmax, pH optima, thermal heat stability, and IC50 for inhibitors. The tobrhGAA in seeds was stable for 15 years at room temperature. Thus, Oral-ERT with ground tobrhGAA seeds is an innovative approach that overcomes some of the challenges of alglucosidase alfa-ERT and provides a more effective, safe, and significantly less expensive treatment.
BCR-ABL, the pioneering gene fusion resulting from chromosomal translocation, has marked a major milestone in understanding genetic alterations in cancer. Initially, gene fusions were linked solely to chromosomal rearrangements, serving as diagnostic markers and cancer drivers. However, advancements in high-throughput sequencing and bioinformatics have revealed additional mechanisms underlying gene fusion. The term “gene fusion” primarily refers to fusion events at the DNA level, whereas “chimeric RNA” encompasses a wide range of transcripts containing exons from different parental genes, including gene fusion transcripts. Recent developments have identified numerous chimeric RNAs in various cancer types, extending even to non-cancerous tissues. Chimeric RNAs, originating from events such as trans-splicing, read-through, and intergenic splicing, form a complex landscape with varied functions. While some chimeric RNAs have defined roles and therapeutic potential, a comprehensive understanding of their diverse functions remains a priority. Exploring the full spectrum of chimeric RNA activities is crucial for revealing their clinical and therapeutic implications. In addition, chimeric RNAs are key players in tumorigenesis, affecting cellular processes, and driving cancer progression. Understanding their intricate interactions with cellular pathways is essential for developing targeted therapies and precision medicine approaches. The dynamic nature of chimeric RNAs highlights the need for ongoing research to fully harness their diagnostic and therapeutic potential.
Sirtuin 1 (SIRT1) plays a complex role in cancer, significantly influencing cancer prognosis. However, its true impact remains unclear, necessitating a comprehensive and unified analysis. This study investigates the prognostic value of SIRT1 expression across different cancers worldwide. Relevant studies were retrieved from Google Scholar, PubMed, and Web of Science. Only human studies exploring the prognostic role of SIRT1 in various cancers were included in the study. Data on patient demographics, SIRT1 expression levels, and overall survival (OS) rates were extracted, followed by subsequent analyses, including meta-regression for heterogeneity and Egger’s regression for publication bias. A total of 15 studies (pooled hazard ratio = 1.483 ± 0.2974 [95% CI: 0.900 - 2.065]), predominantly from Asia (n = 10), were selected for the meta-analysis. The analysis demonstrated a robust and consistent association between elevated SIRT1 expression and poorer OS across diverse variables (P < 0.001), with minimal heterogeneity (I2 = 0.0001). Subgroup analyses confirmed significant effects of SIRT1 on OS rates based on regions (Asia: P < 0.001; non-Asia: P < 0.001), study size (small: P = 0.001, medium: P = 0.002, and large cohorts: P = 0.021), and specific cancer types (ovarian: P = 0.041, lung: P = 0.025, and gastric cancer: P = 0.025). However, no significant impact was observed in breast (P = 0.136) and colorectal cancers (P = 0.221). Overall, SIRT1 demonstrates consistent prognostic significance across various cancers and populations. However, the assessment of its long-term prognostic effects remains elusive, highlighting the need for further mechanistic research to guide targeted interventions and precision medicine in cancer therapy.
Apolipoprotein A-I (Apo A-I) plays a central role in the function of high-density lipoprotein (HDL). The rs670 single-nucleotide polymorphism (SNP) was identified as a cytosine-to-thymine (C>T) transition in a cytosine-phosphate-guanine site within the promoter region of APOA1. Given its location, studies have hypothesized that this polymorphism may influence APOA1 expression, potentially impacting lipid and carbohydrate metabolism. The aim of this integrative review was to summarize all observational and experimental studies on the rs670 SNP available in the Scopus, ScienceDirect, dbSNP, and LitVar2 databases up to July 2024. In total, 162 articles were identified, of which 28 met the inclusion criteria. Most studies originated from Asia and were published between 2009 and 2023. Of the selected studies, 14 (50%) examined the association of the rs670 SNP with metabolic disorders. Among these, eight (28.57%) reported an association between the polymorphic allele and alterations in lipid profiles, proinflammatory markers, and insulin resistance. The remaining studies explored associations between the polymorphic allele and ischemic events, pharmacological therapies, diet, neurodegenerative diseases, pancreatitis, and breast cancer. The rs670 SNP occurs in more than 20% of the global population. Its position within the promoter region enables it to potentially regulate the APO cluster on chromosome 11. This review underscores the need for further investigation into the impact of this polymorphism on gene expression and its role in the pathogenesis of metabolic syndrome, cardiovascular disease, and cancer.
Sickle cell disease (SCD) is a disorder characterized by the polymerization of hemoglobin chains in the deoxy-form, sickling of red blood cells, and hence vaso-occlusive crisis, multiple organ damage, and increased mortality due to an inherited defect in hemoglobin structure. SCD can also lead to a host of complications, which include acute chest syndrome, avascular necrosis, stroke, pulmonary hypertension, splenic sequestration, gallstones, deep vein thrombosis, pregnancy complications, and end-organ damage. Complications are of varying complexities and can be as grave as life-threatening. According to a report in 2005, the median life expectancy for male and female patients with SCD in the United States (US) was around 42 and 38 years, respectively. However, the survival rate of SCD patients in high-income countries has steadily improved. Treatment options that were mainly for symptomatic relief and led to better well-being of the patient, containment of complication recurrence, and decrease in mortality rates have evolved into curative treatment options such as stem cell transplantations and gene therapy. The present paper is a review of the disease, its complications and implications on the community, and a historical tracking of the evolution of treatment options up to modern-day gene therapy.
Estrogen receptors (ERs) and their ligands play a crucial role in physiological and pathophysiological processes, particularly in the central nervous and cardiovascular systems. There is increasing evidence that besides the two cytosolic and nuclear ERs, namely, ERα and ERβ, the seven-transmembrane G protein-coupled ER 1 (GPER1) is of great importance in the molecular mechanisms underlying various neurological and cardiovascular diseases and is probably responsible for sex-specific differences. In contrast to ERα and ERβ, GPER1 mediates its effects through not only transcriptional regulation but also rapid nongenomic signaling. This emphasizes the role of GPER1 in the modulation of acute pathophysiological mechanisms involving changes in diverse signaling pathways related to neurological and cardiological aspects. In this review, we have summarized the role of GPER1 in disorders of excitable tissues, including neuroinflammation, learning and memory, Alzheimer’s disease, Parkinson’s disease, depression and mood disorders, schizophrenia, epilepsy, autism spectrum disorders and attention-deficit/hyperactivity disorder, migraine and pain, cardiovascular hypertension, cardiovascular function and fibrosis, hypertrophy, and atrial fibrillation, with a special focus on its involvement in sex-specific differences. We have assessed reports investigating the role of GPER1 in rodents and humans using in vivo and in vitro data. We have also reviewed the role of nutraceuticals, especially phytoestrogens, in this context. Furthermore, we have discussed the potential of GPER1 as a target for novel therapeutic interventions and prognostic indicator of neurological and cardiovascular diseases with a focus on sex-specific differences.
Congenital myopathies are a group of clinically and genetically diverse neuromuscular diseases that often present with stable and/or slowly progressive trunk and proximal weakness. Genetic analysis can help diagnose each congenital myopathy more accurately. Although an increasing number of other causative genes have been reported, ryanodine receptor 1 (RYR1)-related myopathy is the most common cause. Herein, we report the clinical presentation of a patient with congenital myopathy-1B (multiminicore disease) that was caused by a c.115 G>A homozygous variant of RYR1. The patient had normal cognitive abilities but was developmentally delayed and unable to walk. Electromyography revealed myogenic changes. The c.115G>A variant located in the second exon of RYR1 was found to be homozygous in the congenital neuromuscular gene panel. The patient’s parents and sister both carried the heterozygous variant. Clinical differences between family members with the homozygous and heterozygous variants of RYR1 highlight the correlation between the genotype and phenotype.
Major depressive disorder (MDD) is a heterogeneous condition influenced by a complex interplay of social, psychological, and biological factors. Fisetin (FT), a flavonoid polyphenol found in various plants, has demonstrated neuroprotective properties that may be beneficial in treating MDD. This research aims to evaluate the potential molecular mechanisms of FT in treating MDD using network pharmacology analysis, with validation through molecular docking methods. We assessed the drug-like properties of FT using the TCMSP and SwissADME platforms. Potential drug targets for FT were identified through SuperPred and SwissTargetPrediction. We compiled MDD-associated targets from established databases and identified common genes shared between FT and MDD. The common targets were analyzed for protein-protein interactions using the STRING database to identify essential targets. Consequently, these key targets were further investigated through Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO) enrichment analyses with the help of ShinyGO software. The results indicated that FT targets are linked to specific pathways involved in the pathogenesis of MDD, with the IL-17 signaling pathway emerging as a significant pathway of interest. Strong binding affinities were found between FT and key proteins, including glycogen synthase kinase 3 beta, monoamine oxidase A, acetylcholinesterase, matrix metalloproteinase 9, and myeloperoxidase, suggesting that FT may serve as a promising therapeutic agent for MDD by targeting components of the IL-17 pathway. In conclusion, this research successfully employed computational methods to elucidate the potential effectiveness of FT in managing MDD. It offered important perspectives on the regulatory mechanisms involved and emphasized the IL-17 signaling pathway as a possible target for MDD therapy.
Post-transcriptional regulation by RNA-binding proteins (RBPs) is critical for mRNA stability, localization, and translation, primarily through interaction with the 3’-untranslated region. Dysregulation of RBPs has been associated with various cancers, with fragile X-related protein 1 (FXR1) emerging as a critical RBP involved in tumorigenesis through its interactions with target mRNAs. Despite its significance, the specific role of FXRI in cancer progression remains underexplored. In this study, we investigated FXR1’s function using SH-SY5Y cells. RNA immunoprecipitation (RNA-IP) assay was employed to isolate RNA complexes associated with FXR1. We generated stable cell lines with either FXR1 overexpression or silencing to assess the impact of FXRI binding to mRNA complexes. Subsequent analyses, including quantitative reverse transcription polymerase chain reaction, correlation analysis, gene expression profiling, and survival analysis, were performed to validate the interactions of FXR1 with target mRNAs. Our RNA-IP analysis identified several mRNAs significantly enriched in FXR1-bound RNA complexes, including SHISAL1, SLC43A3, NBAT1, PDZK1IP1, ACKR3, KCNN3, NECAB2, ANO5, ATOH8, IGFBP7, LEMD1, GPR35, WNT7A, and F2RL3. Notably, we observed changes in the expression levels of these genes following FXR1 overexpression or depletion, indicating FXR1-mediated functional regulation. Co-expression analysis further supported FXR1’s association with these target mRNAs. These findings highlight the significant role of FXR1 in regulating the stability and expression of key mRNAs implicated in malignancies. The dysregulation of FXR1 and its interaction with these target transcripts suggest that FXR1 plays a critical role in tumor biology, potentially offering new avenues for therapeutic interventions. This study provides a deeper understanding of FXR1’s involvement in cancer and underscores the importance of RBPs in the post-transcriptional regulatory landscape of cancer progression.
Diarrheal diseases, particularly those caused by rotaviruses, pose a significant health threat, especially among children, and cause huge economic losses to the pig industry in the form of high morbidity, mortality, and stunted growth. Rotavirus A (RVA) remains the predominant viral agent for severe diarrheal episodes, contributing to high hospitalization and mortality rates in India. RVA’s high genetic diversity is attributed to frequent reassortment and mutations. This study aims to characterize the VP4, VP6, VP7, and NSP4 genes of RVA in stool samples collected from children and piglets in and around Bareilly, Uttar Pradesh, India. A total of 300 samples, including 100 from children and 200 from piglets, were screened for the detection of double-stranded RNA of RVA using ribonucleic acid-polyacrylamide gel electrophoresis (RNA-PAGE) and reverse transcription polymerase chain reaction (RT-PCR). Results revealed the RVA incidence, particularly in winter (end of November to beginning of February), aligning with observed seasonal trends. Among the 32 Rotavirus (RV)-positive samples from children, 21 (65.63%) were detected by RNA-PAGE, whereas 28 (87.5%) were identified by RT-PCR. Whereas, of the 80 RT-PCR positive samples from piglets, only 51 (63.75%) were detected by RNA-PAGE, indicating the superiority of RT-PCR. Molecular analysis identified the prevalent genotypes in human strains as G1, G2, G3, and P[8], whereas G9P[13]-I5-E1 dominated among piglets in a single farm outbreak. The findings underscore the critical need for continuous surveillance to monitor evolving RV genotypes from both humans and piglets, enabling the identification of new strains of RVA and subsequent modification of vaccination strategies to reduce RVA’s impact in India.