Search Results (178)

N-Alkyl deoxynojirimycin-derived drugs, belonging to the class of iminosugars, are well-known for their α-glucosidase inhibitory activity. N-Butyl-deoxynojirimycin (N-butyl-DNJ; NB-DNJ; also known as miglustat or UV-1) has been developed for the treatment of type 1 Gaucher disease and Niemann–Pick disease type C as Zavesca^®. Furthermore, it behaves as a host-targeted glucomimetic that inhibits endoplasmic reticulum α-glucosidase I and II (GluI and GluII, respectively) enzymes, resulting in improper glycosylation and misfolding of viral glycoproteins; thus, it is a potential antiviral agent. It is studied against a broad range of viruses in vitro and in vivo; however, its utility as antiviral has not been fully explored. Other N-alkylated congeners of DNJ are in preclinical and clinical studies for diverse viral infections. The iminosugar N-9′-methoxynonyl-1-deoxynojirimycin (MON-DNJ or UV-4) is probably the most studied and potent inhibitor of α-Glu I and α-Glu II in clinical trials. It is often studied in the form of its hydrochloride salt (UV-4B) and has broad-spectrum activity against diverse viruses, including dengue and influenza. In clinical trials, it was found to be safe at all doses tested up to 1000 mg. In this paper, an overview on N-alkyl derivatives of DNJ is reported, focusing on their antiviral activity. The literature search was carried out by means of three literature databases, i.e., PubMed/MEDLINE, Google Scholar, and Scopus, screened using different keywords. A brief history of the discovery of their usefulness as antivirals is given, as well as the most recent studies on new compounds belonging to this class. Since different names are often used for the same compound, we tried to dissipate confusion and bring some order to this jumble of names. Specifically, in the tables, all the diverse names used to identify each compound, were reported. Full article

Rare genetic diseases (RGDs) affect individuals, families, and healthcare systems worldwide. Population-scale genomic data remain largely restricted to Western cohorts with an estimated 10,000 RGDs. South Asian populations remain underrepresented in molecular, clinical, and genomic databases. This study presents the first preliminary molecular genetic characterization of RGDs in the Punjabi population of Pakistan. Data were collected from the provincial RGD registry at the Punjab Thalassemia and Other Genetic Disorders Prevention and Research Institute (PTGDPRI), Lahore. Families diagnosed using next-generation sequencing (NGS) between 2021 and 2023 were enrolled. Structured questionnaires captured clinical, demographic, and socioeconomic information, and statistical and genetic analyses were performed to assess allele frequencies, and disease distribution. The registry included 167 families with 72 distinct RGDs, with a mean burden of 0.81 ± 0.24 affected children per family. Niemann–Pick disease (NP), progressive familial intrahepatic cholestasis (PFIC), and mucopolysaccharidosis (MPS) were the most common diseases. Consanguinity was observed in 89% of families, 77% of which involved first-cousin marriages, and was significantly associated with RGD incidence. Most families belonged to low-income groups despite high literacy rates, underscoring inequity in healthcare. The primary and secondary variants included 131 variants, including copy number variants (CNVs) and single nucleotide variants (SNVs), annotated as pathogenic, likely pathogenic, or variants of unknown significance (VUS) across 109 genes, including 24 South Asian-enriched variants. This study provides the first genomic and epidemiological overview of RGDs in the Punjabi population. The findings reveal how genetic, socioeconomic, and cultural factors converge to amplify the RGD burden and highlight the need for affordable molecular diagnostics, inclusive genomic databases, and regional genomic surveillance initiatives in South Asia. Full article

Lysosomal storage disorders (LSDs) are a group of rare inherited diseases caused by mutations in the genes encoding the proteins involved in normal lysosomal functions, leading to an accumulation of undegraded substrates within lysosomes. Among the most prominent clinical features are neurological impairment and neurodegeneration, arising from widespread cellular dysfunction. The development of powerful and reliable animal model systems that can in vivo recapitulate human LSD pathologies is critical for understanding disease mechanisms and advancing therapeutic strategies. In this study, we identified the Drosophila melanogaster orthologs of human LSD-related genes using the DIOPT tool and performed tissue-specific gene silencing along the brain–midgut axis via the use of GAL4/UAS and RNAi combined technologies. Transgenic fly models presented key features of human LSD pathologies, including significantly shortened lifespans and a progressive locomotor decline that serves as a measure for neuromuscular disintegration, following age- and sex-dependent patterns. These phenotypic parallels in pathology strongly support the functional relevance of the selected orthologs and underscore the value of Drosophila as a versatile in vivo model system for advanced LSD pathology research, offering state-of-the-art genetic tools for molecularly dissecting disease mechanisms and providing cutting-edge novel platforms for high-throughput genetic and/or pharmacological screening, moving towards development of new therapeutically beneficial drug-based regimens and mutant gene-rescue schemes. Full article

Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate immune responses. This review highlights four therapeutic areas where CDs demonstrate particular promise. First, in gene and mRNA therapy, cationic CD derivatives form nanoparticles that protect nucleic acids, promote endosomal escape, and achieve targeted delivery. Second, in neurodegenerative disorders such as Niemann–Pick type C and Alzheimer’s disease, hydroxypropyl-β-CD facilitates cholesterol clearance and reduces pathological lipid accumulation. Third, in detoxification, the γ-CD derivative sugammadex exemplifies a clinically approved agent that encapsulates neuromuscular blockers to reverse anesthesia. Finally, CDs have emerged as safe vaccine adjuvants, inducing robust systemic and mucosal immunity with reduced IgE responses compared to alum. Together, these examples illustrate a paradigm shift: CDs are not only versatile excipients but also active molecules with direct therapeutic effects. Future translation will require careful optimization of safety, scalability, and regulatory compliance, but CDs are poised to contribute meaningfully to next-generation medicines. Full article

Herein we report the very first experiments which were conducted in an attempt to demonstrate the ability of low-field (LF), compact benchtop NMR spectrometers to provide spectral profiles of whole human biofluids, which took place in September–November 2014, and this paper represents a 10-year (decennial) anniversary of this work. LF ¹H NMR analysis was performed on ²H₂O-reconstituted lyophilizates of urine samples (pH 7.00) collected from untreated Niemann-Pick type C1 (NPC1) disease patients and their heterozygous carrier controls (n = 3 in each case). ¹H NMR spectra were acquired on a 60 MHz Oxford Instruments Pulsar compact benchtop spectrometer with spectral filter widths of 5000 Hz, using 1000–1600 scans, and relaxation delays of 15 or 30 s. Further, 400 MHz spectra were also obtained on these samples. Following parameter optimisation, the benchtop system generated reasonable quality urinary ¹H NMR profiles containing ca. 30 signals. Benchtop ¹H NMR analysis confirmed the abnormal urinary metabolic signature of NPC1 disease, and also revealed a gastric permeability disorder in one patient (detection of upregulated urinary sucrose, verified by 400 MHz NMR analysis). Early LF NMR experiments also demonstrated that glucose was trackable in control urine samples pre-spiked with this metabolite. This paper continues with further developments made on LF NMR-based metabolomics technologies, which are systematically discussed for related investigations conducted since 2014. In conclusion, such ‘first-time’ bioanalytical information regarding spectral quality served to pave the way forward for benchtop NMR-based metabolomics investigations of biofluids, which could provide invaluable disease-engendered ‘snapshots’ of disturbances to metabolic pathways and activities, along with those of any co-linked or unlinked comorbidities. Full article

Due to their clinical heterogeneity, nonspecific symptoms, and the limitations of existing biomarkers and imaging modalities, metabolic brain diseases (MBDs), such as mitochondrial encephalopathies, lysosomal storage disorders, and glucose metabolism syndromes, pose significant diagnostic challenges. This review examines the growing potential of cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) epigenetic profiling as a dynamic, cell-type-specific, minimally invasive biomarker approach for MBD diagnosis and monitoring. We review important technological platforms and their use in identifying CNS-specific DNA methylation patterns indicative of neuronal injury, neuroinflammation, and metabolic reprogramming, including cfMeDIP-seq, enzymatic methyl sequencing (EM-seq), and targeted bisulfite sequencing. By synthesizing current findings across disorders such as MELAS, Niemann–Pick disease, Gaucher disease, GLUT1 deficiency syndrome, and diabetes-associated cognitive decline, we highlight the superior diagnostic and prognostic resolution offered by CSF cfDNA methylation signatures relative to conventional CSF markers or neuroimaging. We also address technical limitations, interpretive challenges, and translational barriers to clinical implementation. Ultimately, this review explores CSF cfDNA epigenetic analysis as a liquid biopsy modality. The central objective is to assess whether epigenetic profiling of CSF-derived cfDNA can serve as a reliable and clinically actionable biomarker for improving the diagnosis and longitudinal monitoring of metabolic brain diseases. Full article

Background/Objectives: Niemann-Pick disease Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 100,000 live births that belongs to the lysosomal storage diseases (LSDs). NPC is characterized by the abnormal accumulation of unesterified cholesterol, in addition to being an autosomal recessive inherited pathology, which belongs to LSDs. It occurs in 95% of cases due to mutations in the NPC1 gene, while 5% of cases are due to mutations in the NPC2 gene. In the cerebral cortex (CC), the disease shows lipid inclusions, increased cholesterol and multiple sphingolipids in neuronal membranes, and protein aggregates such as hyperphosphorylated tau, α-Synuclein, TDP-43, and β-amyloid peptide. Mitochondrial damage and oxidative stress are some alterations at the cellular level in NPC. Therefore, the aim of this work was to determine the gene expression profile in the CC of NPC1 mice in order to identify altered molecular pathways that may be related to the pathophysiology of the disease. Methods: In this study, we performed a microarray analysis of a 22,000-gene chip from the cerebral cortex of an NPC mutant mouse compared to a WT mouse. Subsequently, we performed a bioinformatic analysis in which we found groups of dysregulated genes, and their expression was corroborated by qPCR. Finally, we performed Western blotting to determine the expression of proteins probably dysregulated. Results: We found groups of dysregulated genes in the cerebral cortex of the NPC mouse involved in the ubiquitination, fatty acid metabolism, differentiation and development, and underexpression in genes with mitochondrial functions, which could be involved in intrinsic apoptosis reported in NPC, in addition, we found a generalized deregulation in the cortical circadian rhythm pathway, which could be related to the depressive behavior that has even been reported in NPC patients. Conclusions: Recognizing that there are changes in the expression of genes related to ubiquitination, mitochondrial functions, and cortical circadian rhythm in the NPC mutant mouse lays the basis for targeting treatments to new potential therapeutic targets. Full article

Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH. Full article

Background/Objectives: The Niemann–Pick C1 (NPC1) protein regulates cellular cholesterol homeostasis, which is disrupted in hepatocellular carcinoma (HCC). Sex differences in cholesterol metabolism may also be related to NPC1 expression in HCC. A sex-specific analysis was, therefore, performed to investigate this further. Methods: The expression of NPC1 protein in hepatocytes was assessed using immunohistochemistry in HCC tissues from 264 male and 59 female patients, as well as in non-tumor tissues from 41 males and 7 females. Results: The disease etiology was documented for 40% of these patients, and NPC1 protein levels in the tumors of patients with alcoholic, metabolic, and viral liver disease were comparable. The severity of underlying liver fibrosis was similar in both females and males. No difference in hepatocyte NPC1 protein expression was observed between males and females in non-tumor and tumor tissues. However, NPC1 expression was strongly increased in tumor tissues in both sexes. NPC1 protein levels were positively associated with T stage and Union for International Cancer Control (UICC) stage in both sexes. NPC1 protein levels were negatively correlated with overall survival, recurrence-free survival, and metastasis-free survival time in males only. Univariate Cox regression analysis showed a significant association of NPC1 protein levels with metastasis-free survival in males. Positive correlations of NPC1 protein with tumor size and negative associations with tumor inflammation were observed only in women. Conclusions: This study showed that hepatocyte NPC1 protein levels are highly elevated in HCC tissue in both sexes but are more closely associated with survival in male patients than in female patients. Full article

Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann–Pick type C disease (NPCD), where cholesterol export from the endosomal–lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism. Full article

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann–Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases. Full article

Background: Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. Methods: A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann–Pick disease type C, mucopolysaccharidoses and Wolman disease. Results: The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. Conclusions: This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders. Full article

Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction. Full article

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann–Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra^®, Voydeya^®, Iqirvo^®, Voranigo^®, Livdelzi^®, Miplyffa^®, Revuforj^®, and Crenessity^®) are classified as “first-in-class” and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development. Full article

Niemann–Pick Disease Type C (NPC) is a hereditary neurodegenerative disease characterized by selective cell vulnerability, particularly affecting cerebellar anterior Purkinje neurons. These neurons exhibit a distinctive pattern of degeneration due to the loss of NPC1 and/or NPC2 protein function, progressively extending towards posterior cerebellar regions. Our study aimed to explore the early factors influencing this selective vulnerability of anterior Purkinje neurons in NPC. Oxytosis/ferroptosis, a novel form of regulated cell death, has been implicated in neurodegenerative diseases, with its inhibition showing promising therapeutic potential. Our laboratory has previously identified parallels between NPC cellular pathology and ferroptotic markers, including elevated levels of lipid peroxidation and iron, mitochondrial dysfunction, and Ca²⁺ dyshomeostasis. However, whether oxytosis/ferroptosis underlies NPC cellular pathology remains unexplored. We hypothesize that loss of NPC1 function increases vulnerability to ferroptosis and that anti-ferroptotic compounds will reverse NPC cellular pathology. Through bioinformatic analyses of pre-symptomatic Npc1^−/− Purkinje neurons and in vitro studies using primary dermal fibroblasts derived from NPC patients, we provide evidence suggesting that oxytosis/ferroptosis may play a pathogenic role in NPC. These findings highlight the potential of anti-ferroptotic compounds as a promising therapeutic strategy to mitigate neurodegeneration in NPC and potentially other related disorders. Full article