Harmful Side Effects of Synthetic Drugs

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Updated: Aug 21, 2023
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Literature shows that synthetic drugs are more expensive and known to have harmful side effects compared to natural drugs. This fact simply advocates the economic benefit that it’s cheaper to extract the phytochemicals from medicinal plants, rather than using expensive laboratory chemicals.
Medicinal plants are commonly used for the treatment of various diseases because they are considered to be advantageous. Medicinal plants contain numerous phytochemicals with potential biological activities that have been identified. Oxidative stress and inflammation are primarily implicated in many disease pathologies.
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Therefore, attention has been focused on identifying those medicinal phytochemicals that display antioxidant and anti-inflammatory activity, which can inhibit, retard, or reverse the multi-stage pathophysiological events underlying disease pathology.

Cell death is a vital factor in many biological processes, including fundamental physiological processes such as development, immunity, and tissue homeostasis. Moreover, cell death often correlates to degenerative and neoplastic diseases. It is an important process in the body as it promotes the removal of unwanted cells, marking the end of a biological cell’s functional life. In organisms, cell death is necessary for cell-cycle maturation. Cells can die for various reasons, including exposure to radiation, bacterial toxins, heat, stress, infection, starvation, lack of oxygen, and external injury, amongst others. Cells can die in several distinct ways, with some occurring through an organized, programmed process.
Four main types of cell death have been identified: apoptosis, necrosis, autophagy, and ferroptosis. Apoptosis is a process of programmed cell death that occurs in multicellular organisms and involves morphological changes, such as cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. Autophagy is the natural, regulated mechanism of cell destruction that disassembles unnecessary or dysfunctional components. In disease situations, autophagy is seen as an adaptive response to stress, which promotes survival. In other cases, it appears to promote cell death and morbidity.
Necrosis is a form of cell death that results in the premature death of cells in living tissue by autolysis. It is caused by factors such as toxin injection and trauma, which result in the unregulated digestion of cell components.
External and internal factors are the major causes of cell death. Hence, it has gained special attention in treatment by targeting regulated cell death pathways, particularly due to their role in inflammation. Ferroptosis, a newly discovered regulated form of cell death, leads to glutathione depletion resulting from the inhibition of cysteine uptake or inactivation of the glutathione peroxidase enzyme. This causes an iron-dependent accumulation of ROS and lipid-based ROS, particularly lipid hydroperoxide. A selenoprotein is the only reduced glutathione peroxidase that handles lipid hydroperoxides and uses GSH to convert non-toxic lipid alcohols from toxic lipid hydroperoxides. A tripeptide of glutamate, cysteine, and glycine is a well-known intracellular antioxidant that protects cells from oxidative or other forms of stress. It also serves as a cofactor for the glutathione peroxidase and S-transferase enzyme families. Inducers of ferroptosis have been discovered through characterizing the mechanism of action using multipronged approaches. There are four classes of ferroptosis inducers currently in use:
  •  Erastin: inhibits cystine import, causes GSH depletion and inactivation of GPX4.
  •  RSL3: a GPX4 inhibitor that causes accumulation of lipid hydroperoxides.
  •  FIN56: Depletes GPX4 protein and lipophilic antioxidant CoQ10.
  •  FINO2: Indirectly inhibits GPX4 activity and stimulates lipid peroxidation.

In addition to these canonical ferroptosis inducers, several other reagents can also induce ferroptosis:

  • Silica-based nanoparticle: Targets GSH and iron, delivers iron into cells and reduces GSH abundance.
  • Trigonelline and brusatol: Block NRF2 activity.

Several genes have served as markers of ferroptosis:

  • Lipoxygenases: Involved in the peroxidation of PUFA.
  • GPX4 (Glutathione Peroxidase 4): Reduces membrane phospholipid hydroperoxides to suppress ferroptosis.
  • ATP5G3 (ATP Synthase): Knockdown suppresses erastin-induced ferroptosis.
  • TFRC: Transferrin receptor promotes ferroptosis by importing iron into cells.
  • LPCAT3 (Lysophosphotidylcholine Acyltransferase 3): Biosynthesis of phospholipids in the presence of LPCAT3 is one of the factors that cause ferroptosis.
  • GCLC/GCLM (Glutamate-Cysteine Ligase): Involved in the biosynthesis of glutathione.
  • CARS (Cysteinyl t-RNA Synthetase): Increased in the transsulfuration pathway and its activity is caused by the CARS enzyme, resulting in resistance to ferroptosis induced by system Xc inhibitors.
  • NFE2L2 (Nuclear Factor-Erythroid 2-Related Factor 2): Encodes NRF2, a master regulator of antioxidant response that drives resistance to ferroptosis.

 Inhibitors of Ferroptosis

Ferroptosis-induced cell death can be suppressed exclusively by iron chelators, lipophilic antioxidants, and inhibitors of lipid peroxidation. Several studies have identified lipophilic antioxidants (?-tocopherol, Butylated hydroxytoluene, and ?-carotene) as strong suppressors of erastin-induced cell death [8]. Both the Vitamin E family and flavonoids can inhibit lipoxygenases activity in some contexts [9]. Inhibitors of iron metabolism and iron chelators, such as deferoxamine and ciclopirox, suppress ferroptosis by reducing the availability of iron [10]. Similarly, ferrostatins and liproxstatins inhibit lipid peroxidation, possibly by acting as radical trapping antioxidants [11], akin to the lipophilic antioxidants BHT, BHA, and vitamin E.
The following are numerous reagents that modulate ferroptosis:
  • Vitamin E, trolax, tocotrienols, deuterated polyunsaturated fatty acids (D-PUFAs): These block propagation and initiation of lipid peroxidation.
  • Butylated hydroxytoluene, butylated hydroxyanisole, ferrostatins, liproxstatins, CoQ10, idebenone: These block lipid peroxidation.
  • Dopamine: A neurotransmitter that blocks GPx4 (glutathione peroxidase4) degradation.
  • Deferoxamine, cyclopirox, deferiprone: These prevent iron-dependent lipid peroxidation by depleting iron.
According to past research studies, compounds that inhibit the accumulation of lipid peroxidation have the potential to inhibit ferroptosis and may provide promising therapeutic agents to treat pathological conditions previously thought to be untreatable.
Recently, several inhibitors of ferroptosis have been identified by high-throughput screening of a small molecular library, including liprostatin (Figure). They can block pathological cell death events in the brain, kidney, and other tissues.
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Harmful Side Effects of Synthetic Drugs. (2021, May 20). Retrieved from https://papersowl.com/examples/harmful-side-effects-of-synthetic-drugs/