Shigeaki Suenaga

A mitochondrial superoxide theory for oxidative stress diseases and aging.

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O2•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.

Severity of synovium and bone marrow abnormalities of the temporomandibular joint in early rheumatoid arthritis: role of gadolinium-enhanced fat-suppressed T1-weighted spin echo MRI.

PURPOSE Our goal was to evaluate the efficacy of dynamic contrast-enhanced fat-suppressed MRI of the temporomandibular joint (TMJ) in detecting early joint involvement in patients with rheumatoid arthritis (RA). METHOD Conventional T1- and T2-weighted, gadolinium-enhanced T1-weighted, and dynamic gadolinium-enhanced fat-suppressed SE imaging sequences were performed in 22 patients with RA. RESULTS The dynamic gadolinium-enhanced fat-suppressed T1-weighted SE sequence was more sensitive than the other techniques in detecting early changes in inflamed synovium of periarticular tissue and in detecting condylar bone marrow involvement. In patients with RA, 17 joints with joint pain showed synovial proliferation in 10 (59%) cases and joint effusion in 4 (24%). Of 14 joints with joint sound, 4 (29%) showed synovial proliferation and 7 (50%) showed joint effusion. A lower positional change of the disk was observed in joints with RA than in those with TMJ disorders (82 patients). CONCLUSION Gadolinium-enhanced fat-suppressed MRI was extremely effective in diagnosing early changes of the inflamed TMJ.

MRI of the temporomandibular joint disk and posterior disk attachment before and after nonsurgical treatment.

PURPOSE Our goal was to investigate the role of serial dynamic contrast-enhanced SPGR MRI in the nonsurgical follow-up of patients with temporomandibular joint (TMJ) pain. METHOD Ten patients (10 joints) with internal derangement of the TMJ were imaged with T1-weighted SE and serial postgadolinium SPGR MR pulse sequences. RESULTS On T1-weighted images prior to treatment, the disk position was normal in one joint and anteriorly displaced without reduction in nine joints. After treatment, the disk remained normally positioned in one joint, was anteriorly displaced without reduction in eight joints, and was anteriorly displaced with reduction in one joint. The dynamic study after treatment showed a decrease in contrast enhancement of the posterior disk attachment in 7 of 10 joints. These seven patients had resolution or reduction in joint pain. CONCLUSION These results suggest an association between a decrease in contrast enhancement of the posterior disk attachment and resolution or reduction in joint pain. This association was much stronger than the association between the clinical findings and the anatomy of the disk.

Roles of mitochondria-generated reactive oxygen species on X-ray-induced apoptosis in a human hepatocellular carcinoma cell line, HLE

Abstract HLE, a human hepatocellular carcinoma cell line was transiently transfected with normal human MnSOD and MnSOD without a mitochondrial targeting signal (MTS). Mitochondrial reactive oxygen species (ROS), lipid peroxidation and apoptosis were examined as a function of time following 18.8 Gy X-ray irradiation. Our results showed that the level of mitochondrial ROS increased and reached a maximum level 2 hours after X-ray irradiation. Authentic MnSOD, but not MnSOD lacking MTS, protected against mitochondrial ROS, lipid peroxidation and apoptosis. In addition, the levels of mitochondrial ROS were consistently found to always correlate with the levels of authentic MnSOD in mitochondria. These results suggest that only when MnSOD is located in mitochondria is it efficient in protecting against cellular injuries by X-ray irradiation and that mitochondria are the critical sites of X-ray-induced cellular oxidative injuries.

Temporomandibular disorders: MR assessment of inflammatory changes in the posterior disk attachment during the menstrual cycle.

Purpose Our goal was to correlate the menstrual cycle with joint pain, MR evidence of the disk, and posterior disk attachment in patients with temporomandibular disorders. Method Forty-two women underwent MRI involving conventional T1-and T2-weighted gadolinium-enhanced fat-suppressed SE imaging sequences. Results There was a strong statistical difference in the degree of joint pain between proliferated phase and secretory phase groups (p < 0.005). Joint pain had a tendency to increase at the secretory phase. Significantly less contrast enhancement of the posterior disk attachment was observed in the proliferated phase than in the secretory phase (p < 0.001) or menstrual phase (p < 0.01). In addition, anterior disk displacement without reduction of the temporomandibular joint was closely associated with joint pain. Conclusion Our results suggest that positional changes of the disk and the menstrual cycle may play a role in the degree of joint pain and inflammatory pathology of the posterior disk attachment.

Mitochondria as possible pharmaceutical targets for the effects of vitamin E and its homologues in oxidative stress-related diseases.

It is well known that vitamin E functions as an antioxidant, and it is expected to exert an antioxidant effect when taken as a supplement. However, a number of cohort studies have shown that vitamin E does not alleviate oxidative stress and could even worsen it. Recently, Wang et al. investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) based on data from 5 cohort studies with 1,055,546 participants, of which 805 of them had developed ALS. They concluded in this large pooled prospective study, in which long-term vitamin E supplementation was associated with lower ALS rates, and therefore, a possible protective effect of vitamin E deserves further consideration. Performing further large cohort studies may reveal similar findings for other oxidative stress-related diseases. It is still controversial if antioxidants such as vitamin E provide a clinical therapeutic effect against oxidative stress-related diseases. If effective, the dose at which they should be administered and the duration of supplement exposure should be of interest. Vitamin E reduces production of reactive oxygen species by mitochondria and elicits further reactions in cells. It should be noted that mitochondria are important targets for vitamin E and its homologues. Therefore, a proper usage of vitamin E in subjects under high oxidative stress, due to its individually targeting property, will arise its importance in healthy life.

Blue LED light exposure develops intracellular reactive oxygen species, lipid peroxidation, and subsequent cellular injuries in cultured bovine retinal pigment epithelial cells

Abstract The effects of blue light emitter diode (LED) light exposure on retinal pigment epithelial cells (RPE cells) were examined to detect cellular damage or change and to clarify its mechanisms. The RPE cells were cultured and exposed by blue (470 nm) LED at 4.8 mW/cm2. The cellular viability was determined by XTT assay and cellular injury was determined by the lactate dehydrogenase activity in medium. Intracellular reactive oxygen species (ROS) generation was determined by confocal laser microscope image analysis using dihydrorhodamine 123 and lipid peroxidation was determined by 4-hydroxy-2-nonenal protein-adducts immunofluorescent staining (HNE). At 24 h after 50 J/cm2 exposures, cellular viability was significantly decreased to 74% and cellular injury was significantly increased to 365% of control. Immediately after the light exposure, ROS generation was significantly increased to 154%, 177%, and 395% of control and HNE intensity was increased to 211%, 359%, and 746% of control by 1, 10, and 50 J/cm2, respectively. These results suggest, at least in part, that oxidative stress is an early step leading to cellular damage by blue LED exposure and cellular oxidative damage would be caused by the blue light exposure at even lower dose (1, 10 J/cm2).

The usefulness of diagnostic imaging for the assessment of pain symptoms in temporomandibular disorders

Summary The causes of pain symptoms in the temporomandibular joint (TMJ) and masticatory muscle (MM) regions may not be determined by clinical examination alone. In this review, we document that pain symptoms of the TMJ and MM regions in patients with temporomandibular disorders (TMDs) are associated with computed tomography and magnetic resonance (MR) findings of internal derangement, joint effusion, osteoarthritis, and bone marrow edema. However, it is emphasized that these imaging findings must not be regarded as the unique and dominant factors in defining TMJ pain. High signal intensity and prominent enhancement of the posterior disk attachment on fat saturation T2-weighted imaging and dynamic MR imaging with contrast material are closely correlated with the severity of TMJ pain. Magnetic transfer contrast, MR spectroscopy, diffusion tensor imaging, and ultrasonography findings have helped identify intramuscular edema and contracture as one of the causes of MM pain and fatigue. Recently, changes in brain as detected by functional MR neuroimaging have been associated with changes in the TMJ and MM regions. The thalamus, the primary somatosensory cortex, the insula, and the anterior and mid-cinglate cortices are most frequently associated with TMD pain.

MnSOD downregulation induced by extremely low 0.1 mGy single and fractionated X-rays and microgravity treatment in human neuroblastoma cell line, NB-1

A human neuroblastoma cell line, NB-1, was treated with 24 h of microgravity simulation by clinostat, or irradiated with extremely small X-ray doses of 0.1 or 1.0 mGy using single and 10 times fractionation regimes with 1 and 2 h time-intervals. A quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) examination was performed for apoptosis related factors (BAX, CYTC, APAF1, VDAC1–3, CASP3, CASP8, CASP9 P53, AIF, ANT1 and 2, BCL2, MnSOD, autophagy related BECN and necrosis related CYP-40. The qRT-PCR results revealed that microgravity did not result in significant changes except for a upregulation of proapoptotic VDAC2, and downregulations of proapoptotic CASP9 and antiapoptotic MnSOD. After 0.1 mGy fractionation irradiation, there was increased expression of proapoptotic APAF1 and downregulation of proapoptotic CYTC, VDAC2, VDAC3, CASP8, AIF, ANT1, and ANT2, as well as an increase in expression of antiapoptotic BCL2. There was also a decrease in MnSOD expression with 0.1 mGy fractionation irradiation. These results suggest that microgravity and low-dose radiation may decrease apoptosis but may potentially increase oxidative stress.

Mitochondria as Source of Free Radicals

Mitochondria have been considered to be mediators of cell metabolism involved in important life processes, such as aging, cell death, and persistent chronic diseases, in addition to their main functio