Renal impairment with sublethal tubular cell injury in a chronic liver disease mouse model

The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury

Mitochondrial fission in hepatocytes as a potential therapeutic target for nonalcoholic steatohepatitis

[Aim] The mitochondria are highly plastic and dynamic organelles; mitochondrial dysfunction has been reported to play causative roles in diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). However, the relationship between mitochondrial fission and NAFLD pathogenesis remains unknown. We aimed to investigate whether alterations in mitochondrial fission could play a role in the progression of NAFLD. [Methods] Mice were fed a standard diet or choline-deficient, L-amino acid-defined (CDAA) diet with vehicle or mitochondrial division inhibitor-1. [Results] Substantial enhancement of mitochondrial fission in hepatocytes was triggered by 4 weeks of feeding and was associated with changes reflecting the early stage of human nonalcoholic steatohepatitis (NASH), steatotic change with liver inflammation, and hepatocyte ballooning. Excessive mitochondrial fission inhibition in hepatocytes and lipid metabolism dysregulation in adipose tissue attenuated liver inflammation and fibrogenesis but not steatosis and the systemic pathological changes in the early and chronic fibrotic NASH stages (4- and 12-week CDAA feeding). These beneficial changes due to the suppression of mitochondrial fission against the liver and systemic injuries were associated with decreased autophagic responses and endoplasmic reticulum stress in hepatocytes. Injuries to other liver cells, such as endothelial cells, Kupffer cells, and hepatic stellate cells, were also attenuated by the inhibition of mitochondrial fission in hepatocytes. [Conclusions] Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes could play a causative role in NAFLD progression by liver inflammation and fibrogenesis through altered cell cross-talk. This study provides a potential therapeutic target for NAFLD

Combined Spectral and Timing Analysis of the Black Hole Candidate MAXI J1659-152 Discovered by MAXI and Swift

We report on X-ray spectral and timing results of the new black hole candidate (BHC) MAXI J1659-152 with the orbital period of 2.41 hours (shortest among BHCs) in the 2010 outburst from 65 Rossi X-ray Timing Explorer (RXTE) observations and 8 simultaneous Swift and RXTE observations. According to the definitions of the spectral states in Remillard & McClintock (2006), most of the observations have been classified into the intermediate state. All the X-ray broadband spectra can be modeled by a multi-color disk plus a power-law with an exponential cutoff or a multi-color disk plus a Comptonization component. During the initial phase of the outburst, a high energy cutoff was visible at 30-40 keV. The innermost radius of the disk gradually decreased by a factor of more than 3 from the onset of the outburst and reached a constant value of 35 d_10 cos i^-1/2 km, where d_10 is the distance in units of 10 kpc and $i$ is the inclination. The type-C quasi-periodic oscillation (QPO) frequency varied from 1.6 Hz to 7.3 Hz in association with a change of the innermost radius, while the innermost radius remained constant during the type-B QPO detections at 1.6-4.1 Hz. Hence, we suggest that the origin of the type-B QPOs is different from that of type-C QPOs, the latter of which would originate from the disk truncation radius. Assuming the constant innermost radius in the latter phase of the outburst as the innermost stable circular orbit, the black hole mass in MAXI J1659-152 is estimated to be 3.6-8.0 M_solar for a distance of 5.3-8.6 kpc and an inclination angle of 60-75 degrees.Comment: 27 pages, 14 figures, accepted for publication in PAS

The effectiveness and limitations of triphenyltetrazolium chloride to detect acute myocardial infarction at forensic autopsy.

Triphenyltetrazolium chloride (TTC) is one of the most conventional stains to detect infarcted area of the heart in animal experiments. However, its availability and limitations have not been thoroughly discussed in the forensic field. Here, authors stained human hearts with TTC soon after the harvest. Photographs of the samples were analyzed using image analysis software, which evaluated the occupying ratio of the stained area on the surface of each slice. The results showed that the stainability of TTC declines with the length of the postmortem interval (PMI). Specimens reacted well to TTC within 1.5 days after death and then decreased the stainability logarithmically with PMI (y = - 0.294 In (x) + 1.0441; x = PMI, y = TTC-stained areatotal myocardial area, R = 0.5673). Samples with old myocardial infarction produced clear TTC contrast; normal tissue is vivid red, and fibrotic myocardium is white discoloration. In acute myocardial infarction cases where death occurred within 9 hours after the attack, however, the detection of infarcted area was very difficult even when PMI was less than 1.5 days. In summary, the TTC method may be useful within 1.5 days after death, but short suffering period before death disturbs its staining efficiency

A Large X-ray Flare from a Single Weak-lined T Tauri Star TWA-7 Detected with MAXI GSC

We present a large X-ray flare from a nearby weak-lined T Tauri star TWA-7 detected with the Gas Slit Camera (GSC) on the Monitor of All-sky X-ray Image (MAXI). The GSC captured X-ray flaring from TWA-7 with a flux of $3\times10^{-9}$ ergs cm$^{-2}$ s$^{-1}$ in 2--20 keV band during the scan transit starting at UT 2010-09-07 18:24:30.The estimated X-ray luminosity at the scan in the energy band is 3$\times10^{32}$ ergs s$^{-1}$,indicating that the event is among the largest X-ray flares fromT Tauri stars.Since MAXI GSC monitors a target only during a scan transit of about a minute per 92 min orbital cycle, the luminosity at the flare peak might have been higher than that detected. At the scan transit, we observed a high X-ray-to-bolometric luminosity ratio, log $L_{\rm X}/L_{\rm bol}$ = $-0.1^{+0.2}_{-0.3}$; i.e., the X-ray luminosity is comparable to the bolometric luminosity. Since TWA-7 has neither an accreting disk nor a binary companion, the observed event implies that none of those are essential to generate such big flares in T Tauri stars.Comment: 4 pages, 2 figures, 1 table accepted for publication in PAS