Therapeutic Concepts Research Articles

SiREn (simulation of receptors and enzymes): An interactive simulation of enzyme kinetics and pharmacodynamic models

In an era of distance learning and the transition to virtual classrooms, there is a need for strategies to supplement online lectures in an interactive, dynamic way. At California Northstate University, there was a student-observed need to enhance distance learning during the COVID-19 pandemic. In this project, we developed a computer simulation program SiREn (Simulation of Receptors and Enzymes) as one attempt to enhance student learning and retention of key concepts in Enzyme Kinetics and Pharmacodynamics. SiREn is a student-driven idea, and an interprofessional collaboration between members of the College of Health Sciences, College of Graduate Studies, and College of Medicine at California Northstate University. This software was implemented in LabVIEW© language (National Instruments, Inc) and runs on both Windows and Mac Operating Systems. SiREn includes interactive simulations of the Michaelis-Menten, Lineweaver-Burk, Dose-Response, Therapeutic-Index models. All the relevant parameters for the simulation such as substrate concentration, Km, Vmax, and Kd can easily be modified by the user. Two versions of the software were developed: SiREn1 with a teaching emphasis for the College of Graduate Studies and SiREn2 customized for the College of Health Sciences. The latter has already been used in a Pharmacology class in the Spring 2022 semester. Feedback was collected from 16 pharmacology students. Overall, 63% of the users felt that SiREn2 improved their understanding of the Therapeutic Index concept, and 68.8% felt that SiREn2 facilitated self-paced, interactive learning by allowing a dynamic visualization of the formulas under different scenarios. These preliminary results suggest that integrating simulation for complex models is a useful addition to distance learning. This is the first stage of an ongoing project, and SiREn1 is currently being implemented in the Fall 2022 Pharmacology Course with added student suggestions for improvement.

Epigenetics and the role of nutraceuticals in health and disease.

In the post-genomic era, the data provided by complete genome sequencing could not answer several fundamental questions about the causes of many noninfectious diseases, diagnostic biomarkers, and novel therapeutic approaches. The rapidly expanding understanding of epigenetic mechanisms, as well as widespread acceptance of their hypothesized role in disease induction, facilitated the development of a number of novel diagnostic markers and therapeutic concepts. Epigenetic aberrations are reversible in nature, which enables the treatment of serious incurable diseases. Therefore, the interest in epigenetic modulatory effects has increased over the last decade, so about 60,000 publications discussing the expression of epigenetics could be detected in the PubMed database. Out of these, 58,442 were published alone in the last 10years, including 17,672 reviews (69 historical articles), 314 clinical trials, 202 case reports, 197 meta-analyses, 156 letters to the editor, 108 randomized controlled trials, 87 observation studies, 40 book chapters, 22 published lectures, and 2 clinical trial protocols. The remaining publications are either miscellaneous or a mixture of the previously mentioned items. According to the species and gender, the publications included 44,589 human studies (17,106 females, 14,509 males, and the gender is not mentioned in the remaining papers) and 30,253 animal studies. In the present work, the role of epigenetic modulations in health and disease and the influencing factors in epigenetics are discussed.

Cancer Cells Enter an Adaptive Persistence to Survive Radiotherapy and Repopulate Tumor.

Repopulation of residual tumor cells impedes curative radiotherapy, yet the mechanism is not fully understood. It is recently appreciated that cancer cells adopt a transient persistence to survive the stress of chemo- or targeted therapy and facilitate eventual relapse. Here, it is shown that cancer cells likewise enter a "radiation-tolerant persister" (RTP) state to evade radiation pressure in vitro and in vivo. RTP cells are characterized by enlarged cell size with complex karyotype, activated type I interferon pathway and two gene patterns represented by CST3 and SNCG. RTP cells have the potential to regenerate progenies via viral budding-like division, and type I interferon-mediated antiviral signaling impaired progeny production. Depleting CST3 or SNCG does not attenuate the formation of RTP cells, but can suppress RTP cells budding with impaired tumor repopulation. Interestingly, progeny cells produced by RTP cells actively lose their aberrant chromosomal fragments and gradually recover back to a chromosomal constitution similar to their unirradiated parental cells. Collectively, this study reveals a novel mechanism of tumor repopulation, i.e., cancer cell populations employ a reversible radiation-persistence by poly- and de-polyploidization to survive radiotherapy and repopulate the tumor, providing a new therapeutic concept to improve outcome of patients receiving radiotherapy.

The Antibiotic Kitasamycin-A Potential Agent for Specific Fibrosis Preventing Therapy after Fistulating Glaucoma Surgery?

One major complication after fistulating glaucoma surgeries are fibroblast-mediated scarring processes and their specific prevention is key in the development of novel pharmaceutical concepts. Within this study a possible antifibrotic potential of kitasamycin (KM) in a transforming growth factor (TGF)-β1-mediated fibroblast model was evaluated in vitro. Primary ocular fibroblasts were isolated, cultivated and a dose-response test including determination of the half maximal effective concentration (EC50) for KM was conducted. Transformation of fibroblasts into myofibroblasts was induced by TGF-β1and immunofluorescence (IF), and Western blot (WB) analyses were performed with fibroblasts and myofibroblasts. IF analyses were carried out using antibodies against α-smooth muscle actin (α-SMA) and fibronectin, and protein detection of intracellular and extracellular proteins was performed by WB. Using the dose-response test, the viability, cytotoxicity and EC50 of KM after 24 and 48 h were determined. Fibroblasts exposed to various KM concentrations showed no increase in α-SMA and extracellular matrix expression. In TGF-ß1-stimulated myofibroblasts, KM inhibited the expression of α-SMA and fibronectin in a concentration-dependent manner. These findings demonstrate that KM could impair the transformation of fibroblasts into myofibroblasts and the expression of proteins involved in fibrotic processes, representing a potential agent for specific fibrosis prevention in future therapeutic concepts.

Significance of Pulmonary Endothelial Injury and the Role of Cyclooxygenase-2 and Prostanoid Signaling.

The endothelium plays a key role in the dynamic balance of hemodynamic, humoral and inflammatory processes in the human body. Its central importance and the resulting therapeutic concepts are the subject of ongoing research efforts and form the basis for the treatment of numerous diseases. The pulmonary endothelium is an essential component for the gas exchange in humans. Pulmonary endothelial dysfunction has serious consequences for the oxygenation and the gas exchange in humans with the potential of consecutive multiple organ failure. Therefore, in this review, the dysfunction of the pulmonary endothel due to viral, bacterial, and fungal infections, ventilator-related injury, and aspiration is presented in a medical context. Selected aspects of the interaction of endothelial cells with primarily alveolar macrophages are reviewed in more detail. Elucidation of underlying causes and mechanisms of damage and repair may lead to new therapeutic approaches. Specific emphasis is placed on the processes leading to the induction of cyclooxygenase-2 and downstream prostanoid-based signaling pathways associated with this enzyme.

Evolving treatment landscape of advanced endometrial cancer – A current perspective from a German tertiary referral center for gynecological oncology

Endometrial cancer (EC) represents the most prevalent cancer of the female genital tract worldwide. Although EC has an overall good prognosis compared to other gynecological malignancies, a recent report from the American Cancer Society indicated that the cancer-specific survival of patients with EC has decreased since the 1970s, while the incidence has remained stable ( [1] Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan; 72: 7-33 Google Scholar ). The increasing EC-specific mortality is particularly attributable to EC with non-endometrioid histology. Although non-endometrioid histology represents only about 20% of all EC, non-endometrioid EC account for more than half of EC-related deaths ( 2 Clarke M.A. Devesa S.S. Harvey S.V. Wentzensen N. Hysterectomy-Corrected Uterine Corpus Cancer Incidence Trends and Differences in Relative Survival Reveal Racial Disparities and Rising Rates of Nonendometrioid Cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2019 Aug 1; 37: 1895-1908 Google Scholar , 3 McGunigal M. Liu J. Kalir T. Chadha M. Gupta V. Survival Differences Among Uterine Papillary Serous, Clear Cell and Grade 3 Endometrioid Adenocarcinoma Endometrial Cancers: A National Cancer Database Analysis. Int J Gynecol Cancer Off J Int Gynecol Cancer Soc. 2017 Jan; 27: 85-92 Google Scholar ). The determinants underlying the increase in non-endometrioid EC remain elusive. Overall, EC contrasts to the majority of other malignancies, whose cancer-specific survival has improved in recent years ( [1] Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan; 72: 7-33 Google Scholar ). Hence, it is crucial to reconsider and optimize existing therapy strategies and, to incorporate novel scientific findings into therapy algorithms. Here, we compile existing therapeutic concepts for advanced EC and propose a treatment algorithm based on current clinical and translational research findings.

The Role of Inflammation and Therapeutic Concepts in Diabetic Retinopathy-A Short Review.

Diabetic retinopathy (DR) as a microangiopathy is the most common complication in patients with diabetes mellitus (DM) and remains the leading cause of blindness among adult population. DM in its complicated pathomechanism relates to chronic hyperglycemia, hypoinsulinemia, dyslipidemia and hypertension-all these components in molecular pathways maintain oxidative stress, formation of advanced glycation end-products, microvascular changes, inflammation, and retinal neurodegeneration as one of the key players in diabetes-associated retinal perturbations. In this current review, we discuss the natural history of DR with special emphasis on ongoing inflammation and the key role of vascular endothelial growth factor (VEGF). Additionally, we provide an overview of the principles of diabetic retinopathy treatments, i.e., in laser therapy, anti-VEGF and steroid options.

One-dimensional nanomaterials for cancer therapy and diagnosis.

One-dimensional (1-D) nanomaterials possess unique shape-dependent phyicochemical properties and are increasingly recognized as promising materials for nanotechnology. 1-D nanomaterials can be classified according to their shape, such as nanorods, nanotubes, nanowires, self-assembled nanochains, etc., and have been applied in electronics, photonics, and catalysis. The biological characteristics of 1-D nanomaterials, including high drug loading efficiency, prolonged blood circulation, the ability to capture cancer cells, unique cellular uptake mechanisms, efficient photothermal conversion, and material tunability, have aided in extending their potential to biomedical applications, particularly in cancer therapy and diagnosis. This review highlights a novel perspective on emerging 1-D nanomaterials for cancer therapy and diagnosis by introducing the definition of 1-D nanomaterials, their shape-dependent physicochemical properties, biomedical applications, and recent advances in cancer therapy and diagnosis. This review also proposes unexplored potential nanomaterial types and therapeutic applications for 1-D nanomaterials. In particular, the most significant and exciting advances in recent years, including ultrasound-enabled sonodynamic therapy, magnetic field-based therapy, and bioresponsive 1-D nanomaterials for intracellular self-assembly in situ, are discussed along with novel therapeutic concepts, such as piezoelectric 1-D nanomaterials, nanozyme-based nanomedicine, and others.

Refractory and relapsed paediatric ACC in the MET studies – A challenging situation necessitating novel diagnostic and therapeutic concepts

Refractory and relapsed paediatric ACC in the MET studies – A challenging situation necessitating novel diagnostic and therapeutic concepts

Amniotic Fluid Stem Cells: What They Are and What They Can Become.

In the last two decades, fetal amniotic fluid stem cells progressively attracted attention in the context of both basic research and the development of innovative therapeutic concepts. They exhibit broadly multipotent plasticity with the ability to differentiate into cells of all three embryonic germ layers and low immunogenicity. They are convenient to maintain, highly proliferative, genomically stable, non-tumorigenic, perfectly amenable to genetic modifications, and do not raise ethical concerns. However, it is important to note that among the various fetal amniotic fluid cells, only c-Kit+ amniotic fluid stem cells represent a distinct entity showing the full spectrum of these features. Since amniotic fluid additionally contains numerous terminally differentiated cells and progenitor cells with more limited differentiation potentials, it is of highest relevance to always precisely describe the isolation procedure and characteristics of the used amniotic fluid-derived cell type. It is of obvious interest for scientists, clinicians, and patients alike to be able to rely on up-todate and concisely separated pictures of the utilities as well as the limitations of terminally differentiated amniotic fluid cells, amniotic fluid-derived progenitor cells, and c-Kit+ amniotic fluid stem cells, to drive these distinct cellular models towards as many individual clinical applications as possible.

Angina pectoris und die Bedeutung der koronaren Mikrozirkulation in der Praxis

Angina Pectoris and the Importance of Coronary Microcirculation in Practice Abstract. Microvascular angina is a common manifestation of coronary microvascular dysfunction, particulary prevalent in post-menopausal women above the age of 50 and associated with impaired quality of life and poor clinical outcomes. However, microvascular angina remains largely undetected given the underuse of diagnostic tools for the assessment of coronary microvascular function. As a consequence, many of these patients suffering from coronary microvascular dysfunction fail to receive the appropriate medical treatment and remain in the long term symptomatic. Invasive coronary catheterization with measurement of coronary flow reserve and intracoronary acetylcholine provocation testing allows for the assessment of coronary microvascular dysfunction, and a therapy targeting specific physiological pathways can be implemented. A targeted therapy includes lifestyle modifications, secondary prevention measures, and anti-anginal medication. Ongoing clinical research in the field is expected to deliver novel diagnostic and therapeutic concepts for an improved management of patients with coronary microvascular disease.

Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?

Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life. Here, we summarize emerging links between the most common late life neurodegenerative disease, Alzheimer's disease, and the most common early life neurodegenerative diseases, neuronal ceroid lipofuscinoses. Genetic studies reported an overlap of clinically diagnosed Alzheimer's disease and mutations in genes known to cause neuronal ceroid lipofuscinoses. Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders. This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases. A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts, the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations. Here, we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer's disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.

Včasná intervencia ako možnosť predchádzania vzniku syndrómu CAN z pohľadu špeciálnej pedagogiky

The paper presents the possibilities of early care for a child with CAN syndrome. The author presents specific therapeutic concepts of help that can be implemented by professionals, including special educators.

Congenital Oblique Talus Spontaneous Reduction-Case Report

Congenital oblique talus is a very rare condition which presents as an isolated deformity or in association with neuromuscular and/or genetic disorders. Pathoanatomically the deformity shows a dislocated talonavicular and subtalar joint. The ethiology and pathogenesis are still not finally determined, although in some cases a genetic basis has been identified. The clinical picture is that of a flat longitudinal arch. Clinical diagnosis is confirmed by plain radiographic imaging of anteroposterior and lateral views. Congenital oblique talus should not be confused with other deformities of the foot, such as congenital vertical talus, which with stress view X-Ray can be reduced. The object of treatment of congenital oblique talus is to restore a normal anatomical relationship between the talus, navicular bone and calcaneus. Good early results of modified non-operative treatment using serial manipulations, physiotherapy, special shoes or cast treatment may change therapeutic concepts.

Perspectives for novel therapeutic concepts in hepatocellular carcinoma targeting the stromal and innate immune microenvironment

AbstractHepatocellular carcinoma (HCC) is a major public health burden with increasing incidence and mortality worldwide. Arising almost exclusively on the background of chronic liver disease, the tumour microenvironment plays a tremendous role in the occurrence and progression of HCC. With the emergence of checkpoint inhibitor‐based combination therapies as first‐line therapy in advanced HCC, the tumour microenvironment has drawn increasing attention as a target for novel therapeutic approaches. In fact, checkpoint‐inhibitor‐based immunotherapies currently dominate clinical studies on HCC therapy. Importantly, whilst checkpoint‐inhibitor‐based immune‐oncology primarily targets T‐cells, the tumour microenvironment consists of a wide variety of different cell populations that show complex interactions with each other and the malignant tumour cells. Stromal cells and representatives of the innate immune system, such as macrophages, neutrophils and natural killer cells hereby orchestrate the initial immune response and thus appear as attractive targets for broad therapeutic effects, less susceptible to immune escape. In this review, we aim to discuss the current knowledge on the role of innate immune cells and stromal cell populations in HCC initiation and progression as well as related novel therapeutic concepts.

Medical ozone. Pharmacological mechanisms as basis of its effectiveness on the autoimmune response, vascular disorders, surgery and COVID-19/sars-CoV-2

Medical ozone is a therapeutic concept of proven pleiotropy. This means that it will have different effects on multiple pharmacological targets, which have been identified in hundreds of studies (experimental and clinical) on disease models and patients. These targets are closely connected to each other and can occur in different diseases. A good example is the “cytokine storm” in rheumatoid arthritis as well as in COVID-19/SARS-CoV-2. Therefore, the aim of this presentation is to highlight the therapeutic targets of medical ozone in different diseases, their interrelationship, and ozone application in pathological processes with an oxidative etiology.
 In animal models and in patients with rheumatoid arthritis, medical ozone has been shown to reduce proinflammatory cytokines (TNF-? and IL-1?) that contribute to “cytokine storm,” to synovitis, cartilage- and bone damaging autoantibodies and oxidative stress. Vascular complications in patients with diabetes were reduced when superoxide radical scavengers increased, mediated by medical ozone, restoring normal metabolic pathway functions and pancreatic integrity. Ozone prevented ischemic reperfusion injury and improved the systemic condition and quality of life of patients with knee osteoarthritis before and after arthroscopy.
 The integration of the above and other results was the basis for the introduction of medical ozone as a successful treatment in a new disease: COVID-19.

Autophagy impairment is involved in midazolam-induced lipid droplet accumulation and consequent phagocytosis decrease in BV2 cells

An increasing number of experimental and clinical observation suggest that the use of anaesthetics is closely associated with postoperative central nervous system (CNS) complications, such as delirium and cognitive dysfunction. Brain energy rescue is an emerging therapeutic strategy for central nervous system disease (CNSDs). However, the effect of anaesthetics on nerve cell energy utilisation, especially microglia, and its potential effects on cell function still unclear. Elucidating the effects of anaesthetics on lipid droplets, which are specific lipid storage organs, and phagocytosis of microglia is crucial to discover a new therapeutic concept for postoperative CNS complications. Here, we studied the effects of the commonly used anaesthetic midazolam on lipid droplets and phagocytosis in immortalised microglial BV2 cells. Lipid droplets were assessed by flow cytometry and triglyceride quantification. The phagocytosis of BV2 cells was evaluated by detecting their phagocytosis by latex beads. Additionally, the autophagy of BV2 cells was evaluated by western blot and observation under microscopy. Our results showed that midazolam caused lipid droplet accumulation and reduced phagocytosis in BV2 cells, and inhibition of lipid droplet accumulation partially restored phagocytosis. Furthermore, midazolam blocks autophagic degradation by increasing phosphorylated TFEB in BV2 cells, inhibition of midazolam-increased phosphorylated TFEB might contribute to the improvement of autophagic flux by rapamycin. Moreover, promoting autophagy reverse the lipid droplet accumulation and phagocytosis decrease. This study suggests autophagy is a target for attenuating lipid droplet accumulation, normal degradation of lipid droplets is important for maintaining microglia phagocytosis and attenuating the side effects of midazolam on the CNS.

Ozone therapy - present and perspective.

This work connects extensive literature research of the last three decades on medical ozone and the personal clinical experience (more than ten years) of ozone therapy.
 Classical and more recent concepts were considered: hormesis and lowdose concept, ozone action through messenger-molecules – reactive species (well-studied H?O? and 4-HNE), their implication in the redox homeostasis and in cellular signalling and the consecutive cellular response by adaptation or apoptosis. Another issue in the therapy is a correct diagnosis – based on molecular mechanisms. Many current diseases are sharing commune etiopathogenesis – redox homeostasis alteration, mitochondrial dysfunction, chronic inflammation, endothelial disturbances, early cellular senescence, accelerated apoptosis. As such, a new therapeutic concept aimed to adjust these mechanisms appeared: “Many diseases - One therapy”, and the ozone fits perfectly to this pattern.
 The mentioned diseases and their complications have a tremendous emotional and social impact on the patients and their families and a negative economic effect on society. If ozone therapy is correctly applied – proper diagnosis, low/medium doses, standard and safe procedures, complementary to the specific treatment/diet of undergone conditions – it will act on numerous diseases, improving the clinical status, stimulating the healing process, practically without side effects. Despite the O3 clinical efficacy, its potential toxicity as a strong oxidant is a cause for concern. This occurs when the doctor does not correctly evaluate the oxidant status of the patient, while he is not aware of the disease etiopathogenesis and/or when he applies inadvertent ozone operational procedures. Future works, especially controlled randomized studies, are necessary to demonstrate the efficacy and safety of ozone therapy and whether these effects persist over time.

Mid-Term Results following Traumatic Knee Joint Dislocation

Although treatment strategies of knee joint dislocations have evolved, there is still no consensus on the best method and timing. New therapeutic concepts suggest that early one-stage treatment, including suturing and bracing of the cruciate ligaments in acute knee joint dislocation, are leading to improved functional results. This study aimed to evaluate the midterm functional outcome following traumatic knee joint dislocation and to determine whether the outcome is influenced by the surgical management, patient habitus or concomitant injuries. In this retrospective single center study, 38 patients with acute Schenck type II to IV knee dislocations were treated over an eight-year period in a level I trauma center. At follow-up, various clinical scores, such as the International Knee Documentation Committee (IKDC) Score, Lysholm Score, and Tegner Activity Scale (TAS), and individual questions about rehabilitation and activity levels of 38 patients were evaluated. Mean follow-up was 5.5 ± 2.7 years. The mean IKDC Score was 65.6 ± 15.7 points, the average Lysholm Score was 70.5 ± 16.4 points and the median TAS was 4 (0-7), resulting in a loss of activity of 2 (range 0-6) points. There was no significant difference between a one-stage treatment compared to a two-stage approach. Ligament reconstruction of the ACL in a two-stage approach was required in only 33.3%. Further operations (early and late) were performed in 37% of cases. Being overweight was associated with more complications and worse outcomes, and external fixation with arthrofibrosis. Knee dislocation is a severe trauma that often leads to a prolonged loss of function and increased knee pain over years, affecting the patient's activity. Clinical outcome is influenced significantly by concomitant injuries. Severe cases with initial external fixation are associated with a higher risk of knee stiffness and should be considered during rehabilitation. Obese patients present a challenge due to higher complication rates and lower postoperative knee function. Retrospective single center study, level III.

QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice.

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer's disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to β-secretase (BACE), glycogen synthase kinase 3β (GSK3β), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1mg/kg) administration for 45days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aβ) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.