Regio- and Stereoselective α-Allylation with Enolates Prepared from N-C Axially Chiral Thiolactam and Lactam.

The reaction of allyl bromide derivatives with the enolate prepared from enantioenriched N-C axially chiral N-(2,5-di-tert-butylphenyl)-3,4-dihydroquinolin-2-one (lactam) and -thione (thiolactam) proceeded in a completely regio- and stereoselective manner to afford SN2 and SN2'-like products, respectively. Furthermore, through the conversion of thiolactam to lactam, the regiodivergent and stereoselective synthesis of N-C axially chiral lactams bearing a chiral tertiary α-carbon was achieved.

Statins Show Anti-Atherosclerotic Effects by Improving Endothelial Cell Function in a Kawasaki Disease-like Vasculitis Mouse Model.

Kawasaki disease (KD) is an acute inflammatory syndrome of unknown etiology that is complicated by cardiovascular sequelae. Chronic inflammation (vasculitis) due to KD might cause vascular cellular senescence and vascular endothelial cell damage, and is a potential cause of atherosclerosis in young adults. This study examined the effect of KD and HMG-CoA inhibitors (statins) on vascular cellular senescence and vascular endothelial cells. Candida albicans water-soluble fraction (CAWS) was administered intraperitoneally to 5-week-old male apolipoprotein E-deficient (ApoE-) mice to induce KD-like vasculitis. The mice were then divided into three groups: control, CAWS, and CAWS+statin groups. Ten weeks after injection, the mice were sacrificed and whole aortic tissue specimens were collected. Endothelial nitric oxide synthase (eNOS) expression in the ascending aortic intima epithelium was evaluated using immunostaining. In addition, eNOS expression and levels of cellular senescence markers were measured in RNA and proteins extracted from whole aortic tissue. KD-like vasculitis impaired vascular endothelial cells that produce eNOS, which maintains vascular homeostasis, and promoted macrophage infiltration into the tissue. Statins also restored vascular endothelial cell function by promoting eNOS expression. Statins may be used to prevent secondary cardiovascular events during the chronic phase of KD.

Intermolecular Halogen Bond Detected in Racemic and Optically Pure N-C Axially Chiral 3-(2-Halophenyl)quinazoline-4-thione Derivatives.

The halogen bond has been widely used as an important supramolecular tool in various research areas. However, there are relatively few studies on halogen bonding related to molecular chirality. 3-(2-Halophenyl)quinazoline-4-thione derivatives have stable atropisomeric structures due to the rotational restriction around an N-C single bond. In X-ray single crystal structures of the racemic and optically pure N-C axially chiral quinazoline-4-thiones, we found that different types of intermolecular halogen bonds (C=S⋯X) are formed. That is, in the racemic crystals, the intermolecular halogen bond between the ortho-halogen atom and sulfur atom was found to be oriented in a periplanar conformation toward the thiocarbonyl plane, leading to a syndiotactic zig-zag array. On the other hand, the halogen bond in the enantiomerically pure crystals was oriented orthogonally toward the thiocarbonyl plane, resulting in the formation of a homochiral dimer. These results indicate that the corresponding racemic and optically pure forms in chiral molecules are expected to display different halogen bonding properties, respectively, and should be separately studied as different chemical entities.

Genetic dissection of the circuit for hand dexterity in primates.

It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex­PN­motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain.

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain-like behaviors in sciatic nerve-ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level-dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve-ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT-3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve-ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin-2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain-like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice.

Causal Connectivity Network Analysis of Ictal Electrocorticogram With Temporal Lobe Epilepsy Based on Dynamic Phase Transfer Entropy.

Temporallobe epilepsy (TLE) has been conceptualized as a brain network disease, which generates brain connectivity dynamics within and beyond the temporal lobe structures in seizures. The hippocampus is a representative epileptogenic focus in TLE. Understanding the causal connectivity in terms of brain network during seizures is crucial in revealing the triggering mechanism of epileptic seizures originating from the hippocampus (HPC) spread to the lateral temporal cortex (LTC) by ictal electrocorticogram (ECoG), particularly in high-frequency oscillations (HFOs) bands. In this study, we proposed the unified-epoch dynamic causality analysis method to investigate the causal influence dynamics between two brain regions (HPC and LTC) at interictal and ictal phases in the frequency range of 1-500 Hz by introducing the phase transfer entropy (PTE) out/in-ratio and sliding window. We also proposed PTE-based machine learning algorithms to identify epileptogenic zone (EZ). Nine patients with a total of 26 seizures were included in this study. We hypothesized that: 1) HPC is the focus with the stronger causal connectivity than that in LTC in the ictal state at gamma and HFOs bands. 2) Causal connectivity in the ictal phase shows significant changes compared to that in the interictal phase. 3) The PTE out/in-ratio in the HFOs band can identify the EZ with the best prediction performance.

Human Adipose Tissue-Derived Stem Cells Inhibit Coronary Artery Vasculitis in a Mouse Model of Kawasaki Disease.

BACKGROUND: Adipose tissue-derived mesenchymal stem cells (ADSCs) are used for the treatment of various diseases because of their rapid proliferation and high anti-inflammatory and tissue repair properties. Kawasaki disease is a systemic vasculitis with coronary arteritis and aneurysms occurring in pediatric patients. In this study, we examined serologically and pathologically whether the administration of human ADSCs (hADSCs) to a mouse model of Kawasaki disease could suppress vasculitis. METHODS: Candida albicans water-soluble fractions were intraperitoneally injected into DBA/2 mice for 5 consecutive days to generate a mouse model of Kawasaki disease. The model mice were intravenously administered hADSCs or phosphate-buffered saline (PBS). Serum samples collected on days 15 and 29 were used to compare cytokine levels. Mouse hearts dissected on day 29 were subjected to hematoxylin and eosin and immunohistological staining using Galectin-1 (Gal-1), a protein involved in cardiovascular homeostasis, and CD44, a cell-surface marker of hADSCs. RESULTS: Comparison of inflammation-related cytokines showed a significant decrease in IL-1α expression at day 15 (P<0.05) and IL-6 expression at day 29 (P<0.01) in the hADSCs-treated group compared to the PBS group. Evaluation by hematoxylin and eosin staining showed decreased inflammatory cell infiltration and a tendency towards increased Gal-1 expression in the hADSCs group. CD44 expression was not observed in both the groups. The survival curve showed that the hADSCs group had a significantly longer survival time (P<0.05). CONCLUSIONS: The present experimental results indicate that hADSCs have an early anti-inflammatory effect, and that Gal-1 may be involved in preventing inflammation and reducing tissue damage.

Use of tocilizumab to treat arthritis associated with mixed connective tissue disease complicated by ovarian teratoma: a case report.

Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is rare in children. Here, we report a case of MCTD in a 10-year-old girl who presented at our hospital with arthralgia, Raynaud's phenomenon, and fatigue. Blood tests were positive for anti-U1-ribonucleoprotein (RNP) antibodies and for rheumatoid factors (RFs) IgG-RF and anti-galactose-deficient IgG. Levels of myogenic enzymes and hypergammaglobulinemia were elevated. Macrophages were prominent in bone marrow, with scattered phagocytic macrophages. MCTD was diagnosed based on the patient's symptoms and laboratory findings. Methylprednisolone pulse therapy combined with oral tacrolimus was administered, which led to resolution of symptoms. Three months after pulse therapy, arthralgia worsened and methotrexate was administered. Arthralgia improved but did not resolve. Magnetic resonance imaging performed to investigate the hip pain revealed a mature ovarian teratoma, which was surgically removed. Because the pain persisted and interfered with her daily life, she was treated with tocilizumab for joint pain relief, which decreased the pain level. Tocilizumab is a candidate for additional treatment of juvenile idiopathic arthritis-like arthritis associated with childhood-onset MCTD.

High resolution recording of local field currents simultaneously with sound-evoked calcium signals by a photometric patch electrode in the auditory cortex field L of the chick.

BACKGROUND: Functioning of the brain is based on both electrical and metabolic activity of neural ensembles. Accordingly, it would be useful to measure intracellular metabolic signaling simultaneously with electrical activity in the brain in vivo. NEW METHOD: We innovated a PhotoMetric-patch-Electrode (PME) recording system that has a high temporal resolution incorporating a photomultiplier tube as a light detector. The PME is fabricated from a quartz glass capillary to transmit light as a light guide, and it can detect electrical signals as a patch electrode simultaneously with a fluorescence signal. RESULTS: We measured the sound-evoked Local Field Current (LFC) and fluorescence Ca2+ signal from neurons labeled with Ca2+-sensitive dye Oregon Green BAPTA1 in field L, the avian auditory cortex. Sound stimulation evoked multi-unit spike bursts and Ca2+ signals, and enhanced the fluctuation of LFC. After a brief sound stimulation, the cross-correlation between LFC and Ca2+ signal was prolonged. D-AP5 (antagonist for NMDA receptors) suppressed the sound-evoked Ca2+ signal when applied locally by pressure from the tip of PME. COMPARISON WITH EXISTING METHODS: In contrast to existing multiphoton imaging or optical fiber recording methods, the PME is a patch electrode pulled simply from a quartz glass capillary and can measure fluorescence signals at the tip simultaneously with electrical signal at any depth of the brain structure. CONCLUSION: The PME is devised to record electrical and optical signals simultaneously with high temporal resolution. Moreover, it can inject chemical agents dissolved in the tip-filling medium locally by pressure, allowing manipulation of neural activity pharmacologically.

A case of bacteremia and meningitis in a neonate infected with Group B Streptococcus via breastfeeding who survived without neurological sequelae: A case report.

Invasive neonatal infection with Group B Streptococcus (GBS) is a disease of concern that can lead to neurological sequelae. Guidelines for preventing mother-to-child transmission have been introduced to reduce the incidence of early-onset infection, but guidelines for controlling the late-onset form are lacking. Recently, the trans-breastfeeding route of transmission has been highlighted as an example of late-onset infection, but no consensus on how to manage such infections has been reached. In this report, we describe a case of late-onset bacteremia/meningitis in a neonate suspected to have been infected with GBS via breastfeeding. A vaginal culture test of the mother at 35 weeks' gestation was negative for GBS. Since she had symptoms of mastitis, breast milk and nipple cultures were also tested and found to be positive for the strain of GBS identified in the neonate on genetic analysis. Diagnosis of trans-mammary GBS infection is challenging because breastfeeding-related events are difficult to identify. In our case, the diagnosis was based on the mother's history of mastitis, and the patient was treated without escalation to sequelae. When a neonate develops a fever, physicians should consider GBS infection and examine the mother's medical history to facilitate accurate diagnosis, especially if the history includes mastitis. A breast milk culture should be performed if the mother has mastitis, especially in cases of infection in preterm infants and in recurrent cases.

Concise total synthesis of (-)-myxalamide†A.

The MIDA touch: A concise and highly convergent protecting-group-free total synthesis of (-)-myxalamide A involves a stereoselective vinylogous Mukaiyama aldol reaction of a vinylketene silyl N,O-acetal, together with a one-pot Stille/Suzuki-Miyaura cross-coupling reaction using Burke's N-methyliminodiacetic acid (MIDA) boronate to connect left- and right-hand fragments of the molecule (see scheme).

Kawasaki Disease-like Vasculitis Facilitates Atherosclerosis, and Statin Shows a Significant Antiatherosclerosis and Anti-Inflammatory Effect in a Kawasaki Disease Model Mouse.

Kawasaki disease (KD) is an acute form of systemic vasculitis that may promote atherosclerosis in adulthood. This study examined the relationships between KD, atherosclerosis, and the long-term effects of HMG-CoA inhibitors (statins). Candida albicans water-soluble fraction (CAWS) was injected intraperitoneally into 5-week-old male apolipoprotein-E-deficient (Apo E-/-) mice to create KD-like vasculitis. Mice were divided into 4 groups: the control, CAWS, CAWS+statin, and late-statin groups. They were sacrificed at 6 or 10 weeks after injection. Statin was started after CAWS injection in all groups except the late-statin group, which was administered statin internally 6 weeks after injection. Lipid plaque lesions on the aorta were evaluated with Oil Red O. The aortic root and abdominal aorta were evaluated with hematoxylin and eosin staining and immunostaining. CAWS vasculitis significantly enhanced aortic atherosclerosis and inflammatory cell invasion into the aortic root and abdominal aorta. Statins significantly inhibited atherosclerosis and inflammatory cell invasion, including macrophages. CAWS vasculitis, a KD-like vasculitis, promoted atherosclerosis in Apo E-/- mice. The long-term oral administration of statin significantly suppressed not only atherosclerosis but also inflammatory cell infiltration. Therefore, statin treatment may be used for the secondary prevention of cardiovascular events during the chronic phase of KD.

Characterization of Polyurethane Shape Memory Polymer and Determination of Shape Fixity and Shape Recovery in Subsequent Thermomechanical Cycles.

Multifunctional polyurethane shape memory polymers (PU-SMPs) have been of increasing interest in various applications. Here we report structure characterization, detailed methodology, and obtained results on the identification of functional properties of a thermoset PU-SMP (MP4510) with glass transition temperature of 45 °C. The stable, chemically crosslinked network of this thermoset PU-SMP results in excellent shape memory behavior. Moreover, the proximity of the activation temperature range of this smart polymer to room and body temperature enables the PU-SMP to be used in more critical industrial applications, namely fast-response actuators. The thermomechanical behavior of a shape memory polymer determines the engineering applications of the material. Therefore, investigation of the shape memory behavior of this class of commercial PU-SMP is of particular importance. The conducted structural characterization confirms its shape memory properties. The shape fixity and shape recovery properties were determined by a modified experimental approach, considering the polymer's sensitivity to external conditions, i.e., the temperature and humidity variations. Three thermomechanical cycles were considered and the methodology used is described in detail. The obtained shape fixity ratio of the PU-SMP was approximately 98% and did not change significantly in the subsequent cycles of the thermomechanical loading due to the stability of chemical crosslinks in the thermoset materials structure. The shape recovery was found to be approximately 90% in the first cycle and reached a value higher than 99% in the third cycle. The results confirm the effect of the thermomechanical training on the improvement of the PU-SMP shape recovery after the first thermomechanical cycle as well as the effect of thermoset material stability on the repeatability of the shape memory parameters quantities.

Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons.

Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

A calcitonin receptor-expressing subregion of the medial preoptic area is involved in alloparental tolerance in common marmosets.

Like humans, common marmoset monkeys utilize family cooperation for infant care, but the neural mechanisms underlying primate parental behaviors remain largely unknown. We investigated infant care behaviors of captive marmosets in family settings and caregiver-infant dyadic situations. Marmoset caregivers exhibited individual variations in parenting styles, comprised of sensitivity and tolerance toward infants, consistently across infants, social contexts and multiple births. Seeking the neural basis of these parenting styles, we demonstrated that the calcitonin receptor-expressing neurons in the marmoset medial preoptic area (MPOA) were transcriptionally activated during infant care, as in laboratory mice. Further, site-specific neurotoxic lesions of this MPOA subregion, termed the cMPOA, significantly reduced alloparental tolerance and total infant carrying, while sparing general health and other social or nonsocial behaviors. These results suggest that the molecularly-defined neural site cMPOA is responsible for mammalian parenting, thus provide an invaluable model to study the neural basis of parenting styles in primates.

Stereoselective vinylogous Mukaiyama aldol reaction of α-haloenals.

We have developed a high-yielding and stereoselective vinylogous Mukaiyama aldol reaction (VMAR) of α-haloenals. Contrary to the simple α,ß-unsaturated aldehyde, α-haloenals were found to be reactive affording the corresponding VMAR adducts in excellent yields. Some transformations of VMAR adducts by Pd-mediated cross-coupling were also examined in order to demonstrate the synthetic utility of VMAR of α-haloenals.

Avian adeno-associated virus as an anterograde transsynaptic vector.

BACKGROUND: Retrograde and anterograde transsynaptic viral vectors are useful tools for studying the input and output organization of neuronal circuitry, respectively. While retrograde transsynaptic viral vectors are widely used, viral vectors that show anterograde transsynaptic transduction are not common. NEW METHOD: We chose recombinant avian adeno-associated virus (A3V) carrying the mCherry gene and injected it into the eyeball, cochlear duct, and midbrain auditory center of chickens. We observed different survival times to examine the virus transcellular transport and the resulting mCherry expression. To confirm the transcellular transduction mode, we co-injected A3V and cholera toxin B subunit. RESULTS: Injecting A3V into the eyeball and cochlea labeled neurons in the visual and auditory pathways, respectively. Second-, and third-order labeling occurred approximately two and seven days, respectively, after injection into the midbrain. The distribution of labeled neurons strongly suggests that A3V transport is preferentially anterograde and transduces postsynaptic neurons. COMPARISON WITH EXISTING METHOD(S): A3V displays no extrasynaptic leakage and moderate speed of synapse passage, which is better than other viruses previously reported. Compared with AAV1&9, which have been shown to pass one synapse anterogradely, A3V passes several synapses in the anterograde direction. CONCLUSIONS: A3V would be a good tool to study the topographic organization of projection axons and their target neurons.

trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway.

trans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

A Case of Kawasaki Disease with Intussusception.

Kawasaki disease (KD) is a systemic vasculitis of unknown cause and is associated with various digestive disorders, although only a few cases of intussusception associated with KD have been reported. We describe a case of intussusception followed by KD in a 3-year-old boy. The patient was admitted to our hospital for evaluation of severe abdominal pain. Because the target sign was seen on ultrasonography, intussusception was diagnosed and hydrostatic reduction was performed. On the second day after admission, he developed a high fever (38°C) and an irregular rash over his whole body. On the fourth day after admission, the high fever continued, and bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, strawberry tongue, indurated edema of the dorsa of the hands and feet, and diffuse erythema of the palms and soles appeared, and KD was ultimately diagnosed. He was treated with intravenous immunoglobulin 2 g/kg, aspirin 30 mg/kg/day, and prednisolone 2 mg/kg/day. The high fever and other clinical symptoms resolved immediately after the start of treatment. There was no relapse of KD symptoms after initial treatment, and periungual desquamation was observed on the 10th day after admission. He was discharged on the 15th day, without abnormalities such as coronary dilatation, 3 months after the onset of KD symptoms. Patients with intussusception and KD were older (≥3 years vs <3 years) than those with intussusception alone. In addition, the site of intussusception in KD was mainly colonic rather than ileocolic. If intussusception precedes development of the characteristic clinical symptoms of KD, diagnosis of KD may be delayed. KD should be considered in children older than 3 years with intussusception at a colonic site.

trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop.

trans-Fatty acids (TFAs) are unsaturated fatty acids that contain one or more carbon-carbon double bonds in trans configuration. Epidemiological evidence has linked TFA consumption with various disorders, including cardiovascular diseases. However, the underlying pathological mechanisms are largely unknown. Here, we show a novel toxic mechanism of TFAs triggered by DNA damage. We found that elaidic acid (EA) and linoelaidic acid, major TFAs produced during industrial food manufacturing (so-called as industrial TFAs), but not their corresponding cis isomers, facilitated apoptosis induced by doxorubicin. Consistently, EA enhanced UV-induced embryonic lethality in C. elegans worms. The pro-apoptotic action of EA was blocked by knocking down Sab, a c-Jun N-terminal kinase (JNK)-interacting protein localizing at mitochondrial outer membrane, which mediates mutual amplification of mitochondrial reactive oxygen species (ROS) generation and JNK activation. EA enhanced doxorubicin-induced mitochondrial ROS generation and JNK activation, both of which were suppressed by Sab knockdown and pharmacological inhibition of either mitochondrial ROS generation, JNK, or Src-homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) as a Sab-associated protein. These results demonstrate that in response to DNA damage, TFAs drive the mitochondrial JNK-Sab-ROS positive feedback loop and ultimately apoptosis, which may provide insight into the common pathogenetic mechanisms of diverse TFA-related disorders.