Recovery from Diabetic Macular Edema in a Diabetic Patient After Minimal Dose of a Sodium Glucose Co-Transporter 2 Inhibitor.

BACKGROUND Diabetic macular edema (DME) causes serious visual impairments in diabetic patients. The standard treatments of DME are intra-vitreous injections of corticosteroids or anti-vascular endothelial growth factor antibodies and pan-photocoagulation. These treatments are unsatisfactory in their effects and impose considerable physical and economic burdens on the patients. CASE REPORT A 63-year-old woman was diagnosed as type 2 diabetes with retinopathy 7 years ago. Before the initiation of an SGLT2 inhibitor, the dipeptidyl peptidase-4 inhibitor, sitagliptin (50 mg daily), and metformin (250 mg dai- ly) were used for her glycemic control. The level of her hemoglobin A1c had been controlled around 7%. She began to feel decreased visual acuity and blurred vision of her left eye 8 months before the visit to our clin- ic. She was diagnosed as DME, which turned out to be corticosteroid-resistant. Her visual acuity further de- creased to 20/50. Metformin was changed to ipraglifl (25mg/day). Her left visual acuity started to improve after 4 weeks of treatment with ipragliflozin and improved to 20/22 after 24 weeks. The macular edema did not change until 12 weeks of the treatment, however, it decreased prominently after 16 weeks. CONCLUSIONS In our patient with steroid-resistant DME, her visual symptoms and macular edema recovered after the initiation of an SGLT2 inhibitor. SGLT2 inhibitors might be a potential candidate for the DME treatment.

Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy.

Retinopathy and nephropathy are life-threatening diabetic complications that decrease patient quality of life. Although the mechanisms underlying these conditions have been extensively studied, they remain unknown. Recent reports have demonstrated the presence of sodium glucose cotransporter 2 (SGLT2) in retinal pericytes and mesangial cells. Hyperglycemia results in functional and morphological changes in these cells, but these effects are attenuated by phlorizin, a nonselective SGLT inhibitor. Based on these findings, we hypothesized that SGLT2 plays a pivotal role in the development of diabetic nephropathy and retinopathy and that SGLT2 inhibitors may directly protect against these complications.

Sodium Glucose Cotransporter 2 (SGLT2) Plays as a Physiological Glucose Sensor and Regulates Cellular Contractility in Rat Mesangial Cells.

PURPOSE: Mesangial cells play an important role in regulating glomerular filtration by altering their cellular tone. We report the presence of a sodium glucose cotransporter (SGLT) in rat mesangial cells. This study in rat mesangial cells aimed to evaluate the expression and role of SGLT2. METHODS: The SGLT2 expression in rat mesangial cells was assessed by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). Changes in the mesangial cell surface area at different glucose concentrations and the effects of extracellular Na+ and Ca2+ and of SGLT and Na+/Ca2+ exchanger (NCX) inhibitors on cellular size were determined. The cellular sizes and the contractile response were examined during a 6-day incubation with high glucose with or without phlorizin, an SGLT inhibitor. RESULTS: Western blotting revealed an SGLT2 band, and RT-PCR analysis of SGLT2 revealed the predicted 422-bp band in both rat mesangial and renal proximal tubular epithelial cells. The cell surface area changed according to the extracellular glucose concentration. The glucose-induced contraction was abolished by the absence of either extracellular Na+ or Ca2+ and by SGLT and NCX inhibitors. Under the high glucose condition, the cell size decreased for 2 days and increased afterwards; these cells did not contract in response to angiotensin II, and the SGLT inhibitor restored the abolished contraction. CONCLUSIONS: These data suggest that SGLT2 is expressed in rat mesangial cells, acts as a normal physiological glucose sensor and regulates cellular contractility in rat mesangial cells.

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases.

Psoriasis, a chronic inflammatory skin disease, is caused by infiltrating lymphocytes and associated cytokines, including tumor necrosis factor (TNF)α, interleukin (IL)-6, and IL-17. Effective treatments, including pathogenesis-based biological agents against psoriasis, are currently under development. Although the role of reactive oxygen species (ROS) in the pathogenesis of psoriasis has been investigated, it remains to be fully elucidated; ROS-targeted therapeutic strategies are also lacking at present. Therefore, the objective of the present study was to assess whether H2, a ROS scavenger, has a therapeutic effect on psoriasis-associated inflammation by reducing hydroxyl radicals or peroxynitrite in the immunogenic psoriasis cascade. Three methods were used to administer H2: Drop infusion of saline containing 1 ppm H2 (H2-saline), inhalation of 3% H2 gas, and drinking of water containing a high concentration (5-7-ppm) of H2 (high-H2 water). Treatment efficacy was estimated using the disease activity score 28 (DAS28) system, based on C-reactive protein levels, and the psoriasis area and severity index (PASI) score, determined at baseline and following each H2 treatment. Furthermore, levels of TNFα, IL-6, and IL-17 were analyzed. The DAS28 and PASI score of the three patients decreased during H2 treatment, regardless of the administration method. The psoriatic skin lesions almost disappeared at the end of the treatment. IL-6 levels decreased during H2 treatment in Case 1 and 2. IL-17, whose concentration was high in Case 1, was reduced following H2 treatment, and TNFα also decreased in Case 1. In conclusion, H2 administration reduced inflammation associated with psoriasis in the three cases examined and it may therefore be considered as a treatment strategy for psoriasis-associated skin lesions and arthritis.

Effects of hydrochlorothiazide on oxidative stress and pulse pressure in hypertensive patients with chronic stroke: the EMINENT study.

OBJECTIVE: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. METHODS: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. RESULTS: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. CONCLUSION: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.

Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function.

BACKGROUND: The redox imbalance between nitric oxide and superoxide generated in the endothelium is thought to play a pivotal role in the development of endothelial dysfunction. A third reactive oxygen species (ROS), H2O2, is known to have both beneficial and detrimental effects on the vasculature. Nonetheless, the influence of the hydroxyl radical, a byproduct of H2O2 decay, is unclear, and there is no direct evidence that the hydroxyl radical impairs endothelial function in conduit arteries. Molecular hydrogen (H2) neutralizes detrimental ROS, especially the hydroxyl radical. OBJECTIVES: To assess the influence of the hydroxyl radical on the endothelium and to confirm that a gaseous antioxidant, H2, can be a useful modulator of blood vessel function. METHODS: The efficacy of water containing a high concentration of H2 was tested by measuring flow-mediated dilation (FMD) of the brachial artery (BA). The subjects were randomly divided into two groups: the high-H2 group, who drank high-H2 water containing 7 ppm H2 (3.5 mg H2 in 500 mL water); and the placebo group. Endothelial function was evaluated by measuring the FMD of the BA. After measurement of diameter of the BA and FMD at baseline, volunteers drank the high-H2 water or placebo water immediately and with a 30-minute interval; FMD was compared to baseline. RESULTS: FMD increased in the high-H2 group (eight males; eight females) from 6.80%±1.96% to 7.64%±1.68% (mean ± standard deviation) and decreased from 8.07%±2.41% to 6.87%±2.94% in the placebo group (ten males; eight females). The ratio to the baseline in the changes of FMD showed significant improvement (P<0.05) in the high-H2 group compared to the placebo group. CONCLUSION: H2 may protect the vasculature from shear stress-derived detrimental ROS, such as the hydroxyl radical, by maintaining the nitric oxide-mediated vasomotor response.

Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study.

The aim of this study was to demonstrate the safety and efficacy of H2-saline infusion for treatment of rheumatoid arthritis (RA). We conducted a randomized, double-blind, placebo-controlled investigation of the infusion of 1 ppm H2-dissolved saline (H2-saline) in 24 RA patients. Patients were randomized 1:1 to receive 500 ml of either H2-saline or placebo-saline, which was drop infused intravenously (DIV) daily for 5 days. The disease activity score in 28 joints (DAS28) was measured at baseline, immediately post infusion, and after 4 weeks. Therapeutic effects of H2-saline on joint inflammation were estimated by measuring serum biomarkers for RA, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and urinary 8-hydroxydeoxyguanosine (8-OHdG). In the H2-infused group, average DAS28 decreased from 5.18 ± 1.16 to 4.02 ± 1.25 immediately post infusion and reached 3.74 ± 1.22 after 4 weeks. No significant decrease in DAS28 was observed in the placebo group throughout the study. IL-6 levels in the H2 group significantly decreased in 4 weeks by 37.3 ± 62.0% compared to baseline, whereas it increased by 33.6 ± 34.4% in the placebo group. TNFα levels did not change remarkably in the H2 or placebo groups in 4 weeks post-infusion compared to baseline. The relative ratio of 8-OHdG in the H2 group also significantly decreased by 4.7%. After 4 weeks, MMP3 was significantly reduced by 19.2% ± 24.6% in the H2 group, and increased by 16.9% ± 50.2% in the placebo group. Drop infusion of H2 safely and effectively reduced RA disease activity.

Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of RA. Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical. Also, the method to prepare water containing extremely high concentration of H2 has been developed. We hypothesized that H2 in the water could complement conventional therapy by reducing the oxidative stress in RA. METHODS: Twenty patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2 water) every day for 4 weeks. After a 4-week wash-out period, the patients drank the high H2 water for another 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period. RESULTS: Drinking high H2 water seems to raise the concentration of H2 more than the H2 saturated (1.6 ppm) water in vivo. Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 also decreased from 3.83 to 3.02 (p < 0.01) during the same period. After the wash-out period, both the urinary 8-OHdG and the mean DAS28 decreased, compared to the end of the drinking period. During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value. All the 5 patients with early RA (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study. CONCLUSIONS: The results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water.

[A case of metronomic chemotherapy as an alternative cancer therapy for palliation].

An 82-year-old woman underwent colostomy and standard chemotherapy using tegafur/uracil and calcium folinate under a diagnosis of colon cancer. Recurrence occurred, with pulmonary metastasis, hydroureter, and numbness in the low extremities. When admitted to our palliative care unit, she and her family wanted to have mild and minimally toxic chemotherapy. We initiated oral combination of UFT and cyclophosphamide metronomic chemotherapy. She was able to eat for more than 7 months. Her body weight was maintained, and tumor markers were kept suprressed until her death. This case suggests the usefulness of an oral anti-cancer drug low dose metronomic chemotherapy as an alternative cancer therapy in elderly cancer patients requiring palliation.

Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke in the Japanese population. The Fukuoka Stroke Registry and the Hisayama Study.

BACKGROUND AND PURPOSE: Lymphotoxin alpha (LTA), one of the tumor necrosis factor family proteins, is an important proinflammatory cytokine and appears to play a putative role in the inflammatory process of atherosclerosis. Recent genetic studies have suggested that variations in the gene encoding LTA, which affect its expression and biological function, may contribute to the development of vascular diseases. We conducted a case-control study to clarify the association of LTA gene polymorphisms with ischemic stroke in a large Japanese population. METHODS: Genotyping for LTA A252G and C804A polymorphisms was achieved by a rapid-cycle polymerase chain reaction and melting curve analysis using fluorescent probes in 1,044 incident cases of ischemic stroke recruited from the Fukuoka Stroke Registry and 1,044 age- and sex-matched control subjects recruited from the Hisayama Study. RESULTS: The overall distribution of allele and genotype for each polymorphism was similar between stroke patients and control subjects. The allele frequencies of 252G and 804A were slightly lower in stroke patients than in control subjects; however, conditional logistic regression analysis adjusted for potential risk factors found no association between the risk of ischemic stroke and either polymorphism. In terms of stroke subtype, we also found no association of these polymorphisms with any subtypes of ischemic stroke. CONCLUSIONS: Neither the A252G nor C804A polymorphism of the LTA gene was associated with stroke overall and any subtypes of ischemic stroke in the Japanese population.

Role of CA(2+)-activated K+ channels in the regulation of basilar arterial tone in spontaneously hypertensive rats.

1. Ionic channels appear to play an important role in contractile responses of the cerebral arteries and, thereby, contribute to the regulation of cerebral circulation. In the present study, we investigated the role of large-conductance Ca(2+)-activated K+ (BK(Ca)) channels in the regulation of cerebral arterial tone during chronic hypertension. 2. Ring segments of the basilar artery from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were placed in bath chambers and the isometric tension of each ring was measured. 3. Application of inhibitors of BK(Ca) channels, namely tetraethylammonium (TEA; > or = 0.1 mmol/L) and charybdotoxin (CTX; > or = 0.1 nmol/L), produced spontaneous contraction with rhythmic oscillation in the basilar artery from SHR. 4. The oscillatory contraction was not induced by 5-hydroxytryptamine (0.01-10 micromol/L) or depolarization by external high K+ (20-60 mmol/L). 5. The rhythmic contraction was completely abolished by either the removal of external Ca(2+) or the application of nicardipine (10 nmol/L). 6. The oscillation was not affected by the substitution of external Cl(-) by various equimolar anions (i.e. acetate, benezenesulphonate, bromide and isethianate). 7. The amplitude of the oscillation was dose-dependently increased by the vasodilators forskolin and sodium nitroprusside, as well as by stimulation of the endothelium with histamine and acetylcholine, whereas the frequency was decreased. 8. In contrast, the oscillation was eliminated by depletion of Ca(2+) stores by caffeine. Neither TEA (10 mmol/L) nor CTX (10 nmol/L) produced any significant contraction of the basilar artery in WKY rats. 9. These results suggest that BK(Ca) channels may play an important role in regulating the resting tone of the cerebral artery in SHR.