scholarly journals Immune-Regulatory Mechanisms in Systemic Autoimmune and Rheumatic Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Yuya Takakubo ◽  
Yrjö T. Konttinen
Keyword(s):  
Rheumatic Diseases ◽  
Intracellular Signaling ◽  
Clinical Results ◽  
New Drugs ◽  
Disease Mechanisms ◽  
Tolerogenic Dendritic Cells ◽  
Th 17 ◽  
Current Therapies ◽  
Low Costs ◽  
Made In

Systemic autoimmune and rheumatic diseases (SAIRDs) are thought to develop due to the failure of autoimmune regulation and tolerance. Current therapies, such as biologics, have improved the clinical results of SAIRDs; however, they are not curative treatments. Recently, new discoveries have been made in immune tolerance and inflammation, such as tolerogenic dendritic cells, regulatory T and B cells, Th 17 cells, inflammatory and tolerogenic cytokines, and intracellular signaling pathways. They lay the foundation for the next generation of the therapies beyond the currently used biologic therapies. New drugs should target the core processes involved in disease mechanisms with the aim to attain complete cure combined with safety and low costs compared to the biologic agents. Re-establishment of autoimmune regulation and tolerance in SAIRDs by the end of the current decade should be the final and realistic target.

scholarly journals Idiopathic Pulmonary Comorbidities and Mechanisms

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Maricica Pacurari ◽  
Amal Mitra ◽  
Timothy Turner
Keyword(s):  
Risk Factor ◽  
Scientific Evidence ◽  
New Drugs ◽  
Unknown Etiology ◽  
Disease Development ◽  
Cellular Mechanisms ◽  
Progressive Decline ◽  
The Past ◽  
Disease Mechanisms ◽  
Made In

Idiopathic pulmonary fibrosis (IPF) is a disease with an unknown etiology mainly characterized by a progressive decline of lung function due to the scarring of the tissue deep in the lungs. The overall survival after diagnosis remains low between 3 and 5 years. IPF is a heterogeneous disease and much progress has been made in the past decade in understanding the disease mechanisms that contributed to the development of two new drugs, pirfenidone and nintedanib, which improved the therapeutic management of the disease. The understanding of the cofactors and comorbidities of IPF also contributed to improved management of the disease outcome. In the present review, we evaluate scientific evidence which indicates IPF as a risk factor for other diseases based on the complexity of molecular and cellular mechanisms involved in the disease development and of comorbidities. We conclude from the existing literature that while much progress has been made in understating the mechanisms involved in IPF development, further studies are still necessary to fully understand IPF pathogenesis which will contribute to the identification of novel therapeutic targets for IPF management as well as other diseases for which IPF is a major risk factor.

scholarly journals PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

2021 ◽  
Vol 22 (7) ◽  
pp. 3464
Author(s):  
Rosalin Mishra ◽  
Hima Patel ◽  
Samar Alanazi ◽  
Mary Kate Kilroy ◽  
Joan T. Garrett
Keyword(s):  
Clinical Trials ◽  
Intracellular Signaling ◽  
Pi3k Pathway ◽  
Combination Therapies ◽  
Intracellular Signaling Pathway ◽  
Pi3k Inhibitors ◽  
Promising Therapeutic Target ◽  
Cancer Cell Survival ◽  
Current Therapies ◽  
Cancer Types

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

scholarly journals Newly Identified Antibacterial Compounds Are Topoisomerase Poisons in African Trypanosomes

2009 ◽  
Vol 54 (2) ◽  
pp. 620-626 ◽  
Author(s):  
Sonya C. Tang ◽  
Theresa A. Shapiro
Keyword(s):  
Topoisomerase Ii ◽  
Protozoan Parasite ◽  
New Drugs ◽  
Chemical Library ◽  
African Trypanosomes ◽  
Topoisomerase Poisons ◽  
Type Ia ◽  
Library Screen ◽  
Circular Dnas ◽  
Current Therapies

ABSTRACT Human African trypanosomiasis, caused by the Trypanosoma brucei protozoan parasite, is fatal when left untreated. Current therapies are antiquated, and there is a need for new pharmacologic agents against T. brucei targets that have no human ortholog. Trypanosomes have a single mitochondrion with a unique mitochondrial DNA, known as kinetoplast DNA (kDNA), a topologically complex network that contains thousands of interlocking circular DNAs, termed minicircles (∼1 kb) and maxicircles (∼23 kb). Replication of kDNA depends on topoisomerases, enzymes that catalyze reactions that change DNA topology. T. brucei has an unusual type IA topoisomerase that is dedicated to kDNA metabolism. This enzyme has no ortholog in humans, and RNA interference (RNAi) studies have shown that it is essential for parasite survival, making it an ideal drug target. In a large chemical library screen, two compounds were recently identified as poisons of bacterial topoisomerase IA. We found that these compounds are trypanocidal in the low micromolar range and that they promote the formation of linearized minicircles covalently bound to protein on the 5′ end, consistent with the poisoning of mitochondrial topoisomerase IA. Surprisingly, however, band depletion studies showed that it is topoisomerase IImt, and not topoisomerase IAmt, that is trapped. Both compounds are planar aromatic polycyclic structures that intercalate into and unwind DNA. These findings reinforce the utility of topoisomerase IImt as a target for development of new drugs for African sleeping sickness.

scholarly journals Translational strategies in peripheral neuroinflammation and neurovascular repair

2012 ◽  
Vol 3 (4) ◽  
Author(s):  
Eroboghene Ubogu
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Axonal Degeneration ◽  
Peripheral Nerve Regeneration ◽  
Treatment Strategies ◽  
Normal Function ◽  
New Drugs ◽  
Immune Mediated ◽  
Current Therapies

AbstractCurrent therapies for immune-mediated inflammatory disorders in peripheral nerves are non-specific, and partly efficacious. Peripheral nerve regeneration following axonal degeneration or injury is suboptimal, with current therapies focused on modulating the underlying etiology and treating the consequences, such as neuropathic pain and weakness. Despite significant advances in understanding mechanisms of peripheral nerve inflammation, as well as axonal degeneration and regeneration, there has been limited translation into effective new drugs for these disorders. A major limitation in the field has been the unavailability of reliable disease models or research tools that mimic some key essential features of these human conditions. A relatively overlooked aspect of peripheral nerve regeneration has been neurovascular repair required to restore the homeostatic microenvironment necessary for normal function. Using Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as examples of human acute and chronic immune-mediated peripheral neuroinflammatory disorders respectively, we have performed detailed studies in representative mouse models to demonstrate essential features of the human disorders. These models are important tools to develop and test treatment strategies using realistic outcomes measures applicable to affected patients. In vitro models of the human blood-nerve barrier using endothelial cells derived by endoneurial microvessels provide insights into pro-inflammatory leukocyte-endothelial cell interactions relevant to peripheral neuroinflammation, as well as potential mediators and signaling pathways required for vascular proliferation, angiogenesis, remodeling and tight junction specialization necessary to restore peripheral nerve function following injury. This review discusses some of the progress being made in translational peripheral neurobiology and some future

scholarly journals Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

2019 ◽  
Vol 116 (19) ◽  
pp. 9318-9323 ◽  
Author(s):  
Susan Wyllie ◽  
Stephen Brand ◽  
Michael Thomas ◽  
Manu De Rycker ◽  
Chun-wa Chung ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Proteasome Inhibition ◽  
New Drugs ◽  
Resource Poor Setting ◽  
Drug Candidate ◽  
Proteasome Subunits ◽  
Current Therapies ◽  
Mouse Model Of Infection

Visceral leishmaniasis (VL), caused by the protozoan parasitesLeishmania donovaniandLeishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasiteTrypanosoma cruzi. Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevantL. donovaniandL. infantumisolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the β5 subunit of theL. donovaniproteasome. High-resolution cryo-EM structures of apo and compound 8-boundLeishmania tarentolae20S proteasome reveal a previously undiscovered inhibitor site that lies between the β4 and β5 proteasome subunits. This induced pocket exploits β4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Improved Patient Compliance with Cleft Palate Team Regimes

1993 ◽  
Vol 30 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Earlene T. Paynter ◽  
Beth M. Wilson ◽  
William J. Jordan
Keyword(s):  
Cleft Palate ◽  
Patient Compliance ◽  
Clinical Investigation ◽  
Compliance Rate ◽  
Health Belief ◽  
Clinical Results ◽  
Belief Model ◽  
The Health Belief Model ◽  
Improve Patient ◽  
Made In

A cleft palate team's prescribed regimen requires prompt and continued compliance to meet the objectives of the clinical management and to achieve the best clinical results for the patient. In a previous study (Paynter et al., 1990), we reported an overall compliance rate of 64% for patients seen by a cleft palate team during its first 8 years of operation. After the study, changes in the team's operational procedures were made in an attempt to provide better service, improve patient compliance, and improve the efficiency of the clinic. The purposes of the current clinical investigation were to determine the degree of compliance with recommendations made by the cleft palate team for the patients seen during the four years after the implementation of the changes and to identify variables that interfered with compliance. A subject was defined as the person(s) who could best respond to questions concerning the management of the team's patient. Each subject was interviewed using a questionnaire based on the Health Belief Model (Becker et al., 1977). The mean patient compliance rate was 82%. Using Jones and Caldwell's (1981) classification, 56.7% of the patients were classified as compilers, 40% as partial compilers, and 3.3% as noncompliers. Compliance with specific recommendations ranged from 58 to 100%. No specific variable was found to interfere with compliance.

Inclusion body myositis in patients with spinocerebellar ataxia types 3 and 6

2020 ◽  
Vol 91 (8) ◽  
pp. 876-878
Author(s):  
Anke Rietveld ◽  
Judith van Gaalen ◽  
Christiaan Saris ◽  
Kees Okkersen ◽  
Benno Küsters ◽  
...  
Keyword(s):  
Quality Control ◽  
Inclusion Body ◽  
Spinocerebellar Ataxia ◽  
Neurological Examination ◽  
Inclusion Body Myositis ◽  
Disease Mechanisms ◽  
Sporadic Inclusion Body Myositis ◽  
Type 3 ◽  
Muscle Ultrasound ◽  
Made In

ObjectivesTo describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).MethodsA description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.ResultsThe patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients.ConclusionWe report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.

scholarly journals Indirubin and Indirubin Derivatives for Counteracting Proliferative Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Tina Blažević ◽  
Elke H. Heiss ◽  
Atanas G. Atanasov ◽  
Johannes M. Breuss ◽  
Verena M. Dirsch ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Active Component ◽  
Clinical Results ◽  
Chronic Myelocytic Leukemia ◽  
Myelocytic Leukemia ◽  
Pharmacokinetic Properties ◽  
Different Types ◽  
Traditional Chinese Medicine Formulation ◽  
Made In

Indirubin is the active component of Danggui Longhui Wan, a traditional Chinese medicine formulation. The encouraging clinical results from the 1980s obtained in chronic myelocytic leukemia patients treated with indirubin stimulated numerous studies on this compound. These investigations explored the use of indirubin in different types of cancer and reported the synthesis of novel derivatives with improved chemical and pharmacokinetic properties. In this paper, we review the impressive progress that has been made in elucidating the mechanistic understanding of how indirubin and its derivatives affect physiological and pathophysiological processes, mainly by inhibition of cell proliferation and induction of cell death. Furthermore, we survey the therapeutic use of these compounds in combating proliferative diseases such as cancer, restenosis, and psoriasis.

Restoration of Peroxiredoxins and Catalase Is Closely Correlated with the Level of Philadelphia Chromosome during Imatinib Therapy in CML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4539-4539
Author(s):  
Kyoung-Eun Lee ◽  
Hyun-Ae Woo ◽  
Seoug-Ha Yang ◽  
Jung-Won Huh ◽  
Moon Young Choi ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Philadelphia Chromosome ◽  
Bone Marrow Aspiration ◽  
New Drugs ◽  
Aberrant Expression ◽  
Abl Kinase ◽  
Normal Individuals

Abstract Background: Several investigators have recently shown that activated growth factor receptors increase the relative levels of intracellular ROS and that bcr/abl kinase induces the production of ROS in hematopoietic cells. In addition, bcr-abl kinase induces self-mutagenesis via ROS to encode IM resistance. Meanwhile, two members of the peroxiredoxin family, Prx 1 or Prx 2, efficiently lowered the intracellular level of H2O2 and blocked the induction of apoptosis by ceramide, suggesting that the Prx enzymes contribute to intracellular signaling by removing H2O2. In this study, we investigated the changse in the levels of H2O2-removing enzymes like Prxs, glutathione peroxidase 1 (Gpx1), and catalase during Imatinib (IM) therapy in CML. Methods: Mononuclear cells(MNC) were isolated by standard Ficoll-Hypaque from the bone marrow aspiration at the time of diagnosis and during treatment with IM (Gleevec, Novartis, East Hanover, NJ). Standard cytogenetics analysis and RT-PCR for Philadelphia chromosomes were performed. For immunoblot analysis of antioxidant enzymes, cell lysates were fractionated by SDS-PAGE, and the separated proteins were transferred electrophoretically to a nitrocellulose membrane (Protran, Germany) and were probed with antibodies specific for Prx I, II, VI, GPx1, or catalase (AbFrontier, South Korea). Results: Samples from the diagnosis CML patients showed significantly decreased levels of Prx I, Prx II, Prx IV, and Gpx I, but also revealed an increased level of catalase. Especially prominent was the diminished ratio of Prx II to catalase in CML patients when compared with those of normal individuals. As the level of Philadelphia chromosomes decreased to that of normal individuals as the result of IM treatment, the expression levels of Prx(s) (P=0.018) and catalase (P=0.009) were restored to the levels of normal individuals. Conclusions: Decreased Prx 2 and elevated catalase levels at the time of diagnosis are closely correlated with the elevated bcr/abl kinase level in CML. The aberrant expression of those antioxidant enzymes returned to normal with IM treatment. Now, we will attempt to develop these method(s) to assess the changes of Prx(s) and catalase on the single cell level using immunohistochemistry with monoclonal Ab(s). Understanding the molecular mechanisms of changes on antioxidant might be a potent tool in developing more effective new drugs in CML.

WITHDRAWN: Novel Immunological Targets in Rheumatic Diseases: Clues from Current Therapies

2014 ◽  
Author(s):  
Fulvio D’Acquisto ◽  
Lorenza Rattazzi ◽  
Giuseppa Piras ◽  
Maria Letteria Galuppo
Keyword(s):  
Rheumatic Diseases ◽  
Current Therapies
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