Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial.

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

Experiments were conducted to determine the effects of different types of paddy rice (dehulled, crushed and untreated whole-grain forms) on growth performance in broiler chickens. In Experiment 1, a control diet containing 41.6% corn (control), and three experimental diets containing 40.7% dehulled, 43% crushed or 43% whole-grain paddy rice, were formulated to be iso-caloric (3,100 kcal/kg ME) and iso-nitrogenous (20% crude protein), but to contain different levels of fat (6%, 5.6%, 10.7%, 10.7%, respectively). Groups of 0-day-old chickens were the fed experimental diets ad libitum for 28 d. The average final body weight of groups fed the crushed and untreated wholegrain paddy rice was significantly lower (P＜0.05) than that of the control group, but that of dehulled rice-fed group was slightly higher than the control group. This finding implies that the growth retardation seen with crushed or untreated whole rice could be caused by the feed intake-reduction due to the fat addition to the experimental diets. In Experiment 2, the control diet containing corn and the experimental diets containing dehulled and untreated wholegrain paddy rice were formulated to contain similar levels of fat (5.6-6%) and to be iso-nitrogenous (20%), but not to be iso-caloric. As a result, the average body weight gain of the whole-grain rice-fed chickens showed a considerable increase compared with the control diet-fed chickens even though the energy content of the former diet was only about 90% that of the control diet. It is concluded that whole-grain paddy rice could serve as a valuable constituent of broiler chicken feed, but that excess fat in the diet to maintain the ME content (3,100 kcal/g) could have a negative effect on growth performance.

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.

Trehalose is composed of two molecules of D-glucose joined by an α,α-1,1 glucosidic linkage and has antioxidative and anti-inflammatory effects. The present study investigated the effect of feeding a trehalose-supplemented diet on the growth performance, as well as the oxidative status and the intestinal innate immunity of juvenile chicks. A total of 16 d-old male broiler chicks were used in this study: two groups of 8 birds were fed on a 0% (control) or 0.5% trehalose-supplemented diet for 18 d. The mean body weight of the trehalose group was significantly greater than that of the control group, but feed efficiency was not altered by feeding the trehalose-supplemented diet. No differences in the levels of lipid peroxidation in skeletal muscle, liver and plasma were observed between the control and trehalose-supplemented groups. The mRNA levels of interferon-γ, tumour necrosis factor-like ligand 1A, interleukin-10, NADPH oxidase 4 and inducible NO synthase were significantly reduced by the trehalose supplementation. Our results suggest that dietary supplementation with trehalose after hatching may have beneficial effects on the growth performance of juvenile chicks, probably by improving their intestinal innate immunity.

We have previously shown that, under thermoneutral conditions, the growth performance of chicks fed a ricebased diet containing 6% soybean oil [metabolizable energy (ME): 2,800 kcal/kg] for 28 days was comparable to that obtained with a corn-based diet containing 6% soybean oil (ME: 3,100 kcal/kg). However, there is no information available concerning how such diets compare with respect to growth performance under heat stress conditions. The present study was therefore conducted to clarify differences in dietary effectiveness between corn-based and wholegrain paddy rice-based diets [formulated to be equivalent in terms of fat (6%), but not iso-caloric] under the two conditions of acute and chronic heat stress (Experiment 1 and Experiment 2, respectively). In Experiment 1, the body weight gain of a corn-and rice-fed group of chickens exposed to acute heat (33℃-12 h) were significantly decreased compared with that of a corn-fed control group (24℃), with similar results obtained for the two heat-treated groups. Malondialdehyde (MDA) levels in the M. pectoralis superficialis were significantly increased in corn-fed birds exposed to acute heat stress, but not in the rice-fed group (33℃-12 h). In Experiment 2, body weight gains in the corn-and rice-fed groups exposed to chronic heat (33℃-6 d) were significantly decreased, and to a similar extent, compared with the corn-fed control group (24℃). Muscle MDA levels in the corn-and rice-fed groups were similarly increased by the chronic heat exposure compared with the control group. These results suggest that, in response to acute heat stress (but not chronic heat stress) conditions, the feeding of whole-grain paddy rice diet to chickens may attenuate skeletal muscle oxidative damage compared with that in corn-fed chickens. The possible involvement of intestinal morphology (such as the villus height: crypt depth ratio observed here) on growth performance is also discussed.

Previously, we showed that the growth of chicks fed a diet containing 43% whole-grain paddy rice and 10% soybean oil was retarded relative to a control group fed a corn-based diet containing 6% soybean oil. However, feeding chicks with 43% whole-grain paddy rice containing 6% soybean oil resulted in normal growth. It is possible that the observed growth retardation was caused by the high soybean oil content or resulted from the combination of whole-grain paddy rice and the high level of soybean oil which was added to the diet to maintain the overall energy content. The present study was therefore carried out to identify the reasons for the observed growth retardation. Thirty-six chicks (0-day-old) were divided into six equal-sized groups that were fed one of the following six experimental diets ad libitum for 28 d: two kinds of dehulled rice-based diets containing 5% or 10% soybean oil (DS5% or DS10%), another three whole-grain paddy rice-based diets containing 10% soybean oil, corn oil, or rendering oil (WS10%, WC10%, WR10%, respectively), and a WS10% diet supplemented with vitamin B 12 , methionine and ethoxyquin. The body weight gain of groups fed the WS10% and WC10% diets was significantly lower than the weight gain of birds fed the DS5% diet (control). In addition, the liver of birds fed the WS10% and WC10% diet exhibited significantly higher lipid peroxidation than that of the control group. In comparison, supplementation of the WS10% diet with vitamin B 12 , methionine and ethoxyquin dramatically improved growth and hepatic oxidation status. These results indicate that diets combining whole-grain paddy rice and high levels of soybean and corn oil adversely affect performance, presumably via lipid peroxidation in the liver.

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