Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

PurposeThis study investigated the effect of eicosapentaenoic and docosahexaenoic acids-rich fish oil (EPA + DHA) supplementation on eccentric contraction-induced muscle damage.MethodsTwenty-four healthy men were randomly assigned to consume the EPA + DHA supplement (EPA, n = 12) or placebo (PL, n = 12) by the double-blind method. Participants consumed EPA + DHA or placebo supplement for 8 weeks prior to exercise and continued it until 5 days after exercise. The EPA group consumed EPA + DHA-rich fish oil containing 600 mg EPA and 260 mg DHA per day. Subjects performed five sets of six maximal eccentric elbow flexion exercises. Changes in the maximal voluntary contraction (MVC) torque, range of motion (ROM), upper arm circumference, muscle soreness as well as serum creatine kinase, myoglobin, IL-6, and TNF-α levels in blood were assessed before, immediately after, and 1, 2, 3, and 5 days after exercise.ResultsMVC was significantly higher in the EPA group than in the PL group at 2–5 days after exercise (p < 0.05). ROM was also significantly greater in the EPA group than in the PL group at 1–5 days after exercise (p < 0.05). At only 3 days after exercise, muscle soreness of the brachialis was significantly greater in the PL group than in the EPA group (p < 0.05), with a concomitant increase in serum IL-6 levels in the PL group.ConclusionEight-week EPA + DHA supplementation attenuates strength loss and limited ROM after exercise. The supplementation also attenuates muscle soreness and elevates cytokine level, but the effect is limited.

Mg-doped p-type a-plane GaN films were grown on high-quality unintentionally doped GaN on þ0:5 -off r-plane sapphire substrates by metalorganic vapor phase epitaxy (MOVPE). A maximum hole concentration of 2:0 Â 10 18 cm À3 was reproducibly achieved at room temperature, which was higher than the maximum hole concentration of p-type c-plane GaN. The activation energy of Mg acceptors in p-type a-plane GaN with a hole concentration of 2:0 Â 10 18 cm À3 was found to be 118 meV by temperature-dependent Hall-effect measurement.

cFLIP (cellular FLICE-like inhibitory protein) is structurally related to caspase-8 but lacks proteolytic activity due to multiple amino acid substitutions of catalytically important residues. cFLIP protein is evolutionarily conserved and expressed as three functionally different isoforms in humans (cFLIPL, cFLIPS, and cFLIPR). cFLIP controls not only the classical death receptor-mediated extrinsic apoptosis pathway, but also the non-conventional pattern recognition receptor-dependent apoptotic pathway. In addition, cFLIP regulates the formation of the death receptor-independent apoptotic platform named the ripoptosome. Moreover, recent studies have revealed that cFLIP is also involved in a non-apoptotic cell death pathway known as programmed necrosis or necroptosis. These functions of cFLIP are strictly controlled in an isoform-, concentration- and tissue-specific manner, and the ubiquitin-proteasome system plays an important role in regulating the stability of cFLIP. In this review, we summarize the current scientific findings from biochemical analyses, cell biological studies, mathematical modeling, and gene-manipulated mice models to illustrate the critical role of cFLIP as a switch to determine the destiny of cells among survival, apoptosis, and necroptosis.

Recent findings suggest that the unfolded protein response plays important roles in insulin maturation. Tsuchiya et al. demonstrate that constitutive activation of the IRE1α–XBP1 pathway maintains high expression of five protein disulfide isomerases, promoting the oxidative folding of proinsulin.

BackgroundThis study investigated the effect of supplementation with fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the M-wave latency of biceps brachii and muscle damage after a single session of maximal elbow flexor eccentric contractions (ECC).MethodsTwenty-one men were completed the randomized, double-blind, placebo-controlled, and parallel-design study. The subjects were randomly assigned to the fish oil group (n = 10) or control group (n = 11). The fish oil group consumed eight 300-mg EPA-rich fish oil softgel capsules (containing, in total, 600 mg EPA and 260 mg DHA) per day for 8 weeks before the exercise, and continued this for a further 5 days. The control group consumed an equivalent number of placebo capsules. The subjects performed six sets of ten eccentric contractions of the elbow flexors using a dumbbell set at 40% of their one repetition maximum. M-wave latency was assessed as the time taken from electrical stimulation applied to Erb’s point to the onset of M-wave of the biceps brachii. This was measured before and immediately after exercise, and then after 1, 2, 3, and 5 days. Changes in maximal voluntary isometric contraction (MVC) torque, range of motion (ROM), upper arm circumference, and delayed onset muscle soreness (DOMS) were assessed at the same time points.ResultsCompared with the control group, M-wave latency was significantly shorter in the fish oil group immediately after exercise (p = 0.040), MVC torque was significantly higher at 1 day after exercise (p = 0.049), ROM was significantly greater at post and 2 days after exercise (post; p = 0.006, day 2; p = 0.014), and there was significantly less delayed onset muscle soreness at 1 and 2 days after exercise (day 1; p = 0.049, day 2; p = 0.023).ConclusionEight weeks of EPA and DHA supplementation may play a protective role against motor nerve function and may attenuate muscle damage after eccentric contractions.Trial registrationThis trial was registered on July 14th 2015 (https://upload.umin.ac.jp/cgi-open-bin/ctr/index.cgi).

Emery±Dreifuss muscular dystrophy is a neuromuscular disorder that has three characteristics: (a) early contracture of the elbows, Achilles tendons and postcervical muscles; (b) slowly progressive wasting and weakness of skeletal muscle; and (c) cardiomyopathy with severe conduction block. The responsible gene for the X-linked recessive form of this disease encodes an inner nuclear membrane protein named emerin. Although emerin is absent in tissues from patients with this disorder, it remains obscure why the loss of this widely expressed protein affects selectively skeletal muscle, heart and joints. As the first step to address this question, we examined the molecular regions of emerin that are essential for nuclear membrane targeting and stability of the protein. We found that the C-terminal hydrophobic region was necessary, but not sufficient, for nuclear membrane anchoring and stability of the protein. In the absence of this transmembrane domain, the upstream nucleoplasmic domain showed no firm association with the nuclear rim, but showed the tendency to accumulate at the nucleolus-like structures. Furthermore, proper targeting of emerin to the nuclear membrane required the latter half of the nucleoplasmic domain. These characteristics are distinct from those of lamina-associated polypeptide 2. Our findings indicate that emerin has distinct interactions with the inner nuclear membrane components that may be required for the stability and function of rigorously moving nuclei in tissues such as skeletal muscle, heart and joints.

Nutritional supplementation not only helps in improving and maintaining performance in sports and exercise, but also contributes in reducing exercise fatigue and in recovery from exhaustion. Fish oil contains large amounts of omega-3 fatty acids, eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3). It is widely known that omega-3 fatty acids are effective for improving cardiac function, depression, cognitive function, and blood as well as lowering blood pressure. In the relationship between omega-3 fatty acids and exercise performance, previous studies have been predicted improved endurance performance, antioxidant and anti-inflammatory responses, and effectivity against delayed-onset muscle soreness. However, the optimal dose, duration, and timing remain unclear. This review focuses on the effects of omega-3 fatty acid on muscle damage and function as evaluated by human and animal studies and summarizes its effects on muscle and nerve damage, and muscle mass and strength.