Therapy For Disease Research Articles

Riboflavin kinase binds and activates inducible nitric oxide synthase to reprogram macrophage polarization

Riboflavin kinase (RFK) is essential in riboflavin metabolism, converting riboflavin to flavin mononucleotide (FMN), which is further processed to flavin adenine dinucleotide (FAD). While RFK enhances macrophage phagocytosis of Listeria monocytogenes, its role in macrophage polarization is not well understood. Our study reveals that RFK deficiency impairs M(IFN-γ) and promotes M(IL-4) polarization, both in vitro and in vivo. Mechanistically, RFK interacts with inducible nitric oxide (NO) synthase (iNOS), which requires FMN and FAD as cofactors for activation, leading to increased NO production that alters energy metabolism by inhibiting the tricarboxylic acid cycle and mitochondrial electron transport chain. Exogenous FAD reverses the metabolic and polarization changes caused by RFK deficiency. Furthermore, bone marrow adoptive transfer from high-riboflavin-fed mice into wild-type tumor-bearing mice reprograms tumor-associated macrophage polarization and inhibits tumor growth. These results suggest that targeting RFK-iNOS or modulating riboflavin metabolism could be potential therapies for macrophage-related immune diseases.

Inhaled aptamer therapy: A hopeful therapy for lung disease

Inhaled aptamer therapy: A hopeful therapy for lung disease

Neuro-regeneration or Repair: Cell Therapy of Neurological Disorders as A Way Forward.

The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.

Leveraging Artificial Intelligence for Predictive Healthcare: A Data-Driven Approach to Early Diagnosis and Personalized Treatment

As noted, healthcare delivery systems are systems that always present organizational difficulties for any user and everyone related to these systems, but AI today is one of the widely-discussed and most frequently considered innovations that have prospects for radical improvement of the patient’s state and quality of life. AI solutions are on the verge of becoming integrated into clinical practice thanks to enhanced developments in the field, which means that there is a need to cover the part played by these technologies in healthcare and equip healthcare providers with the knowledge and resources needed to achieve that. This review article provides a broad, although dated, systematic synthesis of AI in clinical practice today, reviewing potential uses of AI in disease taxonomy and diagnosis, treatment suggestions, patient participation, and utilizing methodologies to consider the ethical and legal issues of AI and the persistent need for human insights and expertise. In order to establish the nature of the relationships and possible effects of AI in healthcare environments, the paper reviews the literature using PubMed/Medline, Scopus, and EMBASE databases. According to the findings, the application of AI technologies in health care delivery can greatly improve disease diagnosis, therapy choice, and clinical testing because, in contrast to human decision-making, AI algorithms analyze extensive data sets and outcompete human experts in specific tasks. It is accurate, cost-effective, time efficient, and free from human errors, advances the fields of pharmacogenomics and personalized medicine, optimizes the dosing of drugs, improves overall population health, establishes virtual healthcare services, and enhances mental health care, education, and trust between patients and physicians. Nevertheless, these and the following issues cannot be left unresolved: data privacy, AI bias, and the indispensability of the human factor.

Interplay of gut microbiota, glucagon-like peptide receptor agonists, and nutrition: New frontiers in metabolic dysfunction-associated steatotic liver disease therapy

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Key metabolites, including lipopolysaccharides, short-chain fatty acids (SCFAs), bile acids, and beneficial gut bacteria such as Bifidobacterium and Lactobacillus, are pivotal in this process. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in managing MASLD by promoting weight loss, enhancing insulin secretion, and improving liver health. They restore gut-liver axis functionality, and their effects are amplified through dietary modifications and gut microbiome-targeted therapies. Emerging research highlights the interplay between GLP-1 RAs and gut microbiota, indicating that the gut microbiome significantly influences therapeutic outcomes. Metabolites produced by gut bacteria, can stimulate glucagon-like peptide-1 (GLP-1) secretion, further improving metabolic health. Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway. Future research is needed to understand personalized effects, with prebiotics and probiotics offering treatment avenues for MASLD.

Editorial Expression of Concern: Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy.

Editorial Expression of Concern: Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy.

Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.

Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC-MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.

Transcriptional Responses of Lacticaseibacillus rhamnosus to TNFα, IL-6, IL-8, and IL-10 Cytokines

The interaction between gut microbiota and the host immune system is a complex and understudied field, with cytokines like TNFα, IL-6, IL-8, and IL-10 playing pivotal roles. Commensal bacteria, including lactobacilli, respond to these cytokines through adaptive mechanisms that support their survival and function within the gut. While the influence of cytokines on pathogenic bacteria is well documented, their impact on commensal bacteria, particularly lactobacilli, remains underexplored. This study investigates the transcriptional responses of Lacticaseibacillus rhamnosus strains K32 and R19-3 to various cytokines using next-generation RNA sequencing (RNA-seq). Our findings reveal that cytokines, especially IL-8 and IL-10, significantly alter the L. rhamnosus transcriptome, affecting genes involved in carbohydrate metabolism, stress response, and transcriptional regulation. Notably, IL-8 and IL-10 induce a significant downregulation of genes related to the phosphotransferase system, suggesting a reduction in metabolic activity in response to inflammatory signals. This study unveils a previously unexplored aspect of L. rhamnosus adaptation, highlighting its intricate response to cytokine signals. By modulating gene expression, L. rhamnosus may mitigate the adverse effects of inflammation and promote gut health. These insights could inform the development of targeted probiotic therapies for inflammatory bowel disease (IBD) and other conditions with altered cytokine levels. Our results suggest that co-evolution between a host and gut microbiota enables bacteria to respond to specific cytokines through gene expression changes, revealing a unique and underexplored facet of the interaction between commensal bacteria and the host organism.

Human Tendon-on-a-Chip for Modeling the Myofibroblast Microenvironment in Peritendinous Fibrosis.

Understanding the myofibroblast microenvironment is critical to developing therapies for fibrotic diseases. Here the development of a novel human tendon-on-a-chip (hToC) is reported to model this crosstalk in peritendinous adhesions, which currently lacks biological therapies. The hToC facilitates cellular and paracrine interactions between a vascular component, which contains endothelial cells and monocytes, and a tissue hydrogel component that houses tendon cells and macrophages. It is found that the hToC replicates some aspects of in vivo inflammatory and fibrotic phenotypes in preclinical and clinical samples, including activated mTOR signaling, vascular inflammation, tissue contraction induced by myofibroblast activation, inflammatory cytokines secretion, and transendothelial migration of monocytes to the tissue hydrogel. Transcriptional analysis demonstrates significant overlap in enriched pathways in the hToC with human tenolysis samples, including the activation of mTOR signaling. Rapamycin suppresses the vascular inflammation and fibrotic phenotype in the hToC, which provides proof-of-concept of its utility as an in vitro tool for investigating multicellular crosstalk in fibrosis and testing therapeutics to mitigate it.

Interfacing Complex Coacervates with Natural Cells

Coacervates have been investigated as protocells or synthetic cells, as well as subcellular compartments for the creation of new materials, thus bridging the gap between living and non‐living systems in materials science, synthetic biology, and bioengineering. Given the design flexibility and simplicity of coacervates, along with the functionality and complexity of natural cells, the interfacing of complex coacervates with natural cells is considered significant for various biotechnological and biomedical applications. In this review, the fundamental mechanisms and underlying theories of coacervate systems are introduced. Recent efforts to interface coacervates with natural cells are summarized in three key scenarios: (i) the integration of coacervates with natural cell components for the living material assembly into protocells; (ii) communication between therapeutic synthetic cells and natural cells for drug delivery and cell repair; and (iii) the formation of intracellular condensates for metabolic regulation, followed by the regulation of their phase transitions for pathological elucidation. Finally, the potential of coacervate‐natural cell interfaces is discussed in the context of developing living/synthetic cell constructs, creating precise disease therapy strategies, and advancing programmable metabolic engineering networks.

Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mitochondria mediated by mitophagy-enhanced nanoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.

Stimuli-responsive chitosan based nanoparticles in cancer therapy and diagnosis: A review.

Chitosan, obtained through deacetylation of chitin, has been shown to a promising biopolymer for the development of nano- and micro-particles. In spite of inherent anti-cancer activity of chitosan, the employment of this carbohydrate polymer for the synthesis of nanoparticles opens a new gate in disease therapy. The properties of chitosan including biocompatibility, biodegradability, and modifiability are vital in enhancing these nanoparticles, allowing for improved solubility and interaction with cellular targets. Among the pathological events, cancer has demonstrated an increase in incidence rate and therefore, the chitosan nanoparticles have been significantly utilized in cancer therapy. The present review emphasizes on the role of stimuli-responsive chitosan nanoparticles in the field of cancer therapy. The stimuli-responsive nanoparticles can release the cargo in the tumor site that not only improves the anti-cancer activity of chemotherapy drugs, but also diminishes their systemic toxicity. The stimuli-responsive chitosan nanoparticles can respond to endogenous and exogenous stimuli including pH, redox and light to release cargo. This improves the specificity towards tumor cells and enhances accumulation of drugs and/or drugs. The light-responsive chitosan nanoparticles can cause photothermal and photodynamic therapy in tumor ablation and provide theranostic feature that is cancer diagnosis and therapy simultaneously.

Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

Harnessing the therapeutic potential of exercise in extracellular vesicle-based therapy in metabolic disease associated cardiovascular complications.

Cardiovascular disease (CVD) is a leading cause of mortality, affecting ∼18 million individuals each year. Obesity and type 2 diabetes mellitus in particular, both chronic metabolic disorders, are risk factors for CVD. The salutary effects of physical activity in preventing and ameliorating CVD have long been acknowledged, as it improves glucose and lipid homeostasis, alongside attenuating oxidative damage, increasing mitochondrial function, and ultimately improving cardiac function. Exercise serves as a catalyst for the secretion of extracellular vesicles (EVs), facilitating inter-tissue communication, by which tissues can deliver important signals from one tissue to another. In recent years, an increasing number of studies have focused on the cargo encapsulated within exercise-derived EVs, as well as the orchestration of inter-tissue crosstalk aimed at modulating metabolism and tissue function in CVDs. The precise mechanisms underpinning the cardioprotective properties of exercise-derived EVs, however, remains only partially elucidated. This review explores novel EV based therapeutic options in CVD and, in particular, EVs derived from models of exercise to alter metabolism and enhance cardiovascular outcomes.

Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of 10, a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD. 10 was optimized from a phenotypic screening hit utilizing insights from X-ray crystallography and computational modeling to improve potency, selectivity and in vivo exposure. In an hNBSGW mouse xenograft model, 10 demonstrated robust WIZ degradation and HbF induction. These results highlight the potential of WIZ degraders as a promising therapy for sickle cell disease.

Synergy between pluripotent stem cell-derived macrophages and self-renewing macrophages: Envisioning a promising avenue for the modelling and cell therapy of infectious diseases.

As crucial phagocytes of the innate immune system, macrophages (Mϕs) protect mammalian hosts, maintain tissue homeostasis and influence disease pathogenesis. Nonetheless, Mϕs are susceptible to various pathogens, including bacteria, viruses and parasites, which cause various infectious diseases, necessitating a deeper understanding of pathogen-Mϕ interactions and therapeutic insights. Pluripotent stem cells (PSCs) have been efficiently differentiated into PSC-derived Mϕs (PSCdMϕs) resembling primary Mϕs, advancing the modelling and cell therapy of infectious diseases. However, the mass production of PSCdMϕs, which lack proliferative capacity, relies on large-scale expansions of PSCs, thereby increasing both costs and culture cycles. Notably, Mϕs deficient in the MafB/c-Maf genes have been reported to re-enter the cell cycle with the stimulation of specific growth factor cocktails, turning into self-renewing Mϕs (SRMϕs). This review summarizes the applications of PSCdMϕs in the modelling and cell therapy of infectious diseases and strategies for establishing SRMϕs. Most importantly, we innovatively propose that PSCs can serve as a gene editing platform to creating PSC-derived SRMϕs (termed PSRMϕs), addressing the resistance of Mϕs against genetic manipulation. We discuss the challenges and possible solutions in creating PSRMϕs. In conclusion, this review provides novel insights into the development of physiologically relevant and expandable Mϕ models, highlighting the enormous potential of PSRMϕs as a promising avenue for the modelling and cell therapy of infectious diseases.

Mediterranean diet as an element of treatment and prevention of cardiovascular diseases

Currently, the issues of treatment and prevention of cardiovascular diseases are still relevant, as cardiovascular pathology remains one of the leading causes of disability and mortality in all developed countries of the world. In the Russian Federation there is a high incidence of the diseases of the circulatory system, so they have the top priority among health problems, despite a slight decrease in morbidity in recent years. The main purpose of this review is to study the experience of applying the Mediterranean diet and its components in therapy and prevention of cardiovascular pathology. Research method: we searched electronic databases PubMed, Scopus, Web of Science, MedLine, Science Direct and eLIBRARY.RU using the following terms: "Mediterranean diet", "cardiovascular diseases", "prevention of cardiovascular diseases", "diet therapy of cardiovascular diseases". On the basis of numerous world clinical studies analysis, it can be assumed that the Mediterranean diet is one of the most reliable and well-studied in terms of prevention of cardiovascular pathology. The aim of this review is to draw the attention of the medical community to such a long-known, extensively studied, scientifically confirmed, accessible and simple way of rationalizing daily nutrition as the consumption of elements of the Mediterranean diet in the daily one. Further wide informing of patients about this way of nutrition from different specialists (general practitioners, cardiologists, nutritionists, gerontologists and others) is required.

A systematic review of progenitor survival and maturation in Parkinsonian models

Stem cell–based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source. Unlike current therapeutic options for patients, this approach has the potential to provide long-term stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients. The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain. Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies, the aim of this systematic review was to assess these parameters in human stem cell–derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease. A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024. After screening, 76 articles were included in the analysis from which 178 separate transplant studies were identified. From these, graft survival could be assessed in 52 studies and differentiation in 129 studies. Overall, we found that graft survival ranged from < 1% to 500% of cells transplanted, with a median of 51% of transplanted cells surviving in the brain; while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%. This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell–derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.

Abstract B072: Molecular targets of caffeine in breast cancer treatment: A network pharmacology approach

Abstract In Ghana, breast cancer leads in female cases (31.8%), demanding advanced treatments. Rising caffeine-filled energy drinks raise concerns. Yet, caffeine's role in breast cancer lacks understanding, urging more research. Our study uses network pharmacology and molecular docking to unravel the intricate molecular targets of caffeine in breast cancer, offering new therapies for this widespread disease We identified breast cancer-related targets from GEO datasets and TCGA databases, while caffeine targets were obtained from the SwissTarget Prediction database and literature. Common targets of both caffeine and breast cancer were considered using Venny software. PPI networks were generated using STRING and Cytoscape, identifying hub genes. Target proteins were annotated using the GO database, and pathway enrichment analysis was performed using KEGG. To investigate the binding affinity target proteins were retrieved from the Protein DataBank and docking studies were conducted using AutoDock Vina to explore the binding interactions between caffeine and potential target proteins identified. We identified 108 targets, and 6 common targets, including Cyclin-Dependent Kinase 1, Cyclin B1, Epidermal Growth Factor Receptor, Cyclin B2, Monoamine Oxidase A, and Carbonic Anhydrase 12 in relation to breast cancer. Gene Ontology (GO) and KEGG pathway enrichment analysis revealed their interactions in key pathways such as the P53 signaling pathway and Foxo signaling pathway, suggesting their critical roles in anti-breast cancer processes. Notably, caffeine exhibited the best overall binding affinity when interacting with CDK1, CCNB1, EGFR, and CCNB2 These findings provide valuable insights into the potential molecular targets and pathways associated with caffeine's anti-breast cancer effects, offering new strategies for therapeutic strategies. Citation Format: Kingsley A Osei, Justina S Owusu. Molecular targets of caffeine in breast cancer treatment: A network pharmacology approach [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B072.

MnNi@PVP Nanoenzyme Based on Regulating Inflammation and Immune Homeostasis for the Therapy of Inflammatory Bowel Disease.

Nanozymes exhibiting remarkable antioxidant capabilities represent an effective therapeutic approach for ulcerative colitis (UC). This study synthesized the MnNi@PVP nanoenzyme through high-temperature pyrolysis and the NaCl template method, which exhibited multienzyme activity comprising glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). This study investigated the therapeutic effect of MnNi@PVP on colitis caused by sodium dextran sulfate (DSS). The findings indicated that MnNi@PVP notably decreased the disease activity index (DAI) score, which encompasses weight loss, colon shortening, and histopathological changes. MnNi@PVP showed effectiveness in addressing oxidative damage and suppressing the levels of proinflammatory markers, such as tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), and interleukin (IL)-6, by inactivating the TLR4 pathway and macrophages. In addition, MnNi@PVP demonstrated the ability to repair tight junction proteins (occludin and ZO-1) and restore the intestinal barrier. The transcriptome sequencing demonstrated that MnNi@PVP could regulate inflammatory factor expression pathways and immune processes. Additionally, negatively charged MnNi@PVP can selectively bind to inflamed colonic tissues through electrostatic interactions, endowing it with targeted reparative capabilities at the location of intestinal inflammation. The MnNi@PVP, which possesses the reactive oxygen and nitrogen species (RONS) clearance capability examined in this section, is expected to provide the basis for the targeted repair of intestinal function.