Drug Treatment Research Articles

Structural characterization and anti-hyperuricemic effect of a mannogalactan from Armillariella tabescens mycelium

Hyperuricemia and its complications caused by purine metabolism disorder continue to occur, which require effective drug treatment with fewer side effects. This study explored the positive effects of a natural homogeneous polysaccharide (AT-W) from the mycelium of Armillariella tabescens in a mouse hyperuricemia model. Structural characterization showed that the average molecular weight of AT-W is 25.6 kDa, and it is composed of mannose, galactose, arabinose, and fucose, with molar percentages of 11.46:70.9:4.96:12.67. The main backbone of AT-W is composed of partially 3-O-methylated →6)-α-Galp-(1→, and the branches are mainly composed of α-Manp-(1→, →3)-α-Fucp-(1→. In vivo bioactivity evaluation showed AT-W could not only reduce serum uric acid levels by inhibiting the activity of xanthine oxidase, upregulating the expression of ABCG2 and OAT1, and downregulating the expression of URAT1 but also have a significant protective effect on renal damage caused by hyperuricemia. These findings indicate that AT-W has therapeutic potential for hyperuricemia diseases.

Exploring Tissue Permeability of Brain Tumours in Different Grades: Insights from Pore-scale Fluid Dynamics Analysis

Interstitial fluid (ISF) flow is identified as an essential physiological process that plays an important role in the development and progression of brain tumours. However, the relationship between the permeability of the tumour tissue, a complex porous medium, and the interstitial fluid flow around the tumour cells at the microscale is not well understood. To shed light on this issue, and in the absence of experimental techniques that can provide direct measurements, we develop a computational model to predict the tissue permeability of brain tumours in different grades by analysing the ISF flow at the pore scale. The 3-D geometrical models of tissue extracellular spaces are digitally reconstructed for each grade tumour based on their morphological properties measured from microscopic images. The predictive accuracy of the framework is validated by experimental results reported in the literature. Our results indicate that high-grade brain tumours are less permeable despite their higher porosity, whereas necrotic areas of glioblastoma are more permeable than the viable tumour areas. This implies that tissue permeability is primarily governed by both tissue porosity and the deposition of hyaluronic acid (HA), a key component of the extracellular matrix, while the HA deposition can have a greater effect than macro-level porosity. Parametric studies show that tissue permeability falls exponentially with increasing HA concentration in all grades of brain tumours, and this can be captured using an empirically derived relationship in a quantitative manner. These findings provide an improved understanding of the hydraulic properties of brain tumours and their intrinsic links to tumour microstructure. This work can be used to reveal the intratumoural physiochemical processes that rely on fluid flow and offer a powerful tool to tune textured and porous biomaterials for desired transport properties. Statement of SignificanceInterstitial fluid flow in the extracellular space of brain tumours plays a crucial role in their progression, development, and response to drug treatments. However, the mechanisms of interstitial fluid transport around tumour cells and the characterization of these microscale transports at the tissue scale to meet clinical requirements are largely unknown. In the absence of advanced experimental techniques to capture these pore-scale transport phenomena, we have developed and validated a computational framework to successfully reveal these phenomena across all grades of brain tumours. For the first time, we have quantitatively determined the tissue permeability of all grades of brain tumours as a function of the concentration of hyaluronic acid, a key component of the extracellular matrix. This framework will enhance our ability to capture the intratumoural physicochemical processes in brain tumours and correlate them with tumour tissue-scale behaviours.

Multimodal spatiotemporal drug assessment platform based on a microelectrode neural network chip in Alzheimer’s disease

The pathogenesis of Alzheimer’s disease (AD) remains elusive. The development of new drugs is protracted, costly, and fraught with failure, largely due to the lack of convenient methods for dynamically studying the pathogenesis of AD and evaluating drug efficacy in vitro. There is a dearth of in vitro multi-site assay platforms capable of observing the therapeutic effects of AD drugs at the level of cellular and network. Consequently, an in vitro multimodal spatiotemporal drug assessment platform has been developed based on a neuronal network chip. It has a symmetric distribution of electrode points with two different sizes (10 μm and 30 μm), which are more suitable for the detection of neuronal connections. The multifaceted neurophysiological properties, including single neuron firing pattern, intercellular connection, transmission speed, and neural network communication, were detected in real time. The results demonstrated that the differences between experimental groups in electrophysiological properties, could significantly distinguish the effects of AD representative drug treatment after different levels of neurological injury. The administration of the drug at the initial stage of β-amyloid oligomers (AβOs) toxicity was found to effectively retard the deterioration of neurons and network (early stage: firing rate increased by 8 %; middle stage: cross-correlation coefficient decreased by 27 %; late stage: similarity index remained positive and relative transmission speed decreased by 11 %). The neurophysiological mechanism of drug interaction was further elucidated, which may provide the guidance for the optimal timing of drug administration. Following the further extension of biosensor longevity and the expansion of synchronous multidimensional parameter detection, including impedance and electrochemistry, it is anticipated that this will become a novel platform for the preclinical evaluation and screening of AD drugs.

Importance of tailored non-clinical safety testing of novel antimalarial drugs: Industry best-practice

Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate.We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs.In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients.

Reconstructing ventricular cardiomyocyte dynamics and parameter estimation using data-assimilation

Cardiac ventricular myocyte action potential dynamics are regulated by intricate and nonlinear interactions between the cell transmembrane potential and ionic currents and concentrations. Present technology limits the ability to measure transmembrane potential and multiple ionic currents simultaneously, which narrows the scope of experiments to provide a complete snapshot of the cardiac myocyte state. This limitation presents an obstacle for understanding how perturbations can trigger arrhythmias and more broadly how the myocyte responds to different conditions, such as changes in pacing rate or responses to drug treatment. In this study, we demonstrate that a data-assimilation approach can successfully reconstruct and predict the dynamics of a heterogeneous virtual cardiac ventricular myocyte population in the presence of parameter uncertainty. A population of heterogeneous cardiac ventricular myocytes is generated by varying ionic current conductance parameters, and additional observational uncertainty is mimicked by the addition of Gaussian noise to the transmembrane potential. We demonstrate that the data-assimilation approach accurately reconstructs transmembrane potential, with error less than the magnitude of the noise. Further, the data-assimilation approach successfully estimates the conductances of ionic currents generally with high accuracy and requiring low computational time. As a proof of concept, we apply the data-assimilation approach to reconstruct action potential dynamics from optical mapping experiments in an ex vivo isolated guinea pig heart. Critically, we demonstrate that the ionic conductance parameters estimated from a recording at one pacing frequency can accurately predict action potential dynamics at different rates.

Triple Artemisinin-based Combination Therapy (TACT): Efficacy of dihydroartemisinin-piperaquine plus chloroquine against Plasmodium berghei ANKA strains with different drug sensitivities in a murine malaria model.

BackgroundEvident detection of artemisinin resistance markers in patient isolates of Plasmodium falciparum from East Africa threatens the efficacy of artemisinin-based combination therapies (ACTs) as first-line treatment of malaria in sub-Saharan Africa. Repositioning previously used antimalarials as complementary addition to ACTs has been suggested as a viable option to mitigating this threat. This study evaluated the potential benefit of chloroquine (CQ) as a complementary partner to dihydroartemisinin/piperaquine (DHA/PQ) in the treatment of malaria in a mice model. MethodsThe comparative efficacy of the combination of DHA/PQ/CQ and DHA/PQ against two strains of Plasmodium berghei ANKA (MRA 311 and 671) with different levels of sensitivities to chloroquine was evaluated in separate experiments. Parasitological activities including; parasite suppression time, parasite clearance time, recrudescence time, and parasite reduction ratio were evaluated in vivo. The mean survival time was also monitored throughout the duration of the study. ResultsIn both parasite lines, 99.99% chemo-suppression was observed on day 4 in the drug treatment groups (CQ alone, DHA/PQ and DHA/PQ/CQ). In the curative test, there were significant differences between DHA/PQ/CQ and DHQ/PQ treatment, highlighted by reduced parasite clearance time (4.75±0.3 Vs 5.5±0.3 days, P<0.05), significantly delayed recrudescence time (28.5±1.04 Vs 13.3±0.48 days, P<0.01), a 1.5-fold change in parasite reduction ratio, and a prolonged mean survival time (34.5±1.04 Vs 26.7±0.48 days, P<0.05). ConclusionThe addition of chloroquine to dihydroartemisinin-piperaquine may be beneficial in the treatment of malaria, especially in areas where malaria parasite sensitivity to chloroquine is predominant.

Risk of dementia associated with anticholinergic drugs for overactive bladder in adults aged ≥55 years: nested case-control study

ObjectiveTo investigate whether different anticholinergic drug treatments for overactive bladder have differential risks for incident dementia, in a large representative population of older adults in England.DesignNested case-control study.SettingGeneral practices in...

Implications of DNA damage in chronic lung disease.

DNA plays an indispensable role in ensuring the perpetuation of life and safeguarding the genetic stability of living organisms. The emergence of diseases linked to a wide spectrum of responses to DNA damage has garnered increasing attention within the scientific community. There is growing evidence that patterns of DNA damage response in the lungs are associated with the onset, progression, and treatment of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, and bronchopulmonary dysplasia (BPD). Currently, some studies have analyzed the mechanisms by which environmental factors induce lung DNA damage. In this article, we summarize inducible factors of lung DNA damage, current indicators, and methods for diagnosing DNA damage in chronic lung diseases and explore repair mechanisms after DNA damage including nonhomologous end-joining and homology-directed repair end joining pathways. Additionally, drug treatments that may reduce DNA damage or promote repair after it occurs in the lungs are briefly described. In general, more accurate assessment of the degree of lung DNA damage caused by various factors is needed to further elucidate the mechanism of lung DNA damage and repair after damage, so as to search for potential therapeutic targets.

Growth of Renal Cancer Cell Lines Is Strongly Inhibited by Synergistic Activity of Low-Dosed Amygdalin and Sulforaphane.

Background: Plant derived isolated compounds or extracts enjoy great popularity among cancer patients, although knowledge about their mode of action is unclear. The present study investigated whether the combination of two herbal drugs, the cyanogenic diglucoside amygdalin and the isothiocyanate sulforaphane (SFN), influences growth and proliferation of renal cell carcinoma (RCC) cell lines. Methods: A498, Caki-1, and KTCTL-26 cells were exposed to low-dosed amygdalin (1 or 5 mg/mL), or SFN (5 µM) or to combined SFN-amygdalin. Tumor growth and proliferation were analyzed by MTT, BrdU incorporation, and clone formation assays. Cell cycle phases and cell cycle-regulating proteins were analyzed by flow cytometry and Western blotting, respectively. The effectiveness of the amygdalin-SFN combination was determined using the Bliss independence model. Results: 1 mg/mL amygdalin or 5 µM SFN, given separately, did not suppress RCC cell growth, and 5 mg/mL amygdalin only slightly diminished A498 (but not Caki-1 and KTCTL-26) cell growth. However, already 1 mg/mL amygdalin potently inhibited growth of all tumor cell lines when combined with SFN. Accordingly, 1 mg/mL amygdalin suppressed BrdU incorporation only when given together with SFN. Clonogenic growth was also drastically reduced by the drug combination, whereas only minor effects were seen under single drug treatment. Superior efficacy of co-treatment, compared to monodrug exposure, was also seen for cell cycling, with an enhanced G0/G1 and diminished G2/M phase in A498 cells. Cell cycle regulating proteins were altered differently, depending on the applied drug schedule (single versus dual application) and the RCC cell line, excepting phosphorylated Akt which was considerably diminished in all three cell lines with maximum effects induced by the drug combination. The Bliss independence analysis verified synergistic interactions between amygdalin and SFN. Conclusions: These results point to synergistic effects of amygdalin and SFN on RCC cell growth and clone formation and Akt might be a relevant target protein. The combined use of low-dosed amygdalin and SFN could, therefore, be beneficial as a complementary option to treat RCC. To evaluate clinical feasibility, the in vitro protocol must be applied to an in vivo model.

Unveiling Tumorigenesis Mechanisms and Drug Therapy in Neuroblastoma by Mass Spectrometry Based Proteomics

Neuroblastoma (NB) is the most common type of extracranial solid tumors in children. Despite the advancements in treatment strategies over the past years, the overall survival rate in patients within the high-risk NB group remains less than 50%. Therefore, new treatment options are urgently needed for this group of patients. Compared with genomic aberrations, proteomic alterations are more dynamic and complex, as well as more directly related to pathological phenotypes and external perturbations such as environmental changes and drug treatments. This review focuses on specific examples of proteomics application in various fundamental aspects of NB research, including tumorigenesis, drug treatment, drug resistance, and highlights potential protein signatures and related signaling pathways with translational values for clinical practice. Moreover, emerging cutting-edge proteomic techniques, such as single cell and spatial proteomics, as well as mass spectrometry imaging, are discussed for their potentials to probe intratumor heterogeneity of NB.

Cotard syndrome in an oncology patient: case report

Cotard's syndrome was described in France after Jules Cotard observed that some patients presented delusions of sensoriperception, denying their own existence or that of people close to them. Currently, little is known about this psychiatric condition, and the literature lacks more robust information. In this article, we report the clinical case of a patient who, after significant emotional stress, began to believe that she was dead and requested to be returned to her grave. Drug treatment was instituted and the patient remained hospitalized, and over time her symptoms remitted.

Effect of severe periodontitis of maxillary molars on the maxillary sinus and the treatment principles of periodontitis related maxillary sinusitis

Maxillary sinus is located in the maxilla bone with the largest volume in all sinuses and is closest to the roots of maxillary posterior teeth, especially the mesiobuccal root of the maxillary second molar. The thickness of the normal maxillary sinus mucosa is about 1 mm. When stimulated or infected, it shows thickening of the mucosa. Periodontitis is one of the most common oral diseases in human beings, and the complex root anatomy of the maxillary molars aggravates the difficulty of inflammation control. Severe periodontitis of maxillary molars without effective treatment can affect the maxillary sinus, increasing the possibility of the mucosa thickening, and is also one of the reasons for the occurrence of odontogenic maxillary sinusitis (OMS). There are many different schemes for the treatment of OMS caused by severe periodontitis of maxillary molars. Extraction of teeth with severe periodontal disease without retention value or successful periodontal treatment can significantly reduce the thickness of maxillary sinus mucosa. For the patients with uncontrollable sinusitis by using drug treatment and eliminating odontogenic causes, or ones with severe symptoms, periodontal treatment and endoscopic sinus surgery can be combined to effectively control the periodontitis related maxillary sinusitis.

Bioactive Compounds in Osteoarthritis: Molecular Mechanisms and Therapeutic Roles.

Osteoarthritis (OA) is the most common and debilitating form of arthritis. Current therapies focus on pain relief and efforts to slow disease progression through a combination of drug and non-drug treatments. Bioactive compounds derived from plants show significant promise due to their anti-inflammatory, antioxidant, and tissue-protective properties. These natural compounds can help regulate the inflammatory processes and metabolic pathways involved in OA, thereby alleviating symptoms and potentially slowing disease progression. Investigating the efficacy of these natural agents in treating osteoarthritis addresses a growing demand for natural health solutions and creates new opportunities for managing this increasingly prevalent age-related condition. The aim of this review is to provide an overview of the use of some bioactive compounds from plants in modulating the progression of osteoarthritis and alleviating associated pain.

Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia

Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.

Soluble immune checkpoints associated with disease activity and treatment response in GD and TED.

Soluble immune checkpoints play an important role in peripheral tolerance that has seldom been investigated in Graves' disease (GD) and thyroid eye disease (TED). The objective of this work is to examine the alteration of soluble immune checkpoints in GD and TED. We performed a quantitative multiplex analysis of 17 immune checkpoint proteins in serum from 50 GD patients without TED, 28 GD patients with TED and 40 healthy controls. The association with demographical, serological, clinical features and 27 cytokines was analyzed. A follow-up was conducted in GD patients without TED. Functional outcomes of sLAG-3 and sGITR were assessed in cell cultures using rh-LAG3, rh-GITR, an antagonistic LAG-3 antibody and an antagonistic GITR antibody. GD patients with TED had distinct sICP and cytokine profiles compared with GD patients without TED. Active TED patients exhibited elevation in the levels of sBTLA, sLAG-3, sGITR, sCD80, sCD86 and sPD-L1. Further, GD patients without TED with high sBTLA, sCD27 and sCD40 levels at baseline showed a better improvement in thyrotropin receptor antibody (TRAb) titers after antithyroid drug (ATD) treatment. Adding recombinant human GITR and LAG-3 to PBMC cultures resulted in increased inflammatory cytokine secretion and decreased anti-inflammatory cytokine secretion. The present study uncovers disturbed soluble immune checkpoints and cytokines in GD patients with and without TED, and may pave the way for novel immunological screening, allowing for identification of TED patients at higher risk of developing active disease and GD patients with better treatment response after ATD treatment.

Disease-Modifying Treatment of Psoriasis in Children

Advances in understanding the mechanisms underlying chronic inflammatory skin diseases, such as psoriasis vulgaris, have led to implementation of new treatment options aimed at symptoms relieving. Moreover, this data may become the basis for new strategies to achieve sustained or treatment-free remission, that is disease modification with potential impact on comorbid conditions. However, achieving this goal requires further study of such crucial aspects as the terms of disease modification and disease activity indicators, deeper understanding of pathogenesis mechanisms, etiology, and systemic side effects, possible opportunities, biomarkers for successful patient stratification and intervention, as well as the adequate study design. Early intervention with genetically engineered biologic drugs such as secukinumab represents new paradigm shift in improvement of immune-mediated diseases outcomes. However, new evidence is needed to determine its efficacy in psoriasis. High level of sustained skin clearance observed on secukinumab therapy compared to standard treatment and phototherapy indicates the potential benefit of early biologic drugs treatment to achieve complete skin clearance and improvement in quality of life, education, and daily activities. It can also become a background for changing treatment strategies for patients with newly diagnosed moderate-to-severe plaque psoriasis. Keywords: psoriasis, children, secukinumab, disease-modifying treatment

Exploring the Link between the Obesity and ADHD

Obesity is a chronic, multifactorial and recurrent disease. ADHD is a chronic neurodevelopmental disorder in early childhood. The core symptoms include attention deficit, hyperactivity/impulsivity and oppositional defiance. Research shows that there is a significant correlation between obesity and ADHD, and the probability of overweight and obese children suffering from ADHD is significantly higher than that of normal weight children. This paper discusses the association mechanism between ADHD and obesity from the perspectives of genetics, eating disorders, intestinal flora and poor physical exercise. At the same time, in view of the prevention and intervention of the comorbidity of ADHD and obesity, this paper also puts forward various means such as diet intervention, exercise prevention intervention and drug treatment. However, the relationship between obesity and ADHD is complex, and the comorbidity problem needs to be solved urgently. Establishing an effective early screening system, implementing targeted prevention and intervention measures, and strengthening public awareness and understanding of comorbidities are important ways to improve the quality of life of this group. Further research is needed in the future.

PATHOPHYSIOLOGY AND MANAGEMENT OF CUSHING SYNDROME: A SYSTEMATIC REVIEW OF CURRENT AND FUTURE PERSPECTIVES

Objective: The general objective of this study is to analyze the scientific literature on Cushing's Syndrome (CS), seeking to identify the main clinical manifestations, complications, and the impact on patients' quality of life. Methodology: Searches were performed in the PubMed Central (PMC) databases, using three descriptors in combination with the Boolean term “AND”: Cushing Syndrome, Clinical Manifestations, Complications, and Quality of Life. A total of 161 articles were found, which were subsequently submitted to the selection criteria. Twenty-two studies were selected to compose this systematic review, of which 12 were used. Results: Cushing's Syndrome is a condition characterized by hypercortisolism, which results in a wide range of clinical manifestations. Complications associated with CS include visceral obesity, arterial hypertension, diabetes mellitus, dyslipidemia, osteoporosis, and myopathy. In addition, CS has a significant impact on patients' mental health, including depression, anxiety, and cognitive impairment. Therapeutic approaches range from transsphenoidal surgery, radiotherapy, to targeted drug treatments to normalize cortisol levels and address comorbidities. Conclusion: CS is associated with several comorbidities that affect multiple body systems, resulting in a significant impact on patients' quality of life. Early diagnosis and multidisciplinary treatment are essential to improve clinical outcomes and quality of life in these patients.

AGCNAF: predicting disease-gene associations using GCN and multi-head attention to fuse the similarity features

Abstract Association prediction between diseases and genes is a critical step in revealing the molecular mechanisms of diseases and developing drug treatment strategies. With the explosive growth of data in the biomedical field, how to effectively utilize these data for accurate prediction has become a hotspot and challenge in current research. To overcome the limitations of current prediction methods in dealing with complex biological network structures and feature extraction, this study proposes AGCNAF, a method that combines an unsupervised Graph Convolutional Network (GCN) and a multi-head attention mechanism. The metagraph-guided random walk strategy enables AGCNAF to capture local and high-order topological structures in the graph, while GCN is responsible for realizing deep feature extraction of these structures. By incorporating similarity features through the multi-attention mechanism, AGCNAF achieves effective integration of global and local features, which significantly improves the prediction performance. By incorporating similarity features through the multi-attention mechanism, AGCNAF achieves effective integration of global and local features, which significantly improves the prediction performance. By utilizing the machine learning binary classification model for prediction, the experimental results through five-fold cross-validation show that AGCNAF demonstrates significant advantages in prediction performance compared to existing methods, with its AUC and AUPR reaching 0.9686 and 0.9709, respectively, and the AUC up to 0.9812 under specific conditions. &amp;#xD;To verify the practical application value of AGCNAF, this study also conduct case studies on Alzheimer's disease, lung cancer, and breast cancer. The results further confirm the excellent performance of AGCNAF in identifying potential disease-gene associations, which opens up new possibilities for future disease-gene research.

Use of immunomodulatory treatment for non-infectious uveitis: an International Ocular Inflammation Society report of real-world practice

BackgroundNon-infectious uveitis is a diverse group of inflammatory conditions that collectively account for substantial blindness worldwide. Expert guidelines and results of clinical trials guide treatment, but real-world clinical care is...