Therapy For Disease Research Articles

Dynamic chest radiographic evaluation of the effects of tiotropium/olodaterol combination therapy in chronic obstructive pulmonary disease: the EMBODY study protocol for an open-label, prospective, single-centre, non-controlled, comparative study

IntroductionTo date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that...

Electrochemical Label-free Methods for Ultrasensitive Multiplex Protein Profiling of Infectious Diseases.

Electrochemical detection methods are the more appropriate detection methods when it comes to the sensitive and specific determination of biomarkers. Biomarkers are the biological targets for disease diagnosis and monitoring. This review focuses on recent advances in label-free detection of biomarkers for infectious disease diagnosis. The current state of the art for rapid detection of infectious diseases and their clinical applications and challenges were discussed. Label-free electroanalytical methods are probably the most promising means to achieve this. We are currently in the early stages of the emerging technology of using label-free electrochemistry of proteins to develop biosensors. To date, antibody-based biosensors have been intensively developed, although many improvements in reproducibility and sensitivity are still needed. Moreover, there is no doubt that a growing number of aptamers and hopefully label-free biosensors based on nanomaterials will soon be used for disease diagnosis and therapy monitoring. And also here in this review article, we have discussed recent developments in the diagnosis of bacterial and viral infections, as well as the current status of the use of label-free electrochemical methods for monitoring inflammatory diseases.

Comprehensive macro and micro views on immune cells in ischemic heart disease.

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6+ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.

COVID-19 vaccination in patients with classic and variant hairy cell leukemia

Patients with the B-cell malignancy hairy cell leukemia (HCL) and the poorer-prognosis variant HCLv often receive treatments including anti-CD20 monoclonal antibodies (Mabs) which kill normal B-cells, impairing humoral immunity. To study humoral immunity in HCL/HCLv, we measured COVID-19 antibodies after doses of COVID-19 vaccine in patients after different treatments. Patients with HCL (n=415) and HCLv (n=32) were studied. Total immunoglobulin levels were also determined. After the 2nd COVID-19 vaccine dose, spike antibody level most strongly correlated with normal B-cell levels (r=0.365, p<0.0001), followed by CD4+ T-cell count (r=0.244, p=0.0002), and was less related to immunoglobulin G (IgG) level (r=0.101, p=0.14). Spike antibody levels also correlated with normal B-cells after the 3rd to 5th vaccine doses and with CD4+ T-cell count after the 3rd dose. Normal B and CD4+ T-cell levels were interrelated. Normal B-cells were undetectable in 87% of 38 patients within 6 months after the last dose of anti-CD20 Mab and were lower than in patients at 6-12 months (p=0.0003), which in turn were lower than at 12-18 months (p=0.0002). Infection with COVID-19 became more common after use of the 3rd vaccine dose; spike antibody levels were higher in patients with prior infection (positive vs negative nucleocapsid antibodies) (p<0.0001). Spike antibodies decreased with a median half-life of 53 days, faster after ibrutinib or anti-CD20 MAb. We conclude that decreased levels of normal B-cells in HCL/HCLv patients, due to disease and/or anti-CD20 therapy, are associated with lower COVID-19 vaccination efficiency and such patients may not respond well to vaccines. The associated studies are registered at www.clinicaltrials.gov as NCT01087333 (HCL/HCLv) and NCT04362865 (COVID-19).

Nanoparticles as a Novel Platform for Cardiovascular Disease Diagnosis and Therapy.

Cardiovascular disease (CVD) is a major global health issue with high mortality and morbidity rates. With the advances in nanotechnology, nanoparticles are receiving increasing attention in diagnosing and treating CVD. Previous studies have explored the use of nanoparticles in noninvasive diagnostic technologies, such as magnetic resonance imaging and computed tomography. Nanoparticles have been extensively studied as drug carriers and prognostic factors, demonstrating synergistic efficacy. This review summarized the current applications of nanoparticles in CVD and discussed their opportunities and challenges for further exploration.

Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria

Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing it. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.

Photocleavable Guide RNA for Photocontrolled CRISPR/Cas9 System

Objective: The development of CRISPR/Cas-based gene-editing systems having a higher efficacy and specificity, and capable of changing activity in response to light irradiation is an urgent problem. A promising approach to this problem is to modify CRISPR/Cas components, in particular guide RNA, by introducing photocleavable linkers. We developed an approach to the synthesis of photocleavable single guide RNA (sgRNA) for the CRISPR/Cas9 system containing linkers on the basis of 1-(2-nitrophenyl)-1,2-ethanediol. Such photomodified guide RNAs are cleaved under UV irradiation, thereby inactivating the CRISPR/Cas9 system. Methods: Automatic solid-phase phosphoramidate method was used for photomodified sgRNA synthesis. Model plasmid was used for designed system testing. Results and Discussion: We obtained three variants of photomodified sgRNA with different photolinker positions. Evidence was obtained showing that the sgRNA with the photolinker introduced in the protein Cas9 site of binding and hairpin formation is able to effectively guide Cas9 nuclease for target DNA cleavage before UV irradiation and lose its activity after irradiation. The conditions of controllable 40% cleavage of a model target DNA were chosen. Conclusions: The work presents the results of photocleavable sgRNA design and usage as a component of photoregulated CRISPR/Cas9 system. The developed approach makes possible specific inactivation of the CRISPR/Cas9 gene editing system in a specific time moment in a definite place. The photoregulation of the gene-editing system not only allows one to reduce undesirable off-target effects, but also forms the basis for genetic disease therapy.

Comparative in silico analysis of CNS-active molecules targeting the blood-brain barrier choline transporter for Alzheimer's disease therapy.

The online version contains supplementary material available at 10.1007/s40203-024-00245-w.

Evaluation of the pharmacoeconomical effectiveness of triple therapy of chronic obstructive pulmonary disease in employees at the large transport company

Evaluation of the pharmacoeconomical effectiveness of triple therapy of chronic obstructive pulmonary disease in employees at the large transport company

Beyond Amyloid-β: Reevaluating Its Physiological Role to Find Safe Therapies Against Alzheimer's Disease.

This commentary critically examines the long-standing emphasis on amyloid-β (Aβ)-based therapies in Alzheimer's disease (AD), despite numerous clinical trial failures. It highlights the urgency to reassess research methodologies and challenges the initiation of anti-Aβ trials in preclinical stages of the disease without conclusive proofs of their safety and efficacy. Instead, a comprehensive approach that considers Aβ's physiological roles and addresses AD complex nature is suggested, encouraging the idea that clinical trial failures may result from targeting the wrong mechanism. Evidence-based scientific research is needed to advance with AD treatment, moving beyond the current conception of Aβ hypothesis.

Impulse control disorders in Parkinson’s disease: a national Swedish registry study on high-risk treatments and vulnerable patient groups

BackgroundImpulse control disorders (ICDs) are known psychiatric conditions in Parkinson’s disease (PD), especially as a side effect of antiparkinsonian therapy. Screening for vulnerable patients and avoiding high-risk treatments can be...

Biopolymeric Insulin Membranes for Antimicrobial, Antioxidant, and Wound Healing Applications.

Delayed wound healing increases the wound's vulnerability to possible infections, which may have lethal outcomes. The treatments available can be effective, but the urgency is not fully encompassed. The drug repositioning strategy proposes effective alternatives for enhancing medical therapies for chronic diseases. Likewise, applying wound dressings as biodegradable membranes is extremely attractive due to their ease of application, therapeutic effectiveness, and feasibility in industrial manufacturing. This article aims to demonstrate the pleiotropic effects during insulin repositioning in wound closure by employing a biopolymeric membrane-type formulation with insulin. We prepared biopolymeric membranes with sodium alginate cross-linked with calcium chloride, supported in a mixture of xanthan gum and guar gum, and plasticized with glycerol and sorbitol. Human insulin was combined with poloxamer 188 as a protein stabilizing agent. Our investigation encompassed physicochemical and mechanical characterization, antioxidant and biological activity through antibacterial tests, cell viability assessments, and scratch assays as an in vitro and in vivo wound model. We demonstrated that our biopolymeric insulin membranes exhibited adequate manipulation and suitable mechanical resistance, transparency, high swelling capability (1100%), and 30% antioxidant activity. Furthermore, they exhibited antibacterial activity (growth inhibition of S. aureus at 85% and P. aeruginosa at 75%, respectively), and insulin promoted wound closure in vitro with a 5.5-fold increase and 72% closure at 24 h. Also, insulin promoted in vivo wound closure with a 3.2-fold increase and 92% closure at 10 days compared with the groups without insulin, and this is the first report that demonstrates this therapeutic effect with two administrations of 0.7 IU. In conclusion, we developed a multifunctional insulin-loaded biopolymeric membrane in this study, with the main activity derived from insulin's role in wound closure and antioxidant activity, augmented by the antimicrobial effect attributed to the polymer poloxamer 188. The synergistic combination of excipients enhances its usefulness and highlights our innovation as a promising material in wound healing materials.

Human induced pluripotent stem cells (NIHTVBi029-A and NIHTVBi030-A) generated from two patients with a heterozygous mutation in the CDC42 gene

Induced pluripotent stem cells (iPSCs) were successfully generated from peripheral blood mononuclear cells obtained from two patients with a heterozygous mutation in the CDC42 gene. Both iPSC lines expressed pluripotency markers, differentiated into the three germ layers in vitro, showed normal karyotypes, and retained the disease-causing mutation. Created iPSC lines and their differentiated derivatives may be of interest in the study of the physiology of disease mechanisms and therapy.

Advanced Bioinspired Multifunctional Platforms Focusing on Gut Microbiota Regulation.

Gut microbiota plays a crucial role in maintaining host homeostasis, impacting the progression and therapeutic outcomes of diseases, including inflammatory bowel disease, cancer, hepatic conditions, obesity, cardiovascular pathologies, and neurologic disorders, via immune, neural, and metabolic mechanisms. Hence, the gut microbiota is a promising target for disease therapy. The safety and precision of traditional microbiota regulation methods remain a challenge, which limits their widespread clinical application. This limitation has catalyzed a shift toward the development of multifunctional delivery systems that are predicated on microbiota modulation. Guided by bioinspired strategies, an extensive variety of naturally occurring materials and mechanisms have been emulated and harnessed for the construction of platforms aimed at the monitoring and modulation of gut microbiota. This review outlines the strategies and advantages of utilizing bioinspired principles in the design of gut microbiota intervention systems based on traditional regulation methods. Representative studies on the development of bioinspired therapeutic platforms are summarized, which are based on gut microbiota modulation to confer multiple pharmacological benefits for the synergistic management of diseases. The prospective avenues and inherent challenges associated with the adoption of bioinspired strategies in the refinement of gut microbiota modulation platforms are proposed to augment the efficacy of disease treatment.

TGFβ-mediated inhibition of hypodermal adipocyte progenitor differentiation promotes wound-induced skin fibrosis.

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4+Ly6A+THY1+ hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFβ pathway signature. TGFβ was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFβ receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFβ pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFβ-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases.

Linalool and Geraniol Defend Neurons from Oxidative Stress, Inflammation, and Iron Accumulation in In Vitro Parkinson's Models.

Parkinson's disease is one of the most prevalent neurological disorders affecting millions of people worldwide. There is a growing demand for novel and natural substances as complementary therapies. Essential oils and their various compounds are highly investigated natural plant-based products as potential treatment options for common human diseases, such as microbial infections, chronic diseases, and neurodegenerative disorders. The present study focuses on the beneficial effects of linalool and geraniol, the major compounds of lavender (Lavandula angustifolia L.) and geranium (Pelargonium graveolens L'Hér. in Aiton) essential oils, on oxidative stress, inflammation, and iron metabolism of the rotenone and 6-hydroxydopamine-induced in vitro Parkinson's models. The experiments were carried out on all-trans retinoic acid differentiated SH-SY5Y cells. The effects of linalool and geraniol were compared to rasagiline, an MAO-B inhibitor. The results revealed that both essential oil compounds reduce the level of reactive oxygen species and alter the antioxidant capacity of the cells. They lower the secretion of IL-6, IL-8, and IL-1β pro-inflammatory cytokines. Moreover, linalool and geraniol change the expression of iron-related genes, such as the iron importer transferrin receptor 1, heme-oxygenase-1, and ferroportin iron exporter, and influence the intracellular iron contents. In addition, it has been unveiled that iron availability is concatenated with the actions of the essential oil compounds. Based on the results, linalool and geraniol are vigorous candidates as an alternative therapy for Parkinson's disease.

Scenarios for the long-term efficacy of amyloid-targeting therapies in the context of the natural history of Alzheimer's disease.

Recent clinical trials of amyloid beta (Aβ)-targeting therapies in Alzheimer's disease (AD) have demonstrated a clinical benefit over 18 months, but their long-term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long-term scenarios. Results from recent phase 3 trials of Aβ-targeting antibodies were integrated with an estimate of the long-term patient-level natural history trajectory of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score to explore realistic long-term efficacy scenarios. Three distinct long-term efficacy scenarios were examined, ranging from conservative to optimistic. These extrapolations of positive phase 3 trials suggested treatments delayed onset of severe dementia by 0.3 to 0.6 years (conservative), 1.1 to 1.9 years (intermediate), and 2.0 to 4.2 years (optimistic). Our study provides a common language for long-term impact of disease-modifying treatments. Our work calls for studies with longer follow-up and results from early intervention trials to provide a comprehensive assessment of these therapies' true long-term impact. We present long-term scenarios of the efficacy of AD therapies. In this framework, scenarios are defined relative to the natural history of AD. Long-term projections with different levels of optimism can be compared. It provides a common language for expressing beliefs about long-term efficacy.

Micro/Nanomotor-Driven Intelligent Targeted Delivery Systems: Dynamics Sources and Frontier Applications.

Micro/nanomotors represent a promising class of drug delivery carriers capable of converting surrounding chemical or external energy into mechanical power, enabling autonomous movement. Their distinct autonomous propulsive force distinguishes them from other carriers, offering significant potential for enhancing drug penetration across cellular and tissue barriers. A comprehensive understanding of micro/nanomotor dynamics with various power sources is crucial to facilitate their transition from proof-of-concept to clinical application. In this review, micro/nanomotors are categorized into three classes based on their energy sources: endogenously stimulated, exogenously stimulated, and live cell-driven. The review summarizes the mechanisms governing micro/nanomotor movements under these energy sources and explores factors influencing autonomous motion. Furthermore, it discusses methods for controlling micro/nanomotor movement, encompassing aspects related to their structure, composition, and environmental factors. The remarkable propulsive force exhibited by micro/nanomotors makes them valuable for significant biomedical applications, including tumor therapy, bio-detection, bacterial infection therapy, inflammation therapy, gastrointestinal disease therapy, and environmental remediation. Finally, the review addresses the challenges and prospects for the application of micro/nanomotors. Overall, this review emphasizes the transformative potential of micro/nanomotors in overcoming biological barriers and enhancing therapeutic efficacy, highlighting their promising clinical applications across various biomedical fields.

IL-10-modulated dendritic cells from birch pollen- and hazelnut-allergic patients facilitate Treg-mediated allergen-specific and cross-reactive tolerance.

Approximately 70% of individuals allergic to birch pollen (Bet v 1.01 [Bet]) develop a secondary food allergy (e.g., hazelnut: Cor a 1.04 [Cor]), due to allergen cross-reactivity. However, standard immunotherapy for type I allergies often does not improve the food allergy sufficiently. We analyzed the allergen-specific and cross-reactive suppressive capacity of primary human regulatory T cells (Treg) induced by autologous IL-10-modulated dendritic cells (IL-10 DC) invitro and invivo. CD4+ T cells of patients with birch pollen and associated hazelnut allergies were differentiated into Bet-specific or non-specific induced Treg (iTreg). After Bet- or Cor-specific restimulation the phenotype, proliferation, and suppressive capacity of iTreg subsets were analyzed. iTreg function was further investigated in humanized mouse models of airway and intestinal allergy, generated by engraftment of peripheral blood mononuclear cells from allergic donors into immunodeficient animals. After IL-10 DC priming and allergen-specific restimulation (Bet or Cor), non-specific control iTreg remained anergic, whereas Bet-specific iTreg proliferated extensively and exhibited a regulatory phenotype (enhanced expression of CTLA-4, PD-1, TNFR2, IL-10). Accordingly, activated Bet-specific iTreg displayed a high capacity to suppress Bet- and Cor-induced responder Th2 cell responses invitro, indicating induction of both allergen-specific (birch) and cross-reactive tolerance (hazelnut). Invivo, the beneficial effect of Bet-specific iTreg was verified in humanized mouse models of allergic airway and intestinal inflammation, resulting in reduced allergen-induced clinical symptoms, and immune responses. Human IL-10 DC-induced iTreg facilitate allergen-specific and cross-reactive tolerance. Therefore, they are potential candidates for regulatory cell therapy in allergic and autoimmune diseases.

Calcium isotope composition in serum and urine for the assessment of bone mineral balance (BMB) – The Osteolabs post-market follow-up study

To further explore the clinical applicability of the calcium (Ca) isotope marker (CIM), we determined the 44Ca/42Ca isotope ratio in blood serum and urine. This ratio is expressed in the conventional δ-notation (as defined in the text below) specifically as CIM-serum for serum and as CIM-urine for urine. Our study tested the hypothesis that CIM values can differentiate between positive and negative bone mineral balance (BMB) across a diverse clinical population considering variables such as age, gender, and diet. The threshold values (CIM-serum: −0.85 ± 0.06 ‰ and CIM-urine: 0.23 ± 0.06 ‰) established in the OsteoGeo study (NCT02967978, Eisenhauer et al., 2019) were evaluated in 2320 participants as part of a surveillance study referred to as Osteolabs study. The earlier study revealed women with osteoporosis had an average CIM-serum value of −0.91 ± 0.21 ‰ (N = 24) and a CIM-urine value of 0.18 ± 0.33 ‰ (N = 71) that are significantly below the threshold values (p = 0.02 for urine, one-sided Wilcoxon rank test, p < 0.001 for serum, one-sided Student's t-test). Diseases affecting BMB such as osteoporosis, acute and chronic kidney disease (CKD), hyperthyroidism, breast cancer, prostate cancer, and myeloma were associated with significantly lower average CIM values, falling below the equilibrium thresholds and indicating negative BMB. In contrast, patients receiving osteoprotective treatments such as denosumab, Romosozumab, bisphosphonates, or hormone replacement therapy for certain diseases, had CIM values above the equilibrium thresholds indicating a positive BMB. Additionally, Ca supplements taken by some of the patients ((N = 22 (serum), N = 49 (urine), median dose: 500 mg) showed a Ca isotope composition approximately 1 ‰ higher than that from a normal diet. Consequently, their CIM values need to be adjusted to account for the amount and duration of supplementation to be comparable to those with a normal diet. Participants taking vitamin D (237 women; 58 men) showed no significant difference from the average values of the study group. Counterintuitively, the possible impact of malnutrition on individual BMB was most pronounced in vegans, who exhibited the highest average CIM-urine values compared to patients on a normal diet (p < 0.001, N = 17). The results of this study were consistent with the registered OsteoGeo study (NCT02967978) and other earlier published Ca isotope-based studies on BMB. We confirm that the CIM threshold values determined in the OsteoGeo study are generally valid for this much larger and diverse surveillance study group covering a diverse population encompassing various medical conditions and therapies.