Repositioning fluphenazine as a cuproptosis-dependent anti-breast cancer drug candidate based on TCGA database.

Breast cancer is one of the most prevalent malignancies among women. Enhancing the prognosis is an effective approach to enhance the survival rate of breast cancer. Cuproptosis, a copper-dependent programmed cell death process, has been associated with patient prognosis. Inducing cuproptosis is a promising approach for therapy. However, there is currently no anti-breast cancer drug that induces cuproptosis. In this study, we repositioned the clinical drug fluphenazine as a potential agent for breast cancer treatment by inducing cuproptosis. Firstly, we utilized the Cancer Genome Atlas (TCGA) database and Connectivity Map (CMap) database to identify 22 potential compounds with anti-breast cancer activity through inducing cuproptosis. Subsequently, our findings demonstrated that fluphenazine effectively suppressed the viability of MCF-7 cells. Fluphenazine also significantly inhibited the viability of triple negative breast cancer cells MDA-MB-453 and MDA-MB-231. Furthermore, our study revealed that fluphenazine significantly down-regulated the expression of potential prognostic biomarkers associated with cuproptosis, increased copper ion levels, and reduced intracellular pyruvate accumulation. Additionally, it up-regulated the expression of FDX1 at both the mRNA and protein levels, which has been reported to play a crucial role in the induction of cuproptosis. These findings suggest that fluphenazine has the potential to be used as an anti-breast cancer drug by inducing cuproptosis. Therefore, this research provides an insight for the development of novel cuproptosis-dependent anti-cancer agents.

The influence of open disc repositioning surgery on the internal derangement of the contralateral temporomandibular joint: a prospective study of 96 patients.

OBJECTIVE: To assess the influence of unilateral open disc repositioning surgery (ODRS) of the temporomandibular joint (TMJ) on the internal derangement (ID) of the contralateral joint. METHODS: Patients with bilateral ID of TMJ who underwent unilateral ODRS were enrolled and followed-up for one year. They were divided into two groups based on the contralateral disease: the anterior disc displacement with reduction (ADDWR) and without reduction (ADDWoR). Postoperative evaluation included clinical and MRI evaluation. Indices measured were unilateral intermaxillary distance (UID), visual analogue scale (VAS), disc length (DL), condylar height (CH), and disc-condyle angle (DCA). Paired t tests were used to compare the clinical and MRI indices between different time points. RESULTS: Ninety-six patients were enrolled, including 47 in the ADDWR group and 49 in the ADDWoR group. One-year post-surgery, ODRS led to significant increases in MMO, DL, and CH, and decrease in VAS and DCA on the operated side (P < 0.05). In ADDWR group, UID, DL, and CH increased significantly, and VAS decreased (P < 0.05), with no significant change in DCA (P > 0.05). In ADDWoR group, clinical and MRI variables worsened slightly, except for UID, which remained unchanged (P > 0.05). CONCLUSIONS: ODRS is a promising method for correcting TMJ ID and may improve condition of ADDWR and decrease progress of ADDWoR at the contralateral joint. Preoperative bilateral TMJ evaluation is essential for better outcomes. CLINICAL RELEVANCE: ODRS can effectively treat TMJ ID and produce adaptive changes in the contralateral ID, for which continuous monitoring of the contralateral joint is essential.

Antidiabetic drugs in Parkinson's disease.

This review explores the intricate connections between type 2 diabetes (T2D) and Parkinson's disease (PD), both prevalent chronic conditions that primarily affect the aging population. These diseases share common early biochemical pathways that contribute to tissue damage. This manuscript also systematically compiles potential shared cellular mechanisms between T2D and PD and discusses the literature on the utilization of antidiabetic drugs as potential therapeutic options for PD. This review encompasses studies investigating the experimental and clinical efficacy of antidiabetic drugs in the treatment of Parkinson's disease, along with the proposed mechanisms of action. The exploration of the benefits of antidiabetic drugs in PD presents a promising avenue for the treatment of this neurodegenerative disorder.

Wnt/ß-catenin pathway as a potential target for Parkinson's disease: a cohort study of romosozumab using routinely collected health data in Japan.

Introduction: Romosozumab is a monoclonal antibody approved for osteoporosis which targets sclerostin, an endogenous inhibitor of Wnt/ß-catenin pathway. Given the essential roles of the Wnt/ß-catenin pathway in various tissues, we hypothesized romosozumab treatment may influence other conditions. Methods: This cohort study included patients prescribed romosozumab or parathyroid receptor (PTHR) agonists after 1 January 2019, using a Japanese electronic medical record database. The outcomes of interest included autoimmune disease, interstitial pneumonia, cardiovascular outcome, Alzheimer's disease, Parkinson's disease (PD), serious infections, and malignancies. A stabilized inverse probability-weighted Cox proportional hazard model was used to estimate the hazard ratios. Age- and gender-based subgroup analyses were conducted. Exploratory outcomes based on three-digit International Classification of Diseases 10th Revision-based were also examined. Results: In total, 2,673 patients treated with romosozumab and 5,980 treated with PTHR agonists were identified, respectively. While most outcomes of interest showed no association with romosozumab, the risk of PD decreased with romosozumab (hazard ratio [95% confidence interval], 0.37 [0.14-0.94]) compared with PTHR agonist. Regarding the cardiovascular outcome, no notable association was identified overall; however, gender-based subgroup analysis suggested that male sex may be a potential risk factor with romosozumab treatment. Only 16 of 903 exploratory outcomes were potentially influenced by romosozumab. Conclusion: Romosozumab lowered the risk of PD development compared with PTHR agonist. The study also highlights the utility of routinely collected health data for drug repositioning. While further validation is warranted, the findings suggest that the Wnt-ß-catenin pathway holds promise as a therapeutic target for PD.

Incidence of Subsequent Injuries Associated with a New Diagnosis of Benign Paroxysmal Positional Vertigo and Effects of Treatment: A Nationwide Cohort Study.

Background/Objectives: Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo and the most common peripheral vestibular disorder. It is characterized by intense vertigo triggered by head and position changes. This study investigates the risk of subsequent injury in BPPV patients and the effects of treatment. Methods: A population-based retrospective cohort study was conducted using data from the Longitudinal Health Insurance Database 2005 in Taiwan. Patients with and without BPPV were identified between 2000 and 2017. The study outcomes were diagnoses of all-cause injuries. The Kaplan-Meier method determined the cumulative incidence rates of injury in both cohorts, and a log-rank test analyzed the differences. Cox proportional hazard models calculated each cohort's 18-year hazard ratios (HRs). Results: We enrolled 50,675 patients with newly diagnosed BPPV and 202,700 matched individuals without BPPV. During follow-up, 47,636 patients were diagnosed with injuries (13,215 from the BPPV cohort and 34,421 from the non-BPPV cohort). The adjusted HR for injury in BPPV patients was 2.63 (95% CI, 2.49-2.88). Subgroup analysis showed an increased incidence of unintentional and intentional injuries in BPPV patients (aHR 2.86; 95% CI, 2.70-3.13 and 1.10; 95% CI, 1.04-1.21, respectively). A positive dose-response relationship was observed with increasing BPPV diagnoses. Treatment with canalith repositioning therapy (CRT) or medications reduced the risk of injury slightly but not significantly (aHR, 0.78; 95% CI, 0.37-1.29, 0.88; 95% CI, 0.40-1.40, respectively). Conclusions: BPPV is independently associated with an increased risk of injuries. CRT or medications have limited effects on mitigating this risk. Physicians should advise BPPV patients to take precautions to prevent injuries even after treatment.

Overview of pro-inflammatory and pro-survival components in neuroinflammatory signalling and neurodegeneration.

Neurodegenerative diseases (NDDs) are identified by the progressive deterioration of neurons and a subsequent decline in cognitive function, creating an enormous burden on the healthcare system globally. Neuroinflammation is an intricate procedure that initiates the immune response in the central nervous system (CNS) and significantly impacts the expansion of NDDs. This study scrutinizes the complicated interaction between neuronal degeneration and neuroinflammation, with an appropriate emphasis on their reciprocal impacts. It also describes how neuroinflammatory reactions in NDDs are controlled by activating certain pro-inflammatory transcription factors, including p38 MAPK, FAF1, Toll-like receptors (TLRs), and STAT3. Alternatively, it evaluates the impact of pro-survival transcription factors, such as the SOCS pathway, YY1, SIRT1, and MEF2, which provide neuroprotective protection against damage triggered by neuroinflammation. Moreover, we study the feasibility of accommodating drug repositioning as a therapeutic approach for treating neuroinflammatory disorders. This suggests the use of existing medications for novel utilization in the treatment of NDDs. Furthermore, the study intends to reveal novel biomarkers of neuroinflammation that contribute fundamental observation for the initial detection and diagnosis of these disorders. This study aims to strengthen therapy interference and augment patient outcomes by combining ongoing data and evaluating novel therapeutic and diagnostic approaches. The goal is to devote the growth of an effective strategy to reducing the impact of neuroinflammation on neuronal protection in NDDs.

Tratamento integrado para correção do sorriso gengival: relato de caso / Integrated treatment for correction of gingival smile: case report

O sorriso gengival possui inúmeras causas, podendo acontecer por motivos esqueléticos, musculares ou por alteração no desenvolvimento dos tecidos de suporte. No entanto, na atualidade, a estética vermelha e a branca têm se apresentado completamente passíveis de transformações e com uma gama de procedimentos cirúrgicos ou não cirúrgicos para sanar as queixas dos pacientes. O objetivo geral deste trabalho é mostrar o poder que a odontologia tem frente às questões estéticas, como, por exemplo, a vergonha de sorrir por não se sentir confortável com os dentes curtos e com uma grande faixa de gengiva sendo exposta. O método utilizado foi um relato de caso. Que descreve todos os passos clínicos do tratamento de um paciente de 40 anos, que estava insatisfeita com o seu sorriso por apresentar erupção passiva alterada juntamente com hiperatividade do lábio superior. O plano de tratamento escolhido foi de realizar a cirurgia de aumento de coroa clínica estético, seguido de clareamento dentário e posteriormente um reposicionamento labial, com ajuda da toxina botulínica. Finalizando, para ajudar na cicatrização, o uso de laserterapia. O resultado de todo o processo cirúrgico envolvido neste trabalho, é satisfação do paciente, materializando o sonho deste, devolvendo segurança e espontaneidade ao sorrir. Pôde-se observar que através da combinação de técnicas cirúrgicas periodontais para tratar o sorriso gengival, obtém-se êxito tanto no sentido científico quanto no biológico, alcançando um sorriso esteticamente mais atrativo(AU)

Gummy smile has numerous causes, which can occur for skeletal or muscular reasons or due to changes in the development of supporting tissues. However, nowadays, the red and white aesthetics have been completely capable of transformation and with a range of surgical or non-surgical procedures to resolve patients' complaints. The general objective of this work is to show the power that dentistry has in the face of aesthetic issues, such as, for example, the shame of smiling due to not feeling comfortable with short teeth and a large strip of gum being exposed. The method used was a case report. Which describes all the clinical steps of the treatment of a 40-year-old patient, who was dissatisfied with her smile due to an altered passive eruption together with hyperactivity of the upper lip. The chosen treatment plan was to perform aesthetic clinical crown augmentation surgery, followed by tooth whitening and later lip repositioning, with the help of botulinum toxin. Finally, to help with healing, the use of laser therapy. The result of the entire surgical process involved in this work is patient satisfaction, materializing the patient's dream, restoring security and spontaneity when smiling. It was observed that through the combination of periodontal surgical techniques to treat gummy smile, success is achieved both in the scientific and biological sense, achieving a more aesthetically attractive smile(AU)

Activation of the PGE2-EP2 pathway as a potential drug target for treating eosinophilic rhinosinusitis.

Current treatments of eosinophilic chronic rhinosinusitis (ECRS) involve corticosteroids with various adverse effects and costly therapies such as dupilumab, highlighting the need for improved treatments. However, because of the lack of a proper mouse ECRS model that recapitulates human ECRS, molecular mechanisms underlying this disease are incompletely understood. ECRS is often associated with aspirin-induced asthma, suggesting that dysregulation of lipid mediators in the nasal mucosa may underlie ECRS pathology. We herein found that the expression of microsomal PGE synthase-1 (encoded by PTGES) was significantly lower in the nasal mucosa of ECRS patients than that of non-ECRS subjects. Histological, transcriptional, and lipidomics analyses of Ptges-deficient mice revealed that defective PGE2 biosynthesis facilitated eosinophil recruitment into the nasal mucosa, elevated expression of type-2 cytokines and chemokines, and increased pro-allergic and decreased anti-allergic lipid mediators following challenges with Aspergillus protease and ovalbumin. A nasal spray containing agonists for the PGE2 receptor EP2 or EP4, including omidenepag isopropyl that has been clinically used for treatment of glaucoma, markedly reduced intranasal eosinophil infiltration in Ptges-deficient mice. These results suggest that the present model using Ptges-deficient mice is more relevant to human ECRS than are previously reported models and that eosinophilic inflammation in the nasal mucosa can be efficiently blocked by activation of the PGE2-EP2 pathway. Furthermore, our findings suggest that drug repositioning of omidenepag isopropyl may be useful for treatment of patients with ECRS.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

BACKGROUND: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. METHODS: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). RESULTS: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. CONCLUSIONS: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Drug repurposing for obsessive-compulsive disorder using deep learning-based binding affinity prediction models.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disease in which patients suffer from obsessions compelling them to engage in specific rituals as a temporary measure to alleviate stress. In this study, deep learning-based methods were used to build three models which predict the likelihood of a molecule interacting with three biological targets relevant to OCD, SERT, D2, and NMDA. Then, an ensemble model based on those models was created which underwent external validation on a large drug database using random sampling. Finally, case studies of molecules exhibiting high scores underwent bibliographic validation showcasing that good performance in the ensemble model can indicate connection with OCD pathophysiology, suggesting that it can be used to screen molecule databases for drug-repurposing purposes.

Exploring drug repositioning possibilities of kinase inhibitors via molecular simulation.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

Strategies of Pharmacological Repositioning for the Treatment of Medically Relevant Mycoses.

Fungal infections represent a worldwide concern for public health, due to their prevalence and significant increase in cases each year. Among the most frequent mycoses are those caused by members of the genera Candida, Cryptococcus, Aspergillus, Histoplasma, Pneumocystis, Mucor, and Sporothrix, which have been treated for years with conventional antifungal drugs, such as flucytosine, azoles, polyenes, and echinocandins. However, these microorganisms have acquired the ability to evade the mechanisms of action of these drugs, thus hindering their treatment. Among the most common evasion mechanisms are alterations in sterol biosynthesis, modifications of drug transport through the cell wall and membrane, alterations of drug targets, phenotypic plasticity, horizontal gene transfer, and chromosomal aneuploidies. Taking into account these problems, some research groups have sought new therapeutic alternatives based on drug repositioning. Through repositioning, it is possible to use existing pharmacological compounds for which their mechanism of action is already established for other diseases, and thus exploit their potential antifungal activity. The advantage offered by these drugs is that they may be less prone to resistance. In this article, a comprehensive review was carried out to highlight the most relevant repositioning drugs to treat fungal infections. These include antibiotics, antivirals, anthelmintics, statins, and anti-inflammatory drugs.

Tactile acuity and active joint repositioning sense in individuals with and without chronic low back pain: a cross-sectional study.

BACKGROUND: Sensorimotor dysfunction, as measured by tactile acuity and active joint repositioning, has been identified as a contributing factor of chronic low back pain (CLBP). Existing research suggests that further research is necessary to improve the characterization of sensorimotor perception in patients with CLBP. OBJECTIVES: The main aim is to investigate whether tactile acuity and repositioning errors differ between individuals with CLBP and controls without CLBP. A secondary aim was to investigate the association between age, body mass index (BMI) and physical activity, and tactile acuity and repositioning sense. METHODS: Cross-sectional study. Sixty-eight participants (36 with, 32 without CLBP) were examined. Two-Point Discrimination (TPD) test (four measures: horizontal and vertical run, left and right side) and Active Joint Reposition Sense (AJRS) test (2 directions: to flexion and to extension) were used. RESULTS: No differences were found for TPD (right horizontal run: p = .069; left horizontal run: p = .066; right vertical run: p = .933; left vertical run: p = .285) or AJRS (flexion: p = .792; extension: p = .956) between participants with and without CLBP. Older subjects had significantly worse tactile acuity (3 sites, p = .018, p = .004, p = .041) and worse repositioning sense (2 directions, p = .026, p = .040,) than younger subjects. Individuals with BMI ≥ 25 had significantly worse TPD compared to individuals with normal weight (2 sites, p = .028, p = .020). CONCLUSIONS: Individuals with CLBP did not have impaired tactile and repositioning accuracy when compared to controls without CLBP. Future studies comparing sensorimotor performance should consider age and BMI as potential confounding factors.

In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.

PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Awareness of Visual Offset Reduces but Does Not Eliminate Joint Repositioning Errors in Virtual Reality.

The present study investigated the effect of visual offset (visuo-proprioceptive mismatch) in joint repositioning task in a three-dimensional virtual reality (VR) environment when participants were instructed to ignore vision. Twenty-five physically healthy young individuals performed shoulder joint position sense test. Repositioning accuracy was tested under two visual conditions, accurate and offset visions, and two instructions, no guidance or ignore vision. In accurate vision trials, the virtual hand of the tested limb seen in VR was congruent with where the participant placed their hand. In the offset vision condition, the virtual hand was seen 8° above or below their actual hand in the vertical plane. Repositioning error (i.e. constant error) in offset vision trials was lower when the participants were instructed to ignore vision compared to when no instruction about the visual offset was given (p < 0.001). However, constant error in offset vision trials was larger than accurate vision trials when the participants tried to ignore vision in both visual conditions (p < 0.001). Our results suggest that humans may be able to down-weight vision to some extent by conscious effort, while the influence of vision is difficult to eliminate when vision is present.

Repositioning chair treatment procedure for cupulolithiasis: case report (with video).

INTRODUCTION: A cupulolithiasis of the lateral semicircular canal is an accumulation of otolithic debris at the level of the cupula of the same canal. Its pathophysiology generally generates a specific clinical presentation. This situation can be very disabling for the patient and tricky to treat for the clinician. CASE REPORT: The patient was a 70-year-old man with cupulolithiasis of the right lateral semicircular canal. We present here the conversion of cupulolithiasis to canalolithiasis using the Thomas Richard Vitton (TRV) repositioning chair, as well as the treatment of this canalolithiasis through a mechanical liberation maneuver. CONCLUSION: The results of manual therapeutic maneuvers for Benign Paroxysmal Positional Vertigo (BPPV) are generally good regardless of the type of BPPV. It can sometimes be more challenging to resolve an ageotropic-type BPPV of the lateral semicircular canal and mechanically-assisted maneuvers using a repositioning chair may be required. Faced with symptom resistance despite attempts at multiple liberatory maneuvers, clinicians must be able to reconsider their initial diagnosis and investigate other potentially more serious origins of these symptoms. The TRV chair can be a treatment option in the management of cupulolithiasis, especially in cases where classic reduction maneuvers do not always yield good results.

Beyond the lungs: Exploring diverse applications of bromhexine and ambroxol.

The respiratory tract is commonly affected in multisystem disorders. Although many drugs have been developed to target various components of these diseases, there is still a need for effective treatments that can address both respiratory and non-respiratory symptoms. Bromhexine and ambroxol are mucolytic agents with a good safety profile that are widely used to treat respiratory conditions. These compounds seem to present several unresolved questions when carrying out their therapeutic effects, suggesting that they may not merely improve mucociliary clearance. These assumptions have provided the basis for researchers to investigate the specific characteristics of bromhexine and ambroxol. This has led to the emergence of several repositionings for this compound. Accordingly, these compounds have also shown potential benefits in the treatment of various extrapulmonary disorders, including neurological disorders, and inflammatory bowel disease. We gathered findings from relevant studies published in English between 1970 and December 2023 by searching databases including PubMed, Google Scholar, Scopus, Embase, and the Cochrane Library. Our findings revealed that most of the research on extrapulmonary uses has been conducted at the preclinical level. Accordingly, more clinical studies are needed to determine the effectiveness of bromhexine and ambroxol in these conditions. This article provides an overview of the potential extrapulmonary applications of bromhexine and ambroxol and discusses the potential advantages of using these drugs in multisystem disorders.

MiRAGE: mining relationships for advanced generative evaluation in drug repositioning.

MOTIVATION: Drug repositioning, the identification of new therapeutic uses for existing drugs, is crucial for accelerating drug discovery and reducing development costs. Some methods rely on heterogeneous networks, which may not fully capture the complex relationships between drugs and diseases. However, integrating diverse biological data sources offers promise for discovering new drug-disease associations (DDAs). Previous evidence indicates that the combination of information would be conducive to the discovery of new DDAs. However, the challenge lies in effectively integrating different biological data sources to identify the most effective drugs for a certain disease based on drug-disease coupled mechanisms. RESULTS: In response to this challenge, we present MiRAGE, a novel computational method for drug repositioning. MiRAGE leverages a three-step framework, comprising negative sampling using hard negative mining, classification employing random forest models, and feature selection based on feature importance. We evaluate MiRAGE on multiple benchmark datasets, demonstrating its superiority over state-of-the-art algorithms across various metrics. Notably, MiRAGE consistently outperforms other methods in uncovering novel DDAs. Case studies focusing on Parkinson's disease and schizophrenia showcase MiRAGE's ability to identify top candidate drugs supported by previous studies. Overall, our study underscores MiRAGE's efficacy and versatility as a computational tool for drug repositioning, offering valuable insights for therapeutic discoveries and addressing unmet medical needs.

Doxorubicin as a Drug Repurposing for Disruption of α-Chymotrypsinogen-A Aggregates.

Protein conformation is affected by interaction of several small molecules resulting either stabilization or disruption depending on the nature of the molecules. In our earlier communication, Hg2+ was known to disrupt the native structure of α-Cgn A leading to aggregation (Ansari, N.K., Rais, A. & Naeem, A. Methotrexate for Drug Repurposing as an Anti-Aggregatory Agent to Mercuric Treated α-Chymotrypsinogen-A. Protein J (2024). https://doi.org/10.1007/s10930-024-10187-z ). Accumulation of ß-rich aggregates in the living system is found to be linked with copious number of disorders. Here, we have investigated the effect of varying concentration of doxorubicin (DOX) i.e. 0-100 µM on the preformed aggregates of α-Cgn A upon incubation with 120 µM Hg2+. The decrease in the intrinsic fluorescence and enzyme activity with respect to increase in the Hg2+ concentration substantiate the formation of aggregates. The DOX showed the dose dependent decrease in the ThT fluorescence, turbidity and RLS measurements endorsing the dissolution of aggregates which were consistent with red shift in ANS, confirming the breakdown of aggregates. The α-Cgn A has 30% α-helical content which decreases to 3% in presence of Hg2+. DOX increased the α-helicity to 28% confirming its anti-aggregatory potential. The SEM validates the formation of aggregates with Hg2+ and their dissolution upon incubation with the DOX. Hemolysis assay checked the cytotoxicity of α-Cgn A aggregates. Docking revealed that the DOX interacted Lys203, Cys201, Cys136, Ser159, Leu10, Trp207, Val137 and Thr134 of α-Cgn A through hydrophobic interactions and Gly133, Thr135 and Lys202 forms hydrogen bonds.