Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-ß-Activated Kinase-1.

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-ß-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1ß. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

Silicone stent placement for tracheal stenosis induced by a giant goiter due to Graves' disease: a case report.

Background: Although thyroid tumors with tracheal stenosis are occasionally encountered, severe tracheal stenosis caused by benign thyroid tumors is rare. We herein describe a case in which a silicone tracheal stent was placed for severe tracheal stenosis induced by a giant goiter due to Graves' disease. Case Description: A 93-year-old woman had been receiving thiamazole treatment for Graves' disease with a thyroid goiter for 32 years. She emergently presented to the hospital with sudden difficulty breathing and the temporary loss of consciousness. Although marked stridor was heard, the patient's respiratory status was stable in the first visit. Computed tomography revealed a giant thyroid goiter that extended to the mediastinum. The trachea was compressed by the sternal notch and thyroid gland, resulting in severe stenosis, and the tracheal lumen was only 1 mm. Surgical thyroidectomy was expected to be difficult due to the high risk of complications associated with the large size of the goiter and advanced age of the patient. Therefore, we decided to place a tracheal stent. A silicone stent (Dumon tube®) was inserted into the site of tracheal stenosis under general anesthesia. After stent placement, respiratory distress symptoms improved, and no complications were observed. Three months after stent placement, the stent opening side was narrowed due to defective granulation and, thus, was cauterized with argon plasma coagulation. Conclusions: We encountered a patient who was treated by tracheal silicone stent placement for severe tracheal stenosis induced by a giant goiter due to Graves' disease. A silicone stent effectively secures the airway for benign thyroid tumors that cause severe airway stenosis.

Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011-2020) in Individuals with and without Diabetes at a Japanese Community General Hospital.

Since diabetes and its complications have been thought to exaggerate cardiorenal disease, resulting in a short lifespan, we investigated causes of death and lifespans in individuals with and without diabetes at a Japanese community general hospital during the period from 2011 to 2020. Causes of death and age of death in individuals with and those without diabetes were compared, and associations between medications used and age of death were statistically analyzed. A total of 2326 deaths were recorded during the 10-year period. There was no significant difference between the mean ages of death in individuals with and those without diabetes. Diabetic individuals had higher rates of hepato-pancreatic cancer and cardio-renal failure as causes of death. The prescription rates of antihypertensives, antiplatelets, and statins in diabetic individuals were larger than those in non-diabetic individuals. Furthermore, the use of sulfonyl urea or glinides and insulin was independently and inversely associated with the age of death. In conclusion, individuals with diabetes were treated with comprehensive pharmaceutical interventions and had life spans comparable to those of individuals without diabetes. This study's discovery of an inverse relationship between the use of insulin secretagogues or insulin and the age of death suggests that the prevention of life-threatening hypoglycemia is crucial for individuals with diabetes.

Acute accumulation of PIM2 and NRF2 and recovery of ß5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of ß5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of ß5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.