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Foramen of Winslow hernias are a rare, but dangerous form of internal hernia that can present in individuals with signs and symptoms of bowel obstruction. This case report details operative management of a cecal herniation through the foramen of Winslow in an elderly male with no prior history of intra-abdominal surgery. The patient presented with worsening abdominal pain, nausea, vomiting and obstipation. Due to the clinical picture of a complete bowel obstruction and subsequent imaging findings, an urgent abdominal exploration was performed. During the procedure, the cecum was found to be ischemic and strangulated in the lesser sac, herniated through the foramen of Winslow. Following operative reduction and right hemicolectomy, it was decided to close the foramen of Winslow to prevent recurrence and future complications. The patient had an uncomplicated postoperative course with resolution of symptoms. [ABSTRACT FROM AUTHOR]

Mammalian nutrient sensors are novel targets for therapeutic intervention in disease states such as insulin resistance and muscle wasting; however, the proteins responsible for this important task are largely uncharacterized. To address this issue we have dissected an amino acid (AA) sensor/effector regulon that controls the expression of the System A amino acid transporter SNAT2 in mammalian cells, a paradigm nutrient-responsive process, and found evidence for the convergence of at least two sensor/effector pathways. During AA withdrawal, JNK is activated and induces the expression of SNAT2 in L6 myotubes by stimulating an intronic nutrient-sensitive domain. A sensor for large neutral AA (e.g. Tyr, GIn) inhibits JNK activation and SNAT2 up-regulation. Additionally, shRNA and transporter chimeras demonstrate that SNAT2 provides a repressive signal for gene transcription during AA sufficiency, thus echoing AA sensing by transceptor (transporter-receptor) orthologues in yeast (Gap1/Ssy1) and Drosophila (PATH). Furthermore, the SNAT2 protein is stabilized during AA withdrawal. [ABSTRACT FROM AUTHOR]

We have investigated the expression and regulation of the Na+-K+-2Cl- cotransporter (NKCC) by insulin and hyperosmotic stress in L6 rat skeletal muscle cells. NKCC was identified by immunoblotting as a 170 kDa protein in L6 myotubes and mediated 54% of K+ (86Rb+) influx based on the sensitivity of ion transport to bumetanide, a NKCC inhibitor. The residual 86Rb+ influx occurred via the Na+,K+-ATPase and other transporters not sensitive to bumetanide or ouabain. NKCC-mediated 86Rb+ influx was enhanced significantly (∼1.6-fold) by acute cell exposure to insulin, but was inhibited significantly by tyrosine kinase inhibitors, wortmannin and rapamycin, consistent with a role for the insulin receptor tyrosine kinase, phosphoinositide 3 (PI3)-kinase and mTOR, respectively, in cotransporter activation. In contrast, the hormonal activation of NKCC was unaffected by inhibition of the classical Erk-signalling pathway. Subjecting L6 myotubes to an acute hyperosmotic challenge (420 mosmol l-1) led to a 40% reduction in cell volume and was accompanied by a rapid stimulation of NKCC activity (∼2-fold). Intracellular volume recovered to normal levels within 60 min, but this regulatory volume increase (RVI) was prevented if bumetanide was present. Unlike insulin, activation of NKCC by hyperosmolarity did not involve PI3-kinase but was suppressed by inhibition of tyrosine kinases and the Erk pathway. While inhibition of tyrosine kinases, using genistein, led to a complete loss in NKCC activation in response to hyperosmotic stress, immunoprecipitation of NKCC revealed that the cotransporter was not regulated directly by tyrosine phosphorylation. Simultaneous exposure of L6 myotubes to insulin and hyperosmotic stress led to an additive increase in NKCC-mediated 86Rb+ influx, of which, only the insulin-stimulate... [ABSTRACT FROM AUTHOR]

Determines the effects of ceramide on System A amino acid transport, protein synthesis, and intracellular signaling pathways involved in the regulation of protein synthesis in skeletal muscle. Reduction of plasma membrane SNAT2 abundance; Depletion of intracellular amino acid pool; Impairment of myotube protein synthesis.

Abstract Extracellular amino acid (AA) withdrawal/restriction invokes an integrated stress response (ISR) that induces global suppression of protein synthesis whilst allowing transcription and translation of a select group of genes, whose protein products facilitate cellular adaptation to AA insufficiency. Transcriptional induction of the System A/SNAT2 AA transporter represents a classic adaptation response and crucially depends upon activation of the General Control Nonderepressible-2 kinase/Activating transcription factor 4 (GCN2/ATF4) pathway. However, the ISR may also include additional signalling inputs operating in conjunction or independently of GCN2/ATF4 to upregulate SNAT2. Herein, we show that whilst pharmacological inhibition of MEK-ERK, mTORC1 and p38 MAP kinase signalling has no detectable effect on System A upregulation, inhibitors targeting GSK3 (e.g. SB415286) caused significant repression of the SNAT2 adaptation response. Strikingly, the effects of SB415286 persist in cells in which GSK3α/β have been stably silenced indicating an off-target effect. We show that SB415286 can also inhibit cyclin-dependent kinases (CDK) and that roscovitine and flavopiridol (two pan CDK inhibitors) are effective repressors of the SNAT2 adaptive response. In particular, our work reveals that CDK7 activity is upregulated in AA-deprived cells in a GCN-2-dependent manner and that a potent and selective CDK7 inhibitor, THZ-1, not only attenuates the increase in ATF4 expression but blocks System A adaptation. Importantly, the inhibitory effects of THZ-1 on System A adaptation are mitigated in cells expressing a doxycycline-inducible drug-resistant form of CDK7. Our data identify CDK7 as a novel component of the ISR regulating System A adaptation in response to AA insufficiency. Highlights • Roscovitine and flavopiridol (CDK inhibitors) block the System A adaptive response. • Extracellular amino acid (AA) withdrawal induces CDK7 activation. • Pharmacological inhibition of GCN2 represses CDK7 activation in AA-deprived cells. • Targeted suppression of CDK7 represses ATF4 expression and System A adaptation. [ABSTRACT FROM AUTHOR]