mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival. LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. Increased LAM cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs.Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögrens syndrome, or Birt–Hogg–Dubé syndrome.
Mexiletine (INN) (sold under the brand names Mexitil and Namuscla) is a medication used to treat abnormal heart rhythms, chronic pain, and some causes of muscle stiffness. Common side effects include abdominal pain, chest discomfort, drowsiness, headache, and nausea. It works as a non-selective voltage-gated sodium channel blocker and belongs to the Class IB group of anti-arrhythmic medications. Medical uses
Mexiletine has several uses including the treatment of abnormal heart rhythms or arrhythmias, chronic pain, and myotonia. In general when treating arrhythmias, mexiletine is reserved for use in dangerous heart rhythm disturbances such as ventricular tachycardia. It is of particular use when treating arrhythmias caused by long QT syndrome. The LQT3 form of long QT syndrome is amenable to treatment with mexiletine as this form is caused by defective sodium channels that continue to release a sustained current rather than fully inactivating, however other forms of long QT syndrome can also be treated with this medication.Mexiletine has been used to treat chronic pain and may also be used to treat muscle stiffness resulting from myotonic dystrophy (Steinerts disease) or nondystrophic myotonias such as myotonia congenita (Thomsen syndrome or Becker syndrome). Adverse effects
Common side effects of mexiletine include abdominal pain, chest discomfort, drowsiness, headache, nausea and skin reactions. Uncommon or rare side effects include seizures and liver dysfunction. Pharmacology
Mexiletine is an oral analogue of lidocaine. It is a class IB antiarrhythmic which shorten the refractory period and action potential duration (APD). Decrease in APD more than that of ERP so there is increase ERP/APD ratio.