TNF-α and Hormones

Therapeutic Uses of TNF-α and Hormones

• TNF family includes TNF-α and TNF-β, which bind to the same receptors but have limited similarity at the amino acid level.
• TNF-α is mainly synthesized by activated macrophages and is proteolytically processed to its active form as a homotrimer.
• TNF biosynthesis is regulated at both transcriptional and post-translational levels, and its major biological responses include activation of immunity, inflammation, and cytotoxicity against tumor cells.
• TNF-α was initially studied for its anti-tumor activity, which was enhanced by IFN-γ and induced by bacterially derived LPS.
• TNF-α can mediate cell death via apoptosis or necrosis, but systemic administration of TNF-α has severe side effects.
• Beromun is a therapeutic agent based on TNF-α that is used in combination with melphalan to treat soft-tissue sarcoma and prevent limb amputation.
• Anti-TNF monoclonal antibodies or soluble forms of the TNF receptor are used to neutralize TNF-α's biological effects and treat conditions associated with elevated TNF levels.
• Enbrel is an approved product that is used to treat rheumatoid arthritis and is made of the extracellular domain of the TNF receptor fused to the Fc region of human IgG.
• Therapeutic hormones are substances synthesized and released from a specific gland in the body that interact with a receptor on a distant sensitive cell and bring about a change.
• Insulin is a polypeptide hormone produced by pancreatic beta cells that regulates blood glucose levels and targets skeletal muscle fibers, hepatocytes, and adipocytes.
• The most potent stimulus of pancreatic insulin release is an increase in blood glucose levels after meals.
• Other therapeutic hormones include glucagon, growth hormone, and gonadotrophins.

Insulin: its role, structure, and production

• Insulin regulates glucose metabolism by stimulating glucose uptake, inhibiting glycogenolysis, and promoting anabolic pathways.
• Insulin-dependent diabetes mellitus (Type-1 diabetes) results from autoimmune destruction of pancreatic β-cells that produce insulin.
• Insulin is a 51 amino acid protein that is synthesized as a precursor molecule called preproinsulin.
• Proinsulin is processed to mature insulin and C-peptide, which can be used as a marker for insulin secretion.
• Commercial insulin was traditionally extracted from pig or cattle pancreas, but has immunogenicity and availability issues.
• Recombinant DNA technology enabled the production of human insulin, which was approved for therapeutic use in 1982.
• Recombinant human insulin is produced by inserting nucleotide sequences coding for A- and B-chains into E. coli cells, which are then purified and recombined in vitro.
• An alternative approach involves inserting a nucleotide sequence coding for human proinsulin into E. coli, which is then purified and proteolytically modified to produce human insulin.
• Recombinant DNA technology also enables the production of insulin analogues with modified amino acid sequences that alter their biological activity.
• Insulin analogues with aa substitutions at contact points between insulin molecules promote charge repulsion or steric hindrance to prevent dimerization or polymerization.
• Improving insulin analogues has centered on developing faster-acting insulins that do not form higher polymers at therapeutic doses.
• Approximately 170 million people worldwide suffer from diabetes, and the annual insulin requirement has surpassed 5,000 Kg and continues to grow.

Insulin and Glucagon: Types, Modifications, and Alternative Delivery Methods

• Insulin lispro and insulin aspart are fast-acting modified insulins that can be injected at mealtimes rather than one hour before.
• Insulin aspart has an aspartate residue at B28, decreasing self-association and ensuring immediate entry into the bloodstream upon administration.
• Insulin glargine and Levemir are long-acting insulin analogues that exhibit plasma half-lives of up to 35 hours and 25 hours, respectively.
• Insulin glargine has a C-terminal asparagine residue replaced by a glycine residue and an elongated B-chain with two arginine residues, increasing the molecule's pI to reduce its solubility.
• Levemir is devoid of threonine B30 and contains a 14-carbon fatty acid residue covalently attached to the side chain of lysine B29, ensuring constant and prolonged release of free insulin.
• Alternative insulin delivery methods include inhalable insulin and infusion systems.
• Exubera was the first inhalable insulin product, produced by recombinant E. coli and absorbed as quickly as subcutaneously administered rapid-acting insulin analogues.
• Afrezza is a rapid-acting inhalable insulin produced by Mannkind Corporation and licenced to Sanofi, with a delivery system that is small, sleek, and dosed in units rather than milligrams.
• Infusion systems can deliver insulin constitutively and mimic normal changes in blood insulin levels.
• Open-loop systems consist of an infusion pump that automatically infuses soluble insulin subcutaneously, while closed-loop systems have an integral glucose sensor and computer that adjusts the flow rate accordingly.
• Glucagon is a single-chain polypeptide of 29 amino acids synthesized by the A-cells of the islets of Langerhans and increases blood glucose levels.
• The major physiological function of glucagon is to prevent hypoglycemia.

Test your knowledge on therapeutic uses of TNF-α and hormones with this informative quiz. Discover the role of TNF-α in immunity, inflammation, and cytotoxicity, and its potential therapeutic applications. Learn about the side effects of systemic administration of TNF-α and the use of anti-TNF monoclonal antibodies to neutralize its effects. Explore the functions of therapeutic hormones, including insulin, glucagon, growth hormone, and gonadotrophins, and their role in regulating