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Background We describe a unique autopsy case of mitochondrial diabetes mellitus (MDM) with mitochondrial DNA 3316G > A mutation, in which, a characteristic sepsis-associated cholestasis was finally recognized via the pathological examinations, and the clinical diagnosis of the cause of jaundice with conjugated hyperbilirubinemia was very difficult. Case Presentation: A 74-year-old Japanese female was diagnosed with MDM showing a point mutation at mitochondrial DNA 3316G > A on the age of 38. She had been treated with hemodialysis due to the diabetic nephropathy and end-stage renal failure since the age of 66. She noticed urinary tract infection and diabetic gangrene of foot with Gram-negative Bacteroides fragilis bacteremia, followed by aggressive jaundice with high serum level of direct bilirubin, and died 2 months after the symptom onset. At autopsy, multiple foci of bacteremia-induced hemorrhagic infarction were observed in the congestive bilateral lungs, whereas the cholestatic liver revealed no overt gross cholangiectasis. Microscopic findings characteristically showed many bile thrombi in the biliary canaliculi of hepatic lobules without any evidence of severe shock liver. Finally, we diagnosed exclusively and conclusively as sepsis-associated cholestasis due to the marked elevation of Gram-negative bacteria-derived endotoxins and inflammatory cytokines. Conclusion We propose that these unique liver features in our MDM case might be one of new clues to unveil its enigmatic etiology. Further prospective studies are needed to validate the presence and significance of sepsis-associated cholestasis, after collecting and investigating a larger number of MDM cases with mitochondrial DNA 3316 mutation examined.

Osteoblasts release adenosine triphosphate (ATP) out of the cell following mechanical stress. Although it is well established that extracellular ATP affects bone metabolism via P2 receptors [such as purinergic receptor P2X7 (P2X7R) and purinergic receptor P2Y2 (P2Y2R)], the mechanism of ATP release from osteoblasts remains unknown. Recently, a vesicular nucleotide transporter [VNUT, solute carrier family 17 member 9 (SLC17A9)] that preserves ATP in vesicles has been identified. The purpose of this study was to elucidate the role of VNUT in osteoblast bone metabolism. mRNA and protein expression of VNUT were confirmed in mouse bone and in osteoblasts by quantitative real‐time PCR (qPCR) and immunohistochemistry. Next, when compressive force was applied to MC3T3‐E1 cells by centrifugation, the expression of Slc17a9, P2x7r, and P2y2r was increased concomitant with an increase in extracellular ATP levels. Furthermore, compressive force decreased the osteoblast differentiation capacity of MC3T3‐E1 cells. shRNA knockdown of Slc17a9 in MC3T3‐E1 cells reduced levels of extracellular ATP and also led to increased osteoblast differentiation after the application of compressive force as assessed by qPCR analysis of osteoblast markers such as Runx2, Osterix, and alkaline phosphatase (ALP) as well as ALP activity. Consistent with these observations, knockdown of P2x7r or P2y2r by siRNA partially rescued the downregulation of osteoblast differentiation markers, caused by mechanical loading. In conclusion, our results demonstrate that VNUT is expressed in osteoblasts and that VNUT inhibits osteoblast differentiation in response to compressive force by mechanisms related to ATP release and P2X7R and/or P2Y2R activity., In this study, we show that VNUT (SLC17A9), a vesicular nucleotide transporter, regulates osteoblast differentiation in response to mechanical loading. Mechanical loading promotes adenosine triphosphate (ATP) exocytosis via VNUT. Extracellular ATP subsequently inhibits osteoblast differentiation via activation of P2X7 and/or P2Y2 receptors. Thus, VNUT modulation of purinergic signaling contributes to the regulation of bone metabolism by mechanical loading.

TNF-α and NF-κB signaling is involved in the wasting of skeletal muscle in various conditions, in addition to cancer cachexia. TNF-α and NF-κB signaling promotes the expression level of muscle RING finger protein 1, a ubiquitin ligase, causing muscle degradation. Several studies have indicated that of TNF-α and NF-κB signaling suppresses muscle differentiation by reducing the levels of MyoD protein. On the other hand, TNF-α and NF-κB is required for myoblast proliferation. Thus, the role of TNF-α and NF-κB signaling in the process of myogenesis and regeneration of skeletal muscle is not completely elucidated. Here, we reported that TNF-α reduced the width of single fibers of skeletal muscle in an organ culture model. TNF-α and p65 repressed the transactivation of MyoD and suppressed myoblast differentiation. In addition, TNF-α increased the number of satellite cells, and NF-κB signaling was promoted at the proliferation stage during skeletal muscle regeneration in vivo. TNF-α and NF-κB signaling regulate myogenesis to inhibit differentiation and promote proliferation in satellite cells.

The transcription factor NFATc1 and its binding partner AP-1 (a complex containing c-fos and c-Jun) play a central role in osteoclast differentiation. NFATc1 and AP-1 promote the expression of target genes such as Acp5, Ctsk and also auto-regulate NFATc1 expression as well. We previously reported that protein phosphatase 1 regulatory subunit 18 (PPP1r18) is a negative regulator of osteoclast bone resorption by inhibiting cell attachment to bone matrix. We also reported that PPP1r18 potentially regulates NFATc1 expression during osteoclast differentiation. To further explore this, in this study we have examined the effect of PPP1r18 on NFATc1 expression and activity by overexpressing PPP1r18 during the early stage of osteoclast differentiation. We found that PPP1r18 suppressed NFATc1 expression through inhibition of the transcriptional activity of NFATc1. Since PPP1r18 does not regulate NFATc1 directly, we next explored the involvement of AP-1. Our data showed that c-fos phosphorylation and nuclear localization were reduced by PPP1r18 overexpression. Further experiments showed that overexpression of c-fos together with PPP1r18 rescued NFATc1 expression and transcriptional activity. Moreover, c-fos activity inhibition by PPP1r18 was canceled by mutation of the phosphatase binding site of PPP1r18. Taken together, PPP1r18-regulated phosphatase activity targets c-fos phosphorylation and suppresses subsequent NFATc1 expression and activity., Highlights • PPP1r18 suppresses osteoclast differentiation. • PPP1r18 suppresses c-fos phosphorylation and nuclear localization. • PPP1r18 suppresses NFAT via c-fos.

Background/aim An effective bone regenerative method needs to be established for the dental field. To identify a novel osteogenic factor for bone regeneration, we examined the effect of vignacyanidin (VIG) on osteoblastogenesis. Materials and methods W20-17 cells, MC3T3-E1 cells, and primary cultured murine calvarial osteoblasts were used. Osteoblast differentiation was stimulated by β-glycerophosphate, ascorbic acid, or bone morphogenetic protein (BMP)-4. Adipogenesis was induced using dexamethasone, 3-isobutyl-1-methylxanthine, insulin, and rosiglitazone. Differentiation or proliferation markers were determined using western blotting and/or the quantitative reverse transcription polymerase chain reaction. Adipogenic cells were visualized by Oil Red O staining. Results VIG treatment increased the expression of osteoblastic markers and alkaline phosphatase activity of osteoblast-lineage cells in a concentration-dependent manner. However, adipogenesis and cell proliferation were not affected by VIG. Conclusion VIG treatment promoted osteoblast differentiation in osteoblast-lineage cells.

The weight of skeletal muscle accounts for approximately 40% of the whole weight in a healthy individual, and the normal metabolism and motor function of the muscle are indispensable for healthy life. In addition, the skeletal muscle of the maxillofacial region plays an important role not only in eating and swallowing, but also in communication, such as facial expressions and conversations. In recent years, skeletal muscle atrophy has received worldwide attention as a serious health problem. However, the mechanism of skeletal muscle atrophy that has been clarified at present is insufficient, and a therapeutic method against skeletal muscle atrophy has not been established. This review provides views on the importance of skeletal muscle in the maxillofacial region and explains the differences between skeletal muscles in the maxillofacial region and other regions. We summarize the findings to change in gene expression in muscle remodeling and emphasize the advantages and disadvantages of denervation-induced skeletal muscle atrophy model. Finally, we discuss the newly discovered beneficial effects of natural compounds on skeletal muscle atrophy.

Honeybees produce royal jelly (RJ) from their cephalic glands. Royal jelly is a source of nutrition for the queen honey bee throughout its lifespan and is also involved in fertility and longevity. Royal jelly has long been considered beneficial to human health. We recently observed that RJ delayed impairment of motor function during aging, affecting muscle fiber size. However, how RJ affects skeletal muscle metabolism and the functional component of RJ is as of yet unidentified. We demonstrate that feeding mice with RJ daily prevents a decrease in myofiber size following denervation without affecting total muscle weight. RJ did not affect atrophy-related genes but stimulated the expression of myogenesis-related genes, including IGF-1 and IGF receptor. Trans-10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), two major fatty acids contained in RJ. After ingestion, 10H2DA and 10HDAA are metabolized into 2-decenedioic acid (2DA) and sebacic acid (SA) respectively. We found that 10H2DA, 10HDAA, 2DA, and SA all regulated myogenesis of C2C12 cells, murine myoblast cells. These novel findings may be useful for potential preventative and therapeutic applications for muscle atrophy disease included in Sarcopenia, an age-related decline in skeletal muscle mass and strength.