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A single i.v. injection of 3 mg of the F(ab')2 fragment of MoAb 5-1-6 into rats induced immediate proteinuria (128.1±80.7 mg/24 h on day 1) which lasted 1-2 days. In contrast, rats administered 10 mg of the corresponding Fab fragment did not develop abnormal proteinuria even though an equivalent dose of the intact MoAb 5-1-6 far exceeded the nephritogenic dose. The total kidney binding of 125-Fab fragment was 209.5 ± 34.3 μg/2 kidneys. This exceeded that obtained by injection of 3 mg MoAb 5-1-6 IgG1 (58.9 ± 12.5 μg/2 kidneys at 1 h) and was similar to that obtained following injection of 3 mg F(ab)2 fragment (235.3 ± l6.9 μg/2 kidneys). Immunofluorescence (IF) showed a linear pattern along the glomerular capillary wall at 1h after the administration of MoAb 5-1-6 IgG 1, F(ab )2 or Fab fragment. On day 5, fine to coarse granules were observed scattered in F(ab')2-injected rat glomeruli, whereas granules were densely localized in Fab-injected rat glomeruli. Complement-depleted rats injected with 3 mg of MoAb 5-1-6 IgG1 developed proteinuria with the same time course as non-depleted rats. This observation, together with the ability of F(ab')2 to induce proteinuria, indicates that proteinuria induced by MoAb 5-1-6 is complement-independent. This study suggests that MoAb 5-l-6-induced proteinuria is initiated by cross-linking of the epitopes by divalent MoAb 5-1-6 and is independent of complement activity. [ABSTRACT FROM AUTHOR]

Background: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis., Methods and Results: Eight-week-old wild-type male mice (CTSK +/+ ) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl 3 )-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK +/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16 IN4A , p22phox, gp91 phox , intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H 2 O 2 -induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation., Conclusions: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl 3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs., (© 2024. The Author(s).)

Drug-eluting stents (DES) and dual antiplatelet regimens have significantly improved the clinical management of ischemic heart disease; however, the drugs loaded with DES in clinical practice are mostly paclitaxel or rapamycin derivatives, which target symptoms of post implantation proliferation and inflammation, leading to delayed re-endothelialization and neo-atherosclerosis. Along with the treatments already in place, there is a need for novel strategies to lessen the negative clinical outcomes of DES delays as well as a need for greater understanding of their pathobiological mechanisms. This review concentrates on the function of cathepsins (Cats) in the inflammatory response and granulation tissue formation that follow Cat-induced damage to the vasculature scaffold, as well as the functions of Cats in intimal hyperplasia, which is characterized by the migration and proliferation of smooth muscle cells, and endothelial denudation, re-endothelialization, and/or neo-endothelialization. Additionally, Cats can alter essential neointima formation and immune response inside scaffolds, and if Cats are properly controlled in vivo, they may improve scaffold biocompatibility. This unique profile of functions could lead to an original concept for a cathepsin-based coronary intervention treatment as an adjunct to stent placement., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Cysteinyl cathepsins (CTSs) are widely known to have a proteolysis function that mediates recycling of unwanted proteins in endosomes and lysosomes, and investigation of CTSs has greatly improved with advances in live-imaging techniques both in vivo and in vitro, leading to three key findings. (1) CTSs are relocated from the lysosomes to other cellular spaces (i.e., cytosol, nucleus, nuclear membrane, plasma membrane, and extracellular milieu). (2) In addition to acidic cellular compartments, CTSs also exert biological activity in neutral environments. (3) CTSs also exert multiple nontraditional functions in, for example, extracellular matrix metabolism, cell signaling transduction, protein processing/trafficking, and cellular events. Various stimuli regulate the expression and activities of CTSs in vivo and vitro-e.g., inflammatory cytokines, oxidative stress, neurohormones, and growth factors. Accumulating evidence has confirmed the participation of CTSs in vascular diseases characterized by atherosclerosis, plaque rupture, thrombosis, calcification, aneurysm, restenosis/in-stent-restenosis, and neovasel formation. Circulating and tissue CTSs are promising as biomarkers and as a diagnostic imaging tool in patients with atherosclerosis-based cardiovascular disease (ACVD), and pharmacological interventions with their specific and non-specific inhibitors, and cardiovascular drugs might have potential for the therapeutic targeting of CTSs in animals. This review focuses on the update findings on CTS biology and the involvement of CTSs in the initiation and progression of ACVD and discusses the potential use of CTSs as biomarkers and small-molecule targets to prevent deleterious nontraditional functions in ACVD., (© 2023. The Author(s).)

Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and intractable pathology, or the effects of treatment on immunophenotypes. We performed peripheral blood immunophenotyping in GD. We assessed the proportion of functional subsets of T helper cells (such as Th1, Th17, Treg and Tfh cells), B cells (Naïve, IgM memory, Class-switched, IgD - CD27 - double negative and Plasmablasts cells), Monocytes, Dendritic cells and NK cells, and evaluated the relationship of immunophenotypes with clinical indices, disease activity, risk of relapse, and changes in immunophenotypes after treatment with antithyroid drugs. The activated Th17 cells, activated T follicular helper (Tfh) cells, and IgD - CD27 - double-negative B cells were higher in newly onset GD compared with healthy participants. Th17 cells were associated with thyroid autoantibodies, thyroid function, thyroid enlargement, and Graves' Recurrent Events After Therapy (GREAT) score; while double-negative B cells were associated with thyroid autoantibodies. Treatment with antithyroid drugs decreased the activated Tfh cells in parallel with the improvement in thyroid function. However, activated Th17 cells were not associated with clinical improvement and remained unchanged. Peripheral blood immunophenotyping identified the differential involvement of T and B cell subsets in the pathogenesis of GD. Abnormalities in the differentiation of Th17, Tfh, and double-negative B cells reflected the clinical pathology associated with autoantibody production and excess thyroid hormones. And Th17 cells are significantly associated with the marker for resistance to treatment. These results suggest the involvement of Th17 cell activation in the intractable pathology associated with potential immune abnormalities in GD. Clinical trial registration: #UMIN000017726 (Date: June 1st, 2015)., (© 2022. The Author(s).)

The assessment of the efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines in actual practice is extremely important, and monitoring efforts are being implemented worldwide. In Japan, a joint council in the Ministry of Health, Labour and Welfare is held every two to three weeks to summarise information on the adverse events following COVID-19 vaccination, with careful assessment of individual case safety reports and comparison with background incidence rates. In 2021, the joint council mainly reviewed anaphylaxis, death, myocarditis/pericarditis, and thrombosis with thrombocytopenia syndrome. These activities resulted in several safety-related regulatory actions, including the revision of vaccine package inserts with warnings about myocarditis/pericarditis. International sharing of vaccine safety information, as well as details of the evaluation systems, is important for international discussion and decision-making on better safety monitoring of COVID-19 vaccines., Competing Interests: AO receives grants from Eisai Co., Ltd, SHIONOGI & CO., LTD., Takeda Pharmaceutical Co, Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., and Pfizer Japan Inc. All other authors declare no competing interests., (© 2022 The Author(s).)

This prospective study determined the effects of hypoglycemic stimulation on vascular endothelial function in non-diabetic patients using reactive hyperemia peripheral arterial tonometry (RH-PAT). The study included non-diabetic patients who were hospitalized for an insulin tolerance test (ITT) for the diagnosis of hypoadrenocorticism or hypopituitarism. Vascular endothelial function was assessed using the reactive hyperemia index (RHI) measured by the RH-PAT. We also measured the levels of anterior pituitary hormone, adrenaline, noradrenaline, and dopamine at the time of hypoglycemia. The primary endpoint was a change in the RHI at 120 min after insulin administration. The study included 27 patients. ITT was associated with significant increases in systolic blood pressure, pulse rate, and the blood levels of adrenocorticotropic hormone, cortisol, growth hormone, adrenaline, noradrenaline, and dopamine. RHI significantly decreased after ITT from 2.24 ± 0.51 to 1.71 ± 0.42. A significant inverse correlation was observed between the change in RHI and change in adrenaline (r = - 0.670, p = 0.012). We concluded that hypoglycemic stimulation altered vascular endothelial function, as measured by RH-PAT, even in patients free of glucose intolerance. The observed deterioration in vascular endothelial function correlated with increases in catecholamine levels during hypoglycemia.Trial registration: UMIN000033244., (© 2022. The Author(s).)

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular atherosclerosis-based cardiovascular disease (ACVD). Dipeptidyl peptidase-4 (DPP-4) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase. DPP-4 is upregulated in metabolic and inflammatory cardiovascular disorders. DPP-4 exhibits many physiological and pharmacological functions by regulating its extremely abundant substrates, such as glucagon-like peptide-1 (GLP-1). Over the last 10 years, emerging data have demonstrated unexpected roles of DPP-4 in extracellular and intracellular signaling, immune activation, inflammation, oxidative stress production, cell apoptosis, insulin resistance, and lipid metabolism. This mini-review focuses on recent novel findings in this field, highlighting a DPP-4-mediated regulation of GLP-1-dependent and -independent signaling pathways as a potential therapeutic molecular target in treatments of chronic psychological stress-related ACVD in humans and animals.

Background: Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM)., Methods: T2DM patients (n = 293) receiving inpatient care were divided into five groups according to HbA1c level on admission (Group 1: ≥ 6 to < 7%, Group 2: ≥ 7 to < 8%, Group 3: ≥ 8 to < 9%, Group 4: ≥ 9 to < 10%, and Group 5: ≥ 10%). The frequency of hypoglycemia and factors associated with hypoglycemia were analyzed., Results: Hypoglycemia occurred in 15 patients (5.1%), including 4 (8%), 4 (6%), and 7 (10%) patients of Groups 1, 2, and 3, respectively, but in none of groups 4 and 5. Patients with hypoglycemia of Groups 1 had low insulin secretion and were high among insulin users, those of Groups 2 had low homeostasis model assessment of insulin resistance (HOMA-IR). Those of Group 2 and 3 had significantly lower mean blood glucose levels, those of Group 3 only had significantly lower maximum blood glucose level and percentage of AUC > 180 mg/dL. In any of the HbA1c groups, variations in blood glucose level were significantly larger in patients with hypoglycemia than without., Conclusions: Hypoglycemia occurred in patients with a wide range of HbA1c on admission (range 6-9%), suggesting that prediction of hypoglycemia based on HbA1c alone is inappropriate. Among patients with low HbA1c, strict control sometimes induce hypoglycemia. Among patients with high HbA1c, the possibility of hypoglycemia should be considered if there is a marked discrepancy between HbA1c and randomly measured blood glucose level. Larger variations in blood glucose level induce hypoglycemia in any of the HbA1c groups. The treatment to reduce variations in blood glucose level is important to prevent hypoglycemia.

Objective Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both complicated by arteriosclerosis, resulting in increased rates of cardiovascular events. No previous studies have compared the index between RA and T2DM. We assessed the vascular endothelial function in early-stage arteriosclerosis for each disease to determine the influential factors and compared the extent to which these two diseases cause vascular endothelial dysfunction. Methods This study is a retrospective study based on medical records. Differences in the reactive hyperemia index (RHI) among the groups and factors affecting the RHI in each group was analyzed. The vascular endothelial function was assessed by measuring the RHI using peripheral arterial tonometry. Patients The study subjects were 114 patients with non-functional thyroid tumors (healthy n=14), T2DM (T2DM n=64), and RA (RA n=36). Results The RHI was 2.29 in the control, 1.85 in the T2DM, and 1.83 in the RA group, with values lower in the T2DM and RA groups than in the control group (p=0.033) but not markedly different between the two disease groups. The RHI distribution (<1.68/1.68 to <2.10/≥2.1) was as follows: control group: 14.3%/28.6%/57.1%; T2DM group: 42.2%/39.1%/18.8%; and RA group: 36.1%/44.4%/19.4% (p=0.031), respectively. A multivariate analysis identified the triglyceride level and dyslipidemia in the control group and the Disease Activity Score in 28 joints with the erythrocyte sedimentation rate and fasting plasma glucose level in the RA group to influence the RHI. Conclusion The vascular endothelial function was impaired in approximately 80% of patients with T2DM and RA, with comparable degrees of impairment between the two diseases. No factors affecting the function were identified in the T2DM group, while the function was more impaired in patients with a higher disease activity in the RA group.

Aims/introduction: High fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type 2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type 2 diabetes patients., Materials and Methods: Our retrospective study included 294 patients with type 2 diabetes who were divided by HbA1c level into five groups (≥6.0 to <7.0%, ≥7.0 to <8.0%, ≥8.0 to <9.0%, ≥9.0 to <10.0% and ≥10%). The correlation between HbA1c level and CGM data was analyzed. The primary end-point was the difference in blood glucose fluctuations among the HbA1c groups., Results: The mean blood glucose level increased significantly with increasing HbA1c (P trend  < 0.01). The standard deviation increased with increases in HbA1c (P trend  < 0.01). The mean amplitude of glycemic excursions did not vary significantly with HbA1c. The levels of maximum blood glucose, minimum blood glucose, each preprandial blood glucose, each postprandial maximum blood glucose, range of increase in postprandial glucose from pre-meal to after breakfast, the area under the blood concentration-time curve >180 mg/dL and percentage of the area under the blood concentration-time curve >180 mg/dL were higher with higher HbA1c. Mean glucose level and pre-breakfast blood glucose level were significant and independent determinants of HbA1c., Conclusions: In Japanese patients treated for type 2 diabetes, the mean amplitude of glycemic excursions did not correlate with HbA1c, making it difficult to assess blood glucose fluctuations using HbA1c. Parameters other than HbA1c are required to evaluate fluctuations in blood glucose level in patients receiving treatment for type 2 diabetes., (© 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Objective IgG4-related disease is a recently characterized condition presenting with high blood IgG4 levels, swelling of organs, and hypertrophic lesions. This disease is associated with thyroid disease, Hashimoto's disease, and Riedel's thyroiditis. However, there is little information on the association between IgG4-related disease and Basedow's disease. We herein defined the clinical features of patients with Basedow's disease and high IgG4 levels. Methods We compared two groups of patients with Basedow's disease (n=72) who had either normal IgG4 levels (<135 mg/dL; n=67) or high IgG4 levels (≥135 mg/dL; n=5 [6.9%], mean IgG4: 206±116 mg/dL, IgG4/IgG ratio: 10.6%±3.3%). Patients Seventy-two newly diagnosed, untreated patients with Basedow's disease. Results Compared to the normal IgG4 group, patients in the high IgG4 group were predominantly male and showed a significantly higher thyroid low-echo score (1.8±0.4 vs. 1.2±0.5) and eosinophil count (363±354/mm 2 vs. 136±122/mm 2 ). Five patients had high IgG4 levels: one had a pancreatic lesion, and four had thyroid lesions. Conclusion Patients with Basedow's disease and high IgG4 levels may represent a new subtype of Basedow's disease. Further studies with larger sample sizes are needed.

Introduction: The aim of the present study was to determine the actual state of inter-day glycemic variability and identify the factors that affect glycemic variability in diabetic outpatients on insulin therapy., Materials and Methods: The participants were 45 outpatients with diabetes mellitus receiving insulin therapy. The mean plasma glucose (MPG) levels, intra-day glycemic variability (expressed by standard deviation and mean amplitude of glucose excursion) and inter-day glycemic variability (expressed by mean of daily differences [MODD] in blood glucose levels) were measured continuously over 7 days with iPro2 ® . The primary outcome was the relationship between MODD and the life variability index., Results: MODD values were high in 93.3% of the participants, and significantly higher in patients with lifestyle changes than in those without (higher in patients with high life variability index). MODD values were not associated with age, but significantly higher in women. MODD values correlated significantly with glycated hemoglobin and glycoalbumin levels, and negatively with 1,5-anhydroglucitol levels. MODD values were significantly higher in type 1 diabetes patients and not associated with duration of disease. MODD values correlated significantly with insulin dose. Multivariate analysis identified the life variability index as a significant determinant of MODD., Conclusions: iPro2 ® provided detailed information on glycemic profile in diabetic outpatients receiving insulin therapy. The results suggest that patients with large inter-day glycemic variability are unlikely to achieve an improvement in their glycated hemoglobin level. Treatment and instructions based on a patient's characteristics, day-to-day glycemic variability and lifestyle are important to achieve good glycemic control., (© 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Rituximab (RTX) is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Recent reports indicate that RTX is effective against type 1 diabetes mellitus (T1DM) and hematologic as well as autoimmune diseases. Other studies have indicated that RTX therapy leads to the remission of recurrent or active Graves' disease (GD). However, the efficacy of RTX in Japanese patients with autoimmune polyglandular syndrome (APS) has not been reported to date. Herein, we report the case of a patient with GD and T1DM with sustained endogenous insulin secretion capacity. To protect pancreatic β cells, we administered RTX at a dose of 500 mg (approximately 300 mg/m2) on 2 occasions 1 week apart. After treatment, no adverse effects were observed, and thyroid stimulating hormone receptor antibody (TRAb) was no longer detectable 4 months after RTX administration. In addition, the reduction in TRAb level improved thyroid function. Notably, the treatment induced remission over a period of 1 year after the diagnosis of GD.

A 48-year-old woman was diagnosed and treated for Graves' disease (GD) in 1999 but she discontinued treatment at her own discretion. In 2011, she was admitted to a local hospital for management of thyrotoxic crisis. Treatment with propylthiouracil, iodide potassium (KI), and prednisolone (PSL) was started, which resulted in improvement of the general condition. PSL and KI were discontinued before she was transferred to our hospital. At the local hospital, fasting plasma glucose (FPG) was 212 mg/dL and hemoglobin A1c concentration was 11.2%; intensive insulin therapy had been instituted. Upon admission to our hospital, FPG level was 122 mg/dL, but insulin secretion was compromised, suggesting aggravation of thyroid function and deterioration of glycemic control. The FPG level increased to 173 mg/dL; continuous glucose monitoring (CGM) identified dawn phenomenon at approximately 0400 h. Resumption of KI resulted in improvement of FPG and disappearance of the dawn phenomenon, as assessed by CGM. These results indicate that in patients with compromised insulin secretion, hyperthyroidism can induce elevation of not only postprandial blood glucose, but also FPG level due to the dawn phenomenon and that the dawn phenomenon can be alleviated with improvement in thyroid function. To our knowledge, no studies have assessed glucose variability by CGM before and after treatment of Graves' disease. The observations made in this case shed light on the understanding of abnormal glucose metabolism associated with Graves' disease.

Background: Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus, but many of these patients fail to achieve the target LDL-C level. Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin. However, in patients with type 2 diabetes who are already being treated with satins, it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose. Therefore, this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins., Methods: The subjects were type 2 diabetic patients under treatment with rosuvastatin (2.5 mg daily), who had LDL-C levels ≥80 mg/dL. They were randomly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day (combination group, n = 40) or an increase of the rosuvastatin dose to 5 mg/day (dose escalation group, n = 39). These two groups were compared at baseline and after 12 weeks of treatment., Results: The percent change of LDL-C was -31% in the combination group and -12% in the dose escalation group. Both groups showed a significant decrease, but the decrease was greater in the combination group. In both groups, there was a significant decrease in the levels of small dense LDL-C, oxidized LDL and remnant-like lipoprotein cholesterol. For all of these parameters, the percent changes were greater in the combination group. Only the combination group showed a significant decrease of triglycerides. Multivariate analysis was performed to identify factors associated with reaching an LDL-C level <80 mg/dL. As a result, add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C., Conclusions: Compared with increasing the dose of rosuvastatin, the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients, suggesting that this combination could suppress the progression of atherosclerosis., Trial Registration: UMIN000011005.

Although a bioenergetic parameter is unfavorable for production of ATP (DeltapH<0), the growth rate and yield of alkaliphilic Bacillus strains are higher than those of neutralophilic Bacillus subtilis. This finding suggests that alkaliphiles possess a unique energy-producing machinery taking advantage of the alkaline environment. Expected bioenergetic parameters for the production of ATP (DeltapH and DeltaPsi) do not reflect the actual parameters for energy production. Certain strains of alkaliphilic Bacillus spp. possess large amounts of cytochrome c when grown at a high pH. The growth rate and yield are higher at pH 10 than at pH 7 in facultative alkaliphiles. These findings suggest that a large amount of cytochrome c at high pHs (e.g., pH 10) may be advantageous for sustaining growth. To date, isolated cytochromes c of alkaliphiles have a very low midpoint redox potential (less than +100 mV) compared with those of neutralophiles (approximately +220 mV). On the other hand, the redox potential of the electron acceptor from cytochrome c, that is, cytochrome c oxidase, seems to be normal (redox potential of cytochrome a=+250 mV). This large difference in midpoint redox potential between cytochrome c and cytochrome a concomitant with the configuration (e.g., a larger negative ion capacity at the inner surface membrane than at the outer surface for the attraction of H+ to the intracellular membrane and a large amount of cyrochrome c) supporting H+-coupled electron transfer of cytochrome c may have an important meaning in the adaptation of alkaliphiles at high pHs. This respiratory system includes a more rapid and efficient H+ and e- flow across the membrane in alkaliphiles than in neutralophiles.