Therapy For Disease Research Articles

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.

Brown fat-specific mitoribosomal function is crucial for preventing cold exposure-induced bone loss

This study examines the interplay between ambient temperature, brown adipose tissue (BAT) function, and bone metabolism, emphasizing the effects of cold exposure and BAT mitochondrial activity on bone health. Utilizing ovariectomized (OVX) mice to model primary osteoporosis and BAT-specific mitochondrial dysfunction (BKO) mice, we evaluated the impact of housing temperature on bone density, immune modulation in bone marrow, and the protective role of BAT against bone loss. Cold exposure was found to universally reduce bone mass, enhance osteoclastogenesis, and alter bone marrow T-cell populations, implicating the immune system in bone remodeling under cold stress. The thermogenic function of BAT, driven by mitochondrial oxidative phosphorylation, was crucial in protecting against bone loss. Impaired BAT function, through surgical removal or mitochondrial dysfunction, exacerbated bone loss in cold environments, highlighting BAT’s metabolic role in maintaining bone health. Furthermore, cold-induced changes in BAT function led to systemic metabolic shifts, including elevated long-chain fatty acids, which influenced osteoclast differentiation and activity. These findings suggest a systemic mechanism connecting environmental temperature and BAT metabolism with bone physiology, providing new insights into the metabolic and environmental determinants of bone health. Future research could lead to novel bone disease therapies targeting these pathways.

Restoring the acidifying function of lysosomes for Alzheimer's disease therapy

Restoring the acidifying function of lysosomes for Alzheimer's disease therapy

The history and status of dopamine cell therapies for Parkinson's disease.

Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.

Biocompatible and nondegradable microcapsules using an ethylamine-bridged EGCG dimer for successful therapeutic cell transplantation

Conventional alginate microcapsules are widely used for encapsulating therapeutic cells to reduce the host immune response. However, the exchange of monovalent cations with divalent cations for crosslinking can lead to a sol-gel phase transition, resulting in gradual degradation and swelling of the microcapsules in the body. To address this limitation, we present a biocompatible and nondegradable epigallocatechin-3-gallate (EGCG)-based microencapsulation with ethylamine-bridged EGCG dimers (EGCG(d)), denoted as ‘Epi-Capsules’. These Epi-Capsules showed increased physical properties and Ca2+ chelating resistance compared to conventional alginate microcapsules. Horseradish peroxidase (HRP) treatment is very effective in increasing the stability of Epi-Capsule((+)HRP) due to the crosslinking between EGCG(d) molecules. Interestingly, the Epi-Capsules(oxi) using a pre-oxidized EGCG(d) can support long-term survival (>90 days) of xenotransplanted insulin-secreting islets in diabetic mice in vivo, which is attributed to its structural stability and reactive oxygen species (ROS) scavenging for lower fibrotic activity. Collectively, this EGCG-based microencapsulation can create Ca2+ chelating-resistance and anti-oxidant activity, which could be a promising strategy for cell therapies for diabetes and other diseases.

AYURVEDIC PERSPECTIVES ON MANAGING PAMA KUSHTHA (SCABIES) IN CHILDREN: A COMPREHENSIVE REVIEW

Skin diseases are considered a serious health problem in children because they cause discomfort and considerable morbidity. Dermatological disorders account for nearly one-third of all paediatric outpatient appointments. Scabies is a frequent skin infestation caused by tiny mites known as "Sarcoptes scabiei." It is very contagious and typically spreads through skin-to-skin contact with someone who is already afflicted. Almost all skin problems in Ayurveda are explained by the wide term "Kushtha." Pama can be correlated with scabies, which is one type of Kshudra Kushtha as described in the classics. Because it is highly contagious, it spreads swiftly in crowded environments. The scabies rash can lead to cellulitis, folliculitis, boils, and impetigo. It was discovered that "Pama" Vyadhi It has been found that "Pama" vyadhi is one of the most prevalent diseases seen at lower socioeconomic levels and occurs in unsanitary individuals. This paper explored Pama disease diagnosis and therapy using in Ayurveda.

FDA approval of casgevy and lyfgenia: A dual breakthrough in gene therapies for sickle cell disease

FDA approval of casgevy and lyfgenia: A dual breakthrough in gene therapies for sickle cell disease

Nanochannels-based self-correction electrochemical detection of mucin 1 with in-situ generated phosphomolybdic acid

Accurate detection of cancer biomarkers like mucin 1 (MUC-1) is significantly important for diagnosis and prognosis of tumor. Herein, a self-correction electrochemical immunoassay for MUC-1 detection was developed based on bioinspired nanochannels and electrochemistry of molybdophosphate. MUC-1 can be captured in the bioinspired polymer nanochannels via the formation of immunocomplex. Then, diffusion of MoO42− in the nanochannels would be sterically hindered and the in-situ generation of phosphomolybdic acid onto the electrode surface which was modified with phosphate chitosan hydrogel, would be influenced. Therefore, the two well-defined redox peaks of phosphomolybdic acid can be applied to the detection of the antigen. To improve detection sensitivity, the phosphate chitosan was incorporated with carbon nanotubes. Moreover, the occurrence in nanochannels was amplified by hybridization chain reaction, which enhanced the hindrance for transport of MoO42− by increasing steric effect, electrostatic repulsion as well as anchoring sites. Under optimized conditions, currents of the both anodic peaks on square wave voltametric voltammograms decreased linearly with the logarithm of the concentration of MUC-1 ranging from 10 fg∙mL−1 to 100 ng∙mL−1 with a detection limit of 6.0 fg∙mL−1. And thus, the detection results can be self-corrected by the results acquired from the two peaks, which had valuable implications for the reliable MUC-1 detection in disease diagnosis and therapy application.

Exploring the Relationship Between Sporadic Creutzfeldt-Jakob Disease and Gut Microbiota Through a Mendelian Randomization Study.

Observational studies have shown gut microbiota changes in sporadic Creutzfeldt-Jakob disease patients, but the causal relationship remains unknown. We aimed to determine any causal links between gut microbiota and this prion disease. Using Mendelian randomization analysis, we examined the causal relationship between gut microbiota composition and sporadic Creutzfeldt-Jakob disease. Data on gut microbiota (N = 18,340) and disease cases (5208) were obtained. Various analysis methods were used, including inverse variance weighted, Mendelian randomization-Egger, weighted median, simple mode, and weighted mode. In addition, MR-PRESSO was used to evaluate horizontal pleiotropy and detect outliers. Pleiotropy and heterogeneity were assessed, and reverse analysis was conducted. Negative associations were found between sporadic Creutzfeldt-Jakob disease and family Defluviitaleaceae, family Ruminococcaceae, genus Butyricicoccus, genus Desulfovibrio, and genus Eubacterium nodatum. Genus Lachnospiraceae UCG010 showed a positive correlation. Reverse analysis indicated genetic associations between the disease and decreased levels of family Peptococcaceae, genus Faecalibacterium, and genus Phascolarctobacterium, as well as increased levels of genus Butyrivibrio. No pleiotropy, heterogeneity, outliers, or weak instrument bias were observed. This study revealed bidirectional causal effects between specific gut microbiota components and sporadic Creutzfeldt-Jakob disease. Certain components demonstrated inhibitory effects on disease pathogenesis, while others were positively associated with the disease. Modulating gut microbiota may provide new insights into prion disease therapies. Further research is needed to clarify mechanisms and explore treatments for sporadic Creutzfeldt-Jakob disease.

Role and Mechanisms of Tyro3 in podocyte biology and glomerular disease

Background: Podocyte loss occurs in both primary and secondary glomerular diseases, leading to the progression of kidney disease. A large body of evidence suggests that apoptosis and detachment are the mechanisms mediating the reduction in podocyte numbers in glomerular diseases. Recent studies demonstrate a renal protective effect of Protein S (PS) through the activation of Tyro3, one of the TAM receptors. Tyro3 is predominantly expressed in podocytes within the kidney, and its expression increases in early diabetic kidney disease (DKD) but decreases in patients with progressive DKD and FSGS. Glomerular expression of Tyro3 also correlates with the progression of DKD and predicts the progression of primary glomerular diseases. High glucose increases Tyro3 expression, while TNF-α suppresses the expression of PS and Tyro3. PS has anti-inflammatory and anti-apoptotic effects in podocytes, likely via the activation of the Akt pathway and the inhibition of NF-kB activation. In vivo, the knockout of PS or Tyro3 exacerbates podocyte loss and glomerular disease, while the overexpression of PS and Tyro3 attenuates the injury in mice with DKD and FSGS. Tyro3 agonists have also been shown to protect podocytes from injury in these animal models. Summary: Tyro3 plays a critical role in podocyte biology and glomerular disease. Tyro3 agonists could potentially be developed as a new therapy for glomerular disease. Key Message: The aim of this review article is to summarize the role and mechanisms mediating the protective effects of Tyro3 in podocyte biology and glomerular disease. Additionally, we discuss the possibility of developing Tyro3 agonists as potential treatment for glomerular diseases.

Evaluation of nontarget lesions in femoropopliteal disease using near-infrared spectroscopy intravascular ultrasound imaging.

In coronary artery disease (CAD), lipid-core-containing plaque (LCP) in nontarget lesions detected using near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) was related to increased major adverse cardiovascular events in patients with CAD. In the endovascular therapy field, few previous studies using NIRS-IVUS revealed the presence of LCPs in severe stenotic lesions of femoropopliteal disease. This study aimed to assess the plaque morphology of nontarget lesions, especially LCPs, and compare it with that of target lesions using NIRS-IVUS in patients with femoropopliteal disease. This single-center prospective observational study included 14 patients who underwent endovascular therapy for FP disease. NIRS-IVUS assessment was performed on the entire FP arterial segment. Forty-one LCP lesions with a maximum lipid-core burden index in any 4-mm region (max LCBI4mm) > 100 were detected using NIRS-IVUS. We evaluated the patient and lesion characteristics. LCP lesions were divided into the target (n = 18) and nontarget (n = 23) lesion groups for comparison. Patient characteristics were notable for advanced age (76.8 ± 6.6 years); high proportion of males (78.7%); and high incidence of hypertension (100%), dyslipidemia (78.6%), diabetes (64.3%). Regarding NIRS findings, the target lesion group exhibited a significantly smaller proportion of LCPs concerning the lesion length (25.9 ± 15.7% vs. 50.6 ± 29.2%, p = 0.002) than the nontarget lesion group. Conversely, there were no significant differences in the value of max LCBI4mm (284.4 ± 153.4 vs. 289.5 ± 113.1, p = 0.90), length of LCP lesion (9.8 ± 9.7 mm vs. 10.7 ± 6.9 mm, p = 0.74), and distribution of LCPs (p = 0.08) between the groups. In addition, the number of LCPs in the target FP artery positively correlated with max LCBI4mm in the target FP artery (r = 0.671, p = 0.008). NIRS-IVUS findings demonstrated the presence of LCPs in nontarget lesions in patients with FP disease. Moreover, the abundance of LCPs in nontarget lesions was similar to that in target lesions in FP disease.

The role of alternative medicine and complimentary therapies in urologic disease: New horizons.

The world of complementary and alternative medicine (CAM) encompasses a wide range of practices, treatments, and products that fall outside the realm of conventional (mainstream) medicine. The use of complementary and CAM has become increasingly popular in Western nations. People are turning to CAM for a variety of reasons, including managing chronic diseases, relieving symptoms of various conditions, and improving their overall health and well-being. There's a growing trend of people using and showing interest in complementary and alternative medicine therapies, especially in Western countries. CAM encompasses a wide range of treatments, some offering complete alternatives to conventional medicine, while others aim to complement existing medical approaches. Urologists should stay informed about CAM to guide their patients effectively to treat patients in a modern and personalized way. The aim of review is to analyze the scenario of complimentary and alternative medicine with a specific focus in the urological field.

Hydroalcoholic extract of Araucaria sp. brown propolis alleviates ulcerative colitis induced by TNBS in rats by reducing inflammatory cell infiltration and oxidative damage.

To investigate the effects of Araucaria sp. brown propolis (ABP) against trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Animals received vehicle (1% DMSO, 1ml/kg) or hydroalcoholic extract of ABP (hydroalcoholic extract of Araucaria sp. brown propolis (HEABP), 30, 100, and 300mg/kg) orally, or dexamethasone (25mg/kg, s.c.) for 5 days. On day 4, the animals received intracolonic TNBS (150mg/kg), on day 6 they were euthanized. The weight of the animals, the macroscopic and microscopic colonic damage, reduced glutathione (GSH) and malondialdehyde (MDA) levels, and the activity of glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) were measured in colon homogenate. The action of HEABP and two isolated compounds in neutrophil migration was recorded. HEABP (100 and 300mg/kg), but not dexamethasone, decreased colonic lesion, and increased colonic mucin staining. In parallel, HEABP decreased MDA and restored GSH levels and the activity of SOD, CAT, and GST in the colon. A dose-dependent inhibition of MPO activity was observed (LogIC50 = 1.9). Moreover, HEBPA and the junicedric and abietic acids inhibited the neutrophil chemotaxis in vitro and HEBPA reduced neutrophil migration in vivo. HEABP may be promising in the therapies for inflammatory bowel diseases, reducing oxidative and inflammatory damage, especially mediated by neutrophils.

Multiple types of disease-associated RNAs identification for disease prognosis and therapy using heterogeneous graph learning

Multiple types of disease-associated RNAs identification for disease prognosis and therapy using heterogeneous graph learning

Plant-based therapies for urolithiasis: a systematic review of clinical and preclinical studies.

Urolithiasis, the formation of kidney stones, is a common and severe condition. Despite advances in understanding its pathophysiology, affordable treatment options are needed worldwide. Hence, the interest is in herbal medicines as alternative or supplementary therapy for urinary stone disease. This review explores the use of plant extracts and phytochemicals in preventing and treating urolithiasis. Following PRISMA standards, we systematically reviewed the literature on PubMed/Medline, focusing on herbal items evaluated in in vivo models, in vitro studies, and clinical trials related to nephrolithiasis/urolithiasis. We searched English language publications from January 2021 to December 2023. Studies assessing plant extracts and phytochemicals' therapeutic potential in urolithiasis were included. Data extracted included study design, stone type, plant type, part of plant used, solvent type, main findings, and study references. A total of 64 studies were included. Most studies used ethylene glycol to induce hyperoxaluria and nephrolithiasis in rat models. Various extraction methods were used to extract bioactive compounds from different plant parts. Several plants and phytochemicals, including Alhagi maurorum, Aerva lanata, Dolichos biflorus, Cucumis melo, and quercetin, demonstrated potential effectiveness in reducing stone formation, size, and number. Natural substances offer an alternative or supplementary approach to current treatments, potentially reducing pain and improving the quality of life for urolithiasis patients. However, further research is needed to clarify their mechanisms of action and optimize their therapeutic use. The potential of plant-based therapies in treating urolithiasis is promising, and ongoing research is expected to lead to treatment advancements benefiting patients globally.

AR71, Histamine H3 Receptor Ligand—In Vitro and In Vivo Evaluation (Anti-Inflammatory Activity, Metabolic Stability, Toxicity, and Analgesic Action)

The future of therapy for neurodegenerative diseases (NDs) relies on new strategies targeting multiple pharmacological pathways. Our research led to obtaining the compound AR71 [(E)-3-(3,4,5-trimethoxyphenyl)-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)prop-2-en-1-one], which has high affinity for human H3R (Ki = 24 nM) and selectivity towards histamine H1 and H4 receptors (Ki > 2500 nM), and showed anti-inflammatory activity in a model of lipopolysaccharide-induced inflammation in BV-2 cells. The presented tests confirmed its antagonist/inverse agonist activity profile and good metabolic stability while docking studies showed the binding mode to histamine H1, H3, and H4 receptors. In in vitro tests, cytotoxicity was evaluated at three cell lines (neuroblastoma, astrocytes, and human peripheral blood mononuclear cells), and a neuroprotective effect was observed in rotenone-induced toxicity. In vivo experiments in a mouse neuropathic pain model demonstrated the highest analgesic effects of AR71 at the dose of 20 mg/kg body weight. Additionally, AR71 showed antiproliferative activity in higher concentrations. These findings suggest the need for further evaluation of AR71’s therapeutic potential in treating ND and CNS cancer using animal experimental models.

A Framework for Best Practices and Readiness in the Advent of Anti-Amyloid Therapy for Early Alzheimer's Disease in Asia.

Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients.

Recent Advances on Pt–Based Compounds for Theranostic Applications

Since the discovery of cisplatin’s antitumoral activity and its approval as an anticancer drug, significant efforts have been made to enhance its physiological stability and anticancer efficacy and to reduce its side effects. With the rapid development of targeted and personalized therapies, and the promising theranostic approach, platinum drugs have found new opportunities in more sophisticated systems. Theranostic agents combine diagnostic and therapeutic moieties in one scaffold, enabling simultaneous disease monitoring, therapy delivery, response tracking, and treatment efficacy evaluation. In these systems, the platinum core serves as the therapeutic agent, while the functionalized ligand provides diagnostic tools using various imaging techniques. This review aims to highlight the significant role of platinum–based complexes in theranostic applications, and, to the best of our knowledge, this is the first focused contribution on this type of platinum compounds. This review presents a brief introduction to the development of platinum chemotherapeutic drugs, their limitations, and resistance mechanisms. It then describes recent advancements in integrating platinum complexes with diagnostic agents for both tumor treatment and monitoring. The main body is organized into three categories based on imaging techniques: fluorescence, positron emission tomography (PET), single–photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Finally, this review outlines promising strategies and future perspectives in this evolving field.