Decades of accumulated knowledge and improved comprehension of various perspectives on rheumatoid arthritis (RA) pathophysiology has led to the development of new biologic agents that inhibit a specific component of the RA inflammatory process. Especially during the last two decades, several epochal agents which target tumor necrosis factor-alpha, interleukin-1, interleukin-6, CD20-expressing B cell, and cytotoxic T lymphocyte antigen-4 were used in the management of RA and other autoimmune diseases with highly comparable efficacy and safety. Moreover, dozens of innovative agents queue up for clinical trials day by day. Herein, we review the current scenario of RA management in terms of pathogenesis and targeted molecular pathways, and some important controversies in this field as well. Based on the complications that these kinds of diseases pose, it is highly reasonable to hope that further improved therapies and more tailored drugs for RA will be introduced in the near future.
Arthritis, Rheumatoid ; Autoimmune Diseases ; Comprehension ; Interleukin-1 ; Interleukin-6 ; Lymphocytes ; Tumor Necrosis Factor-alpha

Recent progress of genetics has dramatically improved pharmacogenetics for human diseases. Several pharmacogenetic assays such as TPMT/azathioprine and CYP2C9/VKORC1/warfarin have been introduced in clinical practice at the present time. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that leads to irreversible joint damage and disability if it is not adequately treated. Although the introduction of anti-TNF therapy has improved the outcome of therapy in RA, a substantial proportion of patients (approximately 30-40%) fail to respond to the drugs. Recently, pharmacogenetic studies have widely been performed to search for genetic and mRNA expression biomarkers to predict the response of anti-TNF therapy in RA. Other potential serum biomarkers of response have also been explored including cytokines and autoantiboides. None has yet been validated for biomarkers that predict the response of biologic drugs in clinical rheumatology practice. However, future medicine using pharmacogenetic applications in RA might make personalized therapy possible.
Arthritis, Rheumatoid ; Autoimmune Diseases ; Cytokines ; Humans ; Joints ; Pharmacogenetics ; Prognosis ; Rheumatology ; RNA, Messenger ; Biomarkers ; Precision Medicine

This erratum is being published to correct of author name.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are natural by-products of cellular physiological processes involving metabolism of compounds containing oxygen and nitrogen, respectively. Physiological defense mechanisms against ROS/RNS readily convert them into water or urea, but dysregulation of ROS/RNS production damages cells resulting in abnormal conditions such as uncontrolled growth or cell death. ROS/RNS are closely related to the development of a variety of diseases such as cancer, diabetes, neurodegeneration, vascular disease and chronic inflammation. Thus, it has been proposed that the removal of ROS/RNS may prevent or treat oxidative stress-induced diseases. Some antioxidant molecules are synthesized in the body, while others are obtained from food in the diet including fruits, vegetables, meat and even in natural water. In addition to the natural antioxidants, synthetic antioxidants have been modified from natural chemicals so as to increase bioavailability to target organs and increase stability in the air. In developing novel antioxidants for therapeutic use, some factors to consider are: 1) improved efficacy; 2) low side effects (comparatively clear mechanism); 3) competitive price and 4) improved convenience of dosing. In this review, we will discuss the issues mentioned above and the use of antioxidants in clinical application.
Antioxidants ; Biological Availability ; Cell Death ; Defense Mechanisms ; Diet ; Fruit ; Inflammation ; Meat ; Nitrogen ; Oxygen ; Physiological Processes ; Reactive Nitrogen Species ; Reactive Oxygen Species ; Urea ; Vascular Diseases ; Vegetables ; Water

Amyloidogenesis is the key pathological phenomenon commonly observed in various neurodegenerative disorders. alpha-Synuclein is the major constituent of Lewy bodies as a common pathological signature of Lewy body diseases (LBDs) including Parkinson's disease (PD), PD with dementia (PDD), and Dementia with Lewy bodies (DLB). As proteins unfold, they would result in producing either ordered or disordered aggregates unless they are folded back to the native state by molecular chaperones or removed via proteolytic degradation. alpha-Synuclein known as a natively unfolded protein has self-assembled into the ordered protein aggregates of amyloid fibrils which comprise the radiating filaments found in Lewy bodies. Amyloid fibrils are generated via either a template-dependent or template-independent mechanism. The prevalent nucleation-dependent fibrillation accelerates the assembly process in the presence of seeds such as prefibrillar species. As a template-independent process, we have recently proposed the double-concerted fibrillation mechanism in which the oligomeric species of alpha-synuclein act as a growing unit to form the mature fibrils. Despite insufficient understanding of the toxic causes of alpha-synuclein, the oligomeric species have been suggested to be responsible for the cellular degeneration by influencing membrane stability while leaving the amyloid fibrils as a detoxification end product. Alternatively, the transition process from the oligomers to the fibrils has been proposed to affect cell viability. It is, therefore, expected to develop prophylactic and therapeutic strategies toward the synucleinopathies by studying cellular function of alpha-synuclein, molecular mechanism of its assembly into the amyloid fibrils, and their effects on cellular biogenesis. By studying cellular function of alpha-synuclein, its molecular mechanism of assembly into amyloid fibrils and their effects on cellular biogenesis, progress of prophylactic and therapeutic strategies toward synucleinopathy can be seen.
alpha-Synuclein ; Amyloid ; Amyloidosis ; Cell Survival ; Dementia ; Lewy Bodies ; Membranes ; Molecular Chaperones ; Neurodegenerative Diseases ; Parkinson Disease ; Proteins ; Seeds ; Organelle Biogenesis

Reactive Oxygen Species (ROS) are a class of signaling molecules that regulate intracellular signaling cascades in response to external stimuli. Once accumulated in cells, they can damage DNA modifying gene transcription and affecting protein expression and function in ways that accelerate tumorigenesis. In cancer cells, the accumulation of ROS can increase cell proliferation and cell invasion into other tissues, while, antioxidant enzymes and molecules can protect cells from oxidative stress so as to maintain cellular homeostatic redox status. Cancer cells often do not have sufficient levels of antioxidant enzymes which are needed to rescue cells from oxidative stress. The redox status of cancer cells appears to be a key factor in maintaining the malignant phenotype. Cancer stem cells, on the other hand, have been shown to maintain low levels of ROS in order to retain their self renewal and differentiation potential, even though the exact mechanism is not known yet. ROS and antioxidant enzymes are novel targets for developing anti-cancer therapeutics. In this review, the current understanding for redox regulation of cancer cells and neoplastic stem cells as well as the role and function of anti-oxidant enzymes and molecules is discussed.
Antioxidants ; Cell Proliferation ; Cell Transformation, Neoplastic ; DNA ; Hand ; Neoplastic Stem Cells ; Oxidation-Reduction ; Oxidative Stress ; Phenotype ; Reactive Oxygen Species

Various proteomics and immunological methods including mass spectrometry combined with both liquid and 2-D PAGE, and immunodetection have been employed to identify and characterize nitrated proteins from pathological samples. Nitrosative modifications regulate cellular signal transduction and pathogenesis of inflammatory responses and neurodegenerative diseases. Nitric oxide generates reactive nitrosative species, such as peroxynitrite (ONOO-) that may be involved in a number of diseases. ONOO- can mediate protein tyrosine nitration which causes structural changes of affected proteins and leads to their inactivation. Protein tyrosine nitration is a biomarker of oxidative stress and also influences protein structure and function. Recent advances in mass spectrometry have made it possible to identify modified proteins and specific modified amino acid residues. This review focuses on the significance of protein tyrosine nitration and the progress achieved in analytical methods. Although mass spectrometry of nitrated peptides has become a powerful tool for the analysis of nitrated peptides, the low stoichiometry of protein tyrosine nitration clearly demands the use of affinity chromatography to enrich modified proteins (or peptides).
Chromatography, Affinity ; Mass Spectrometry ; Neurodegenerative Diseases ; Nitric Oxide ; Oxidative Stress ; Peptides ; Peroxynitrous Acid ; Proteins ; Proteomics ; Signal Transduction ; Tyrosine

Reactive oxygen species (ROS) are harmful to cellular components such as proteins, DNA and lipids. The continuous production of ROS during the respiratory electron transfer process has been regarded as the major cause of aging. However, the discoveries of proteins whose structure and function switch with cellular ROS suggest that ROS are active players in cellular regulation. OxyR is the first protein whose ROS-regulated mechanism was revealed by the atomic structure studies. The distantly-located two cysteines in OxyR form a disulfide bond by reaction with ROS, resulting in conformational and functional switches in the protein. The heat shock protein 33 is another protein that is activated by increased level of cellular ROS. Many other cellular proteins including protein tyrosine phosphatases are also regulated by ROS. This review focuses on the structure and function of the ROS-regulated proteins and their implications on the ROS's cellular roles. Detailed studies on the ROS-generating protein machinery and the ROS-regulated proteins should contribute to the therapeutic control of ROS-related diseases and aging processes.
Aging ; DNA ; Electrons ; Heat-Shock Proteins ; Protein Tyrosine Phosphatases ; Proteins ; Reactive Oxygen Species

Peroxiredoxins (Prxs) are a family of antioxidant proteins that reduce peroxide levels by using reducing agents such as thioredoxin. These proteins were characterized to have a number of cellular functions, including cell proliferation and differentiation and protection of specific proteins from oxidative damage. Thus, it is important to clarify the physiological role of Prxs by generating mouse models deficient in each Prx to better understand the in vivo function of Prxs. We have generated and characterized mice deficient in Prx I and II that are abundantly expressed in almost all types of cells. The Prx II-/- mice were healthy in appearance and fertile, however showed several pathophysiological disorders. Using the mice, we found that Prx II is an essential antioxidant enzyme that prevents oxidative stress in erythropoiesis, protects against endotoxin-induced lethal shock, regulates platelet-derived growth factor signaling and angiogenesis, inhibits cellular senescence, preserves cognitive function against age-linked hippocampal oxidative damage and exacerbates tumorigenesis in a liver cancer mouse model. The Prx I-/- mice were also healthy in appearance and fertile like Prx II-/- mice. With the mice, we found that Prx I suppresses K-ras-driven lung tumorigenesis by opposing the redox-sensitive extracellular-signal-regulated kinase/cyclin D1 pathway and plays concerted action with sulfiredoxin in preventing against alcohol-induced oxidative injury in the mouse liver. The results obtained suggest that Prx I and II are essential antioxidant enzymes for maintaining redox homeostasis in mice.
Animals ; Antioxidants ; Cell Aging ; Cell Proliferation ; Cell Transformation, Neoplastic ; Erythropoiesis ; Homeostasis ; Humans ; Liver ; Liver Neoplasms ; Lung ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress ; Peroxiredoxins ; Platelet-Derived Growth Factor ; Proteins ; Reducing Agents ; Shock ; Thioredoxins

Release of reactive oxygen species (ROS) generated in the mitochondria to the cytosol is well controlled by various proteins in order to maintain and regulate redox homeostasis and cellular signaling pathways, however, the exact mechanisms by which the proteins located in the mitochondrial membrane control ROS release still remains to be identified. Although there are reports that several proteins play a role in mitochondrial ROS release to the cytosol, little is known about how it is released into the cytosol or its origin. Recently, several reports demonstrated that the ROS modulator 1 (Romo1) protein located on the mitochondrial membrane modulates ROS release into the cytosol and that these ROS are indispensible for survival in both normal cells and tumor cells. If these ROS are over-produced or dysregulated in pathological conditions, they may cause oxidative damages resulting in a variety of diseases. Therefore, understanding and identifying the mechanisms by which ROS are released to the cytosol may offer new strategies for pharmaceutical therapy of diseases related to oxidative stresses.
Cytosol ; Homeostasis ; Mitochondria ; Mitochondrial Membranes ; Oxidation-Reduction ; Oxidative Stress ; Proteins ; Reactive Oxygen Species