Ketone bodies including b-hydroxybutyrate (b-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of b-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of b-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum b-OHB levels by fasting. Renal IRI was attenuated by b-OHB treatment compared to saline control, with similar results in the fasting condition. b-OHB treatment reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although b-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that b-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, b-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by b-OHB through the inactivation of histone deacetylases. In vitro, b-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of b-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, b-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.
Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.
Background Bone tunnel enlargement following primary anterior cruciate ligament (ACL) reconstruction with soft tissue graft might be a severe disadvantage for revision surgery. The postoperative rehabilitation protocol including the non-weight-bearing periods were different depending on the surgeon or institute. To determine the relationship between femoral bone tunnel enlargement and the postoperative non-weight-bearing period after double-bundle ACL reconstruction with hamstring grafts. Methods Forty-two patients who underwent primary double-bundle ACL reconstruction with hamstring grafts were divided into two postoperative non-weight-bearing protocol groups: 1-week non-weight-bearing postoperatively (group A, n = 19); and 2-week non-weight-bearing (group B, n = 18). Five cases were excluded due to additional knee injury, pregnancy, and lost to follow-up. Bone tunnel enlargement was evaluated by computed digital radiographs (anteroposterior (A-P) and lateral views) taken on the first postoperative day and at 12 months. Each tunnel diameter was shown as a percentage to the maximum joint width of the proximal tibia in the A-P view, or a percentage of the maximum diameter of the patella in the lateral view. To determine the incidence of tunnel enlargement, percentage diameter changes of more than 10% were defined as an enlarged tunnel. The magnitude of tunnel enlargement and the standard clinical evaluation were also evaluated. Results There were no significant differences between groups in the incidences of anteromedial and posterolateral bone tunnel enlargement, both in the A-P and lateral views (2 × 2 Chi-squared test). The magnitude of femoral posterolateral bone tunnel enlargement was significantly greater in group A in the A-P view ( p = 0.01) and lateral view ( p = 0.03) (Mann Whitney U-test). Twelve months after surgery, the Lysholm score and Tegner activity level scale were not significantly different between the groups. Conclusions This prospective, clinical and radiographical study showed that early weight-bearing protocol after double-bundle ACL reconstruction with hamstring grafts might have the potential risk of significant postoperative femoral bone tunnel enlargement of the posterolateral bundle. There was no significant difference in clinical outcomes by postoperative non-weight-bearing period. To reduce and prevent the femoral bone tunnel enlargement, the comprehensive management could be considered and required to establish the suitable early stage rehabilitation protocol after surgery. Trial registration Trial registration number; UMIN000036212 . Scientific title: Prospective comparisons of femoral tunnel enlargement with two different postoperative non weight bearing periods after double-bundle anterior c...
Background Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. Methods CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. Results IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. Conclusions Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.
Intra-articular bleeding causes degradation of articular cartilage leading to joint disorders, but the mechanisms is not well understood. The present study examined the effect of hemoglobin on the ability of synovial tissues to produce plasminogen activators and matrix metalloproteinases that play important roles in the degradation of articular cartilage. Human Hb added to primary cultures of human knee synovial cells markedly increased fibrinolytic activity and gelatinolytic activity. The fibrinolytic activity was due to an increase in uPA activity. Western blot analysis and gelatin zymography indicated that the increased gelatinolytic activity was due to increased MMP-2 and -9. In order to know whether the effect of Hb on cultured synovial tissue is also true in in vivo system or not, rabbit hemoglobin was injected into rabbit knee joints. Coinciding with in vitro study, hemoglobin elicited considerable increase in fibrinolytic and gelatinolytic activity. The level of proteoglycan fragments in the hemoglobin-treated joint fluid was significantly elevated, indicating cartilage matrix degradation. Cartilage damage after hemoglobin treatment was also confirmed by histological study. These findings suggest that hemoglobin stimulates the secretion of uPA, MMP-2 and MMP-9 by synovial tissues, and raise a possible role of hemoglobin in joint damage after intra-articular bleeding.
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