Lachesis venom, derived from the bushmaster snake, is a complex cocktail of bioactive molecules that exert potent toxic effects on various physiological systems. This article delves into the molecular constituents of Lachesis venom, their toxic effects on different body parts, and the molecular mechanisms underlying these effects. Understanding these aspects not only provides insights into venom biology but also offers potential avenues for developing novel therapeutic agents.
Lachesis muta, commonly known as the bushmaster snake, is among the largest venomous snakes in the Americas. Its venom comprises a multifaceted array of molecules that target diverse biological pathways, leading to severe envenomation symptoms. This article aims to comprehensively review the molecular constituents of Lachesis venom, their toxicological effects, and the molecular mechanisms through which they act.
Molecular Constituents of Lachesis Venom
Lachesis venom is a rich and complex mixture of proteins, peptides, enzymes, and other bioactive molecules. These constituents can be broadly classified into several categories:
Enzymatic Proteins
Metalloproteinases: These enzymes degrade extracellular matrix components, leading to tissue destruction and hemorrhage. Metalloproteinases in Lachesis venom are implicated in local and systemic bleeding.
Serine Proteinases: These enzymes interfere with blood coagulation pathways, causing coagulopathy. They can either promote or inhibit clot formation, leading to complex hemostatic disturbances.
Phospholipases A2 (PLA2s): PLA2s hydrolyze phospholipids in cell membranes, resulting in cell lysis, inflammation, and neurotoxic effects.
L-Amino Acid Oxidases (LAAOs): These enzymes generate hydrogen peroxide as a byproduct, contributing to oxidative stress and cell death.
Non-Enzymatic Proteins
Disintegrins: These small proteins inhibit platelet aggregation by binding to integrins on the platelet surface, thereby preventing blood clot formation.
Myotoxins: These proteins cause muscle necrosis and disrupt cellular membranes.
Peptides
Small peptides in the venom exhibit various biological activities, including modulation of ion channels, interference with neurotransmitter release, and effects on blood pressure regulation.
Carbohydrates
Glycoproteins and other carbohydrate-containing molecules in the venom contribute to its bioactivity and stability.
Metal Ions
Trace amounts of metal ions such as zinc are crucial for the enzymatic activity of metalloproteinases.
Toxic Effects on Different Parts of the Body
The toxic effects of Lachesis venom are multi-faceted and impact various physiological systems. The primary targets include the cardiovascular system, nervous system, and local tissues at the site of envenomation.
Cardiovascular System
Hemorrhage and Coagulopathy: Metalloproteinases degrade the extracellular matrix, leading to capillary damage and hemorrhage. Serine proteinases disrupt the coagulation cascade, causing bleeding disorders.
Hypotension
Certain peptides and PLA2s in the venom can induce hypotension by interfering with vascular smooth muscle contraction and disrupting endothelial cell function.
Nervous System
Neurotoxicity: PLA2s and other neurotoxic peptides interfere with neurotransmitter release and ion channel function, leading to neuromuscular paralysis and respiratory failure.
Pain and Inflammation: The release of inflammatory mediators and direct activation of pain receptors by venom components contribute to the severe pain and swelling experienced after envenomation.
Local Tissue Effects
Necrosis: Myotoxins and PLA2s cause direct damage to muscle cells and other local tissues, leading to necrosis and severe swelling.
Edema: The degradation of the extracellular matrix and the release of vasoactive substances result in increased vascular permeability and subsequent edema.
Molecular Mechanisms of Action
The molecular mechanisms through which Lachesis venom exerts its toxic effects are intricate and involve multiple pathways:
Metalloproteinases
Metalloproteinases, particularly snake venom metalloproteinases (SVMPs), play a crucial role in tissue destruction and hemorrhage. They degrade various components of the extracellular matrix, such as collagen, laminin, and fibronectin, leading to capillary basement membrane disruption and hemorrhage.
Serine Proteinases
Serine proteinases in Lachesis venom affect blood coagulation by cleaving key coagulation factors. They can activate or inactivate these factors, resulting in complex coagulopathies. For example, some serine proteinases activate prothrombin to thrombin, leading to excessive clotting, while others degrade fibrinogen, preventing clot formation.
Phospholipases A2
PLA2s hydrolyze phospholipids in cell membranes, releasing arachidonic acid and lysophospholipids. This action disrupts cell membranes, leading to cell lysis and the release of inflammatory mediators. The arachidonic acid pathway also produces prostaglandins and leukotrienes, which contribute to inflammation and pain.
L-Amino Acid Oxidases
LAAOs generate hydrogen peroxide and other reactive oxygen species (ROS) during the oxidative deamination of amino acids. These ROS induce oxidative stress, leading to cell damage and apoptosis. LAAOs also have antimicrobial properties, contributing to the venom’s defensive functions.
Disintegrins
Disintegrins inhibit platelet aggregation by binding to integrins, particularly the glycoprotein IIb/IIIa receptor on platelets. This inhibition prevents fibrinogen from cross-linking platelets, thereby impairing clot formation and leading to bleeding.
Myotoxins
Myotoxins disrupt cellular membranes and cause direct muscle cell damage. They interfere with ion channels and cellular signaling pathways, leading to muscle necrosis and inflammation.
Peptides
Various peptides in Lachesis venom modulate ion channels, interfere with neurotransmitter release, and affect blood pressure regulation. For example, certain peptides block potassium channels, leading to prolonged depolarization and neuromuscular paralysis.
Lachesis venom is a potent and complex mixture of bioactive molecules that target multiple physiological systems. Its primary constituents include enzymatic and non-enzymatic proteins, peptides, carbohydrates, and metal ions. These components exert their toxic effects through intricate molecular mechanisms, leading to severe symptoms such as hemorrhage, neurotoxicity, and local tissue damage. Understanding the molecular basis of Lachesis venom’s action not only provides insights into venom biology but also offers potential therapeutic avenues for treating envenomation and other medical conditions. The detailed study of Lachesis venom and its molecular constituents continues to reveal new insights into its mechanisms of action and potential applications in medicine. Future research in this area holds promise for developing novel therapeutic agents derived from venom components, improving our understanding of venom biology, and enhancing the management of snakebite envenomation.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF MYOTOXINS IN LACHESIS VENOM
Myotoxins in Lachesis venom are key contributors to the severe muscle damage observed following envenomation. These potent bioactive molecules disrupt cellular membranes, interfere with ion channels, and induce necrosis and inflammation. This article provides a comprehensive review of the molecular mechanisms underlying the toxic effects of myotoxins from Lachesis venom, highlighting their impact on muscle tissue and potential therapeutic implications.
Myotoxins are responsible for causing severe muscle damage and necrosis, contributing significantly to the morbidity associated with envenomation. Understanding the molecular mechanisms through which these myotoxins exert their toxic effects is crucial for developing effective treatments and antivenoms. This article delves into the molecular pathways and cellular targets of myotoxins in Lachesis venom. Myotoxins are a diverse group of proteins and peptides that vary in their structure and function.
The toxic effects of myotoxins are mediated through several molecular mechanisms, primarily involving the disruption of cellular membranes, induction of oxidative stress, and interference with cellular signaling pathways.
PLA2s hydrolyze the sn-2 acyl bond of phospholipids in cell membranes, releasing lysophospholipids and free fatty acids. This action compromises the integrity of the cell membrane, leading to increased permeability and eventual cell lysis. The hydrolysis products, such as arachidonic acid, are precursors for eicosanoids, which are potent inflammatory mediators. These mediators exacerbate local inflammation and contribute to further tissue damage.
LAAOs catalyze the oxidative deamination of L-amino acids, producing hydrogen peroxide (H2O2) and other ROS as byproducts. These ROS induce oxidative stress, damaging cellular components such as lipids, proteins, and DNA. Oxidative stress triggers cellular apoptosis and necrosis pathways. The accumulation of ROS overwhelms the cell’s antioxidant defenses, leading to mitochondrial dysfunction and cell death.
Myotoxic peptides can modulate ion channels on the cell membrane, particularly those involved in calcium homeostasis. Disruption of calcium ion channels leads to an imbalance in intracellular calcium levels, causing uncontrolled muscle contraction and cell death. These peptides can interfere with intracellular signaling pathways, such as those involving mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Disruption of these pathways leads to altered gene expression and promotion of inflammatory and apoptotic responses.
The primary target of myotoxins in Lachesis venom is skeletal muscle tissue. The toxic effects manifest through several pathological processes. The direct action of PLA2s and myotoxic peptides on muscle cell membranes leads to cell lysis and necrosis. The breakdown of muscle cells releases intracellular contents into the extracellular space, further propagating tissue damage and inflammation. The inflammatory response is a hallmark of myotoxin-induced muscle damage. PLA2s and the products of their enzymatic activity stimulate the release of pro-inflammatory cytokines and chemokines. These mediators attract immune cells to the site of injury, exacerbating tissue damage through the release of additional ROS and proteolytic enzymes.
Increased vascular permeability resulting from the inflammatory response leads to the accumulation of fluid in the interstitial spaces, causing edema. The swelling further impairs tissue perfusion and contributes to muscle pain and dysfunction.
Following the initial necrotic phase, the damaged muscle undergoes a regenerative process. However, severe and extensive damage often leads to fibrosis, where the normal muscle tissue is replaced by fibrotic scar tissue. This fibrosis impairs muscle function and can lead to long-term disability.
Understanding the molecular mechanisms of myotoxin action in Lachesis venom has significant therapeutic implications. Antivenoms containing antibodies against specific myotoxins can neutralize their activity and prevent tissue damage. Developing more effective and targeted antivenoms requires a detailed understanding of the molecular targets and mechanisms of myotoxins. Small molecule inhibitors of PLA2s can prevent the hydrolysis of cell membranes and the subsequent inflammatory response. Such inhibitors could be used as adjunctive therapy in snakebite envenomation to reduce muscle damage and inflammation. Administering antioxidants can help mitigate the oxidative stress induced by LAAOs. Antioxidants such as N-acetylcysteine (NAC) and vitamin E could be used to scavenge ROS and protect muscle cells from oxidative damage.
Drugs that modulate ion channels and maintain calcium homeostasis could help prevent myotoxin-induced muscle cell damage. Calcium channel blockers and other ion channel modulators may be beneficial in reducing muscle necrosis and improving outcomes.
Myotoxins in Lachesis venom are potent bioactive molecules that cause severe muscle damage through a combination of membrane disruption, oxidative stress, and interference with cellular signaling pathways. The intricate molecular mechanisms underlying these toxic effects highlight the complexity of venom action and the need for targeted therapeutic interventions. Continued research into the molecular basis of myotoxin toxicity will enhance our understanding of venom biology and contribute to the development of more effective treatments for snakebite envenomation.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF DISINTEGRINS IN LACHESIS VENOM
Disintegrins are a family of low-molecular-weight, non-enzymatic proteins found in the venom of various snakes, including Lachesis muta, commonly known as the bushmaster. These proteins are notable for their ability to interfere with integrin functions, particularly those involved in cell adhesion, platelet aggregation, and angiogenesis. This article provides an in-depth review of the molecular mechanisms underlying the toxic effects of disintegrins in Lachesis venom, emphasizing their impact on hemostasis, cell signaling, and potential therapeutic applications.
Lachesis muta venom is a complex mixture of bioactive molecules that target various physiological processes. Among these components, disintegrins play a crucial role in disrupting hemostasis and cell-cell interactions. Understanding the molecular mechanisms by which disintegrins exert their effects provides insights into their potential therapeutic applications and helps in developing strategies to mitigate their toxic effects. This article explores the structural features of disintegrins, their molecular targets, and the pathways they influence.
Disintegrins are characterized by their ability to bind to integrins, a family of cell surface receptors involved in cell adhesion and signaling. Disintegrins typically contain an Arg-Gly-Asp (RGD) motif or related sequences, which are crucial for their binding to integrins. The presence of disulfide bonds stabilizes their structure, enhancing their binding affinity and specificity.
Disintegrins bind to integrins, particularly the αIIbβ3 integrin on platelets and other integrins involved in cell adhesion and migration.The toxic effects of disintegrins are primarily mediated through their interaction with integrins, leading to the disruption of various cellular processes. Disintegrins disrupt this clustering by competitively inhibiting integrin binding to ECM components, thereby impairing focal adhesion formation and downstream signaling. Integrin engagement with the ECM activates focal adhesion kinase (FAK) and Src family kinases, initiating various signaling cascades. Disintegrins inhibit these pathways, leading to altered cell behavior, including reduced cell migration and survival. The MAPK and PI3K/Akt pathways, which are crucial for cell proliferation and survival, are also modulated by integrin signaling. Disintegrins’ interference with integrin function can result in the downregulation of these pathways, promoting apoptosis and inhibiting cell proliferation.
Anoikis is a form of programmed cell death induced by detachment from the ECM. By disrupting integrin-ECM interactions, disintegrins promote anoikis in susceptible cells. This mechanism is particularly relevant in epithelial and endothelial cells, which depend on anchorage for survival.
The detachment of cells from the ECM leads to the activation of caspases, particularly caspase-3 and caspase-9, through the mitochondrial apoptotic pathway. Disintegrins facilitate this process by preventing integrin-mediated survival signals.
Disintegrins inhibit the adhesion, migration, and proliferation of endothelial cells by targeting integrins αvβ3 and αvβ5, which are essential for these processes during angiogenesis. Vascular endothelial growth factor (VEGF) signaling, which promotes angiogenesis, is mediated through integrin interactions. By blocking these integrins, disintegrins interfere with VEGF-induced endothelial cell responses, further inhibiting angiogenesis.
The systemic effects of disintegrins from Lachesis venom impact various tissues and organs, primarily through their actions on hemostasis, cell adhesion, and angiogenesis. Disintegrins’ inhibition of platelet aggregation leads to coagulopathy, characterized by prolonged bleeding times and spontaneous hemorrhages. This can result in significant blood loss and potentially life-threatening conditions if not treated promptly. The disruption of endothelial cell adhesion and signaling by disintegrins compromises vascular integrity, leading to increased vascular permeability and edema. This effect exacerbates inflammation and tissue damage at the site of envenomation. The anti-angiogenic properties of disintegrins make them potential candidates for anti-cancer therapy. By inhibiting the formation of new blood vessels, disintegrins can starve tumors of nutrients and oxygen, inhibiting their growth and metastatic potential.
Research into the molecular mechanisms of disintegrins has revealed several potential therapeutic applications beyond their toxic effects. Disintegrins’ ability to inhibit angiogenesis can be harnessed to develop novel anti-cancer therapies. By targeting integrins involved in tumor vascularization, disintegrins can effectively limit tumor growth and metastasis. Disintegrins’ inhibition of platelet aggregation has potential therapeutic applications in preventing thrombosis. Developing disintegrin-based drugs or mimetics could provide new treatments for conditions characterized by excessive clot formation, such as myocardial infarction and stroke.
Disintegrins can be used to modulate wound healing processes by controlling cell migration and adhesion. This application could be beneficial in managing conditions where excessive or abnormal tissue growth is a concern, such as in fibrosis or hypertrophic scarring.
Disintegrins in Lachesis venom are potent bioactive molecules that exert their toxic effects through intricate molecular mechanisms involving integrin binding and signaling disruption. These effects result in impaired hemostasis, altered cell adhesion, and inhibited angiogenesis, leading to significant physiological and pathological outcomes. Understanding these mechanisms not only sheds light on the complexity of snake venom actions but also opens up potential therapeutic avenues for treating various medical conditions. Continued research into disintegrins and their molecular targets promises to enhance our knowledge of venom biology and contribute to the development of innovative medical therapies.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF PEPTIDES IN LACHESIS VENOM
Peptides in Lachesis venom, derived from the bushmaster snake, are potent bioactive molecules that contribute significantly to the venom’s overall toxicity. These peptides exert a wide range of toxic effects through various molecular mechanisms, affecting the cardiovascular, nervous, and immune systems. This article provides a comprehensive review of the molecular mechanisms underlying the toxic effects of peptides in Lachesis venom, highlighting their impact on different body systems and potential therapeutic implications.The peptides in Lachesis venom are diverse and include neurotoxins, cardiotoxins, myotoxins, and other bioactive peptides. Neurotoxins interfere with neurotransmitter release and ion channel function, leading to neuromuscular paralysis. Cardiotoxins affect heart muscle cells, leading to cardiac dysfunction and potential heart failure. Myotoxins induce muscle cell damage and necrosis. Hemorrhagins promote bleeding by disrupting vascular integrity and interfering with coagulation pathways. Bradykinins enhance the effects of bradykinin, a peptide involved in blood pressure regulation and pain.
The toxic effects of peptides in Lachesis venom are mediated through several key molecular mechanisms, primarily involving the disruption of cellular membranes, modulation of ion channels, and interference with signaling pathways.
Cardiotoxins and myotoxins interact directly with cell membranes, leading to pore formation and increased permeability. This disrupts the ionic balance and leads to cell swelling and lysis. These peptides insert into the lipid bilayer, causing structural disruptions that compromise membrane integrity. This results in the leakage of intracellular contents and cell death.
Neurotoxins in Lachesis venom bind to ion channels on nerve and muscle cells, altering their function. For example, they can block potassium channels or prolong the opening of sodium channels, leading to uncontrolled depolarization. By affecting calcium channels, neurotoxins inhibit the release of neurotransmitters at synaptic junctions, leading to neuromuscular paralysis.
Bradykinin-Potentiating Peptides (BPPs) inhibit the activity of angiotensin-converting enzyme (ACE), which normally degrades bradykinin. By potentiating bradykinin levels, BPPs enhance vasodilation and promote inflammatory responses. Elevated bradykinin levels increase vascular permeability, contributing to edema and inflammation.
Myotoxins and Cardiotoxins can induce apoptosis by disrupting mitochondrial membranes, leading to the release of cytochrome c and activation of caspases. Disruption of calcium homeostasis by these peptides results in mitochondrial dysfunction and activation of cell death pathways, leading to necrosis.
The primary targets of Lachesis venom peptides are the cardiovascular, nervous, and muscular systems. The toxic effects manifest through several pathological processes. Bradykinin-potentiating peptides cause vasodilation and hypotension, leading to decreased blood pressure. Hemorrhagins disrupt vascular integrity, causing bleeding and further contributing to hypotension. Cardiotoxins affect heart muscle cells, leading to arrhythmias, reduced contractility, and potential heart failure. Neurotoxins interfere with ion channels and neurotransmitter release, leading to neuromuscular paralysis. This can result in respiratory failure and death if not treated promptly. Myotoxins cause direct damage to muscle cells, leading to necrosis and inflammation. This results in severe pain, swelling, and loss of muscle function.
Therapeutic Applications
Peptides such as bradykinin-potentiating peptides enhance the inflammatory response by increasing vascular permeability and promoting the release of inflammatory mediators. This leads to pain, swelling, and tissue damage.
Despite their toxic effects, peptides from Lachesis venom have potential therapeutic applications. By inhibiting ACE and enhancing bradykinin levels, Bradykinin-Potentiating Peptides can be used to develop new antihypertensive drugs. This mechanism is similar to that of ACE inhibitors currently used to treat high blood pressure. Modified neurotoxins that selectively target pain pathways without causing paralysis could be developed as novel analgesics for chronic pain management. Peptides that inhibit angiogenesis can be used to develop new treatments for cancer by preventing the formation of new blood vessels that supply tumors with nutrients and oxygen. Hemorrhagins that interfere with blood coagulation could be used to develop new anticoagulant therapies for conditions such as deep vein thrombosis and pulmonary embolism.
Peptides in Lachesis venom are potent bioactive molecules that exert their toxic effects through complex molecular mechanisms involving the disruption of cellular membranes, modulation of ion channels, and interference with signaling pathways. These effects lead to significant physiological and pathological outcomes, impacting the cardiovascular, nervous, and muscular systems. Understanding these mechanisms not only provides insights into venom biology but also opens up potential therapeutic avenues for treating various medical conditions. Continued research into the molecular basis of peptide toxicity in Lachesis venom promises to enhance our knowledge of venom biology and contribute to the development of innovative medical therapies.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF L-AMINO ACID OXIDASES IN LACHESIS VENOM
L-Amino Acid Oxidases (LAAOs) are significant components of Lachesis muta (bushmaster) venom, contributing to its overall toxicity. These flavoproteins catalyze the oxidative deamination of L-amino acids, leading to the production of hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). This article delves into the molecular mechanisms underlying the toxic effects of LAAOs in Lachesis venom, examining their impact on various biological systems and potential therapeutic implications.
Lachesis venom contains a complex array of bioactive molecules, including L-Amino Acid Oxidases (LAAOs). LAAOs are known for their ability to generate reactive oxygen species (ROS) through the oxidative deamination of L-amino acids. These enzymes contribute to the venom’s overall toxicity by inducing oxidative stress, disrupting cellular function, and modulating the immune response. This article explores the molecular mechanisms through which LAAOs exert their toxic effects and discusses their impact on different physiological systems.
LAAOs are flavoproteins that catalyze the oxidative deamination of L-amino acids to produce the corresponding keto acids, ammonia, and hydrogen peroxide. LAAOs contain Flavin Adenine Dinucleotide (FAD) as a prosthetic group, essential for their catalytic activity. These enzymes have broad substrate specificity, acting on various L-amino acids. The catalytic cycle involves the oxidation of the L-amino acid substrate, reduction of FAD to FADH2, and subsequent reoxidation of FADH2 by molecular oxygen, generating hydrogen peroxide.
The toxic effects of LAAOs are primarily mediated through the production of reactive oxygen species (ROS) and subsequent oxidative stress. LAAOs catalyze the conversion of L-amino acids to keto acids and ammonia, with the concomitant production of H2O2. This ROS is a potent oxidizing agent, capable of inducing significant cellular damage. H2O2 can undergo further reactions, such as the Fenton reaction, generating more reactive species like hydroxyl radicals (•OH).
ROS generated by LAAOs can initiate lipid peroxidation, damaging cellular membranes and leading to loss of membrane integrity. ROS oxidize amino acid residues in proteins, leading to altered structure and function, enzymatic inactivation, and aggregation. Oxidative stress results in DNA strand breaks and base modifications, potentially causing mutations and cell death.
ROS and other products of LAAO activity can activate immune cells such as macrophages and neutrophils, promoting the release of pro-inflammatory cytokines and chemokines. Oxidative stress modulates signaling pathways involved in inflammation, such as NF-κB and MAPK pathways, enhancing the inflammatory response.
ROS damage mitochondrial membranes, leading to the release of cytochrome c and activation of the intrinsic apoptotic pathway. The release of cytochrome c activates caspase-9 and subsequently caspase-3, executing the apoptotic program.
The ROS produced by LAAOs have direct bactericidal effects, damaging bacterial cell walls, membranes, and intracellular components. The activation of immune responses by LAAO-induced ROS further enhances the antimicrobial activity of the venom.
LAAOs in Lachesis venom affect multiple physiological systems through oxidative stress and immune modulation. The toxic effects manifest through various pathological processes. The oxidative stress induced by LAAOs damages endothelial cells, leading to increased vascular permeability, edema, and hemorrhage. LAAOs can influence platelet function, either promoting or inhibiting aggregation depending on the oxidative environment, contributing to coagulopathies.
The ROS generated by LAAOs can damage neuronal cells, leading to neurodegeneration and functional deficits. This effect is exacerbated by the activation of microglia and subsequent inflammatory responses. LAAO-induced oxidative stress contributes to muscle cell damage and necrosis, exacerbating the myotoxic effects of other venom components.
The activation of immune cells by ROS promotes an inflammatory response, leading to tissue damage and exacerbation of envenomation symptoms.
Potential Therapeutic Applications
Despite their toxic effects, LAAOs from Lachesis venom have potential therapeutic applications, particularly in oncology and antimicrobial therapy. The ability of LAAOs to induce oxidative stress and apoptosis in cells can be harnessed to develop novel anticancer therapies. Targeting LAAOs to tumor cells may selectively induce cell death in malignant tissues.
The ROS produced by LAAOs have potent bactericidal effects, making them potential candidates for developing new antimicrobial agents to combat antibiotic-resistant bacteria.
Understanding the role of LAAOs in immune modulation could lead to new strategies for controlling excessive inflammation in conditions such as autoimmune diseases.
L-Amino Acid Oxidases (LAAOs) in Lachesis venom are potent enzymes that exert their toxic effects through the generation of reactive oxygen species and the induction of oxidative stress. These effects lead to significant damage to various physiological systems, including the cardiovascular, nervous, and muscular systems, and modulate immune responses. Despite their toxicity, LAAOs hold potential for therapeutic applications, particularly in oncology and antimicrobial therapy. Further research into the molecular mechanisms of LAAO action will enhance our understanding of venom biology and contribute to the development of novel medical therapies.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF PHOSPHOLIPASES A2 IN LACHESIS VENOM
Phospholipases A2 (PLA2s) are a critical component of Lachesis muta (bushmaster) venom, known for their diverse and potent toxic effects. These enzymes hydrolyze the sn-2 acyl bond of phospholipids in cell membranes, leading to the release of fatty acids and lysophospholipids. This article provides a detailed examination of the molecular mechanisms by which PLA2s in Lachesis venom exert their toxic effects, focusing on their impact on cellular structures, inflammatory responses, and various physiological systems. Phospholipases A2 (PLA2s) are notable for their significant role in envenomation, contributing to a range of toxic effects. PLA2s not only disrupt cellular membranes but also modulate inflammatory responses and interfere with various signaling pathways.
PLA2s are enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position, releasing free fatty acids and lysophospholipids. PLA2s possess a catalytic dyad or triad involving histidine, aspartate, and sometimes tyrosine, which is essential for their enzymatic activity. Most PLA2s require calcium ions for activity, which facilitate the binding to phospholipid substrates and stabilize the transition state during catalysis. PLA2s in snake venom can be broadly categorized into two groups: secreted PLA2s (sPLA2s) and cytosolic PLA2s (cPLA2s), each with distinct
The toxic effects of PLA2s are mediated through multiple mechanisms, primarily involving membrane disruption, modulation of inflammatory responses, and interference with cellular signaling. PLA2s hydrolyze the sn-2 acyl bond of membrane phospholipids, producing lysophospholipids and free fatty acids, such as arachidonic acid. This action compromises the integrity of cell membranes, leading to increased permeability and cell lysis. Lysophospholipids act as detergents, disrupting lipid bilayers and causing cell membrane destabilization.
The free fatty acids released by PLA2 activity, particularly arachidonic acid, are precursors for eicosanoids, including prostaglandins, leukotrienes, and thromboxanes. These molecules are potent mediators of inflammation, promoting vasodilation, increased vascular permeability, and recruitment of immune cells. PLA2-derived arachidonic acid is metabolized by COX and LOX enzymes, leading to the production of various inflammatory mediators that contribute to pain, swelling, and tissue damage.
PLA2s can activate intracellular signaling pathways, such as mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), which regulate the expression of pro-inflammatory genes. This activation enhances the inflammatory response and promotes cell survival and proliferation in damaged tissues. By hydrolyzing phospholipids, PLA2s can disrupt cellular calcium homeostasis, leading to altered cellular functions, including muscle contraction and neurotransmitter release.
The disruption of mitochondrial membranes by PLA2 activity leads to the release of cytochrome c, which activates the intrinsic apoptotic pathway. This results in caspase activation and programmed cell death. PLA2 activity can generate reactive oxygen species (ROS) through the arachidonic acid pathway, inducing oxidative stress and further contributing to cell damage and apoptosis.
PLA2s can disrupt the release of neurotransmitters at neuromuscular junctions by hydrolyzing phospholipids in presynaptic membranes. This leads to neuromuscular blockade and paralysis. PLA2-derived lysophospholipids and free fatty acids can modulate ion channel activity, affecting neuronal excitability and signal transmission.
The primary targets of PLA2s in Lachesis venom are the cardiovascular, nervous, and muscular systems. The toxic effects manifest through various pathological processes. PLA2-induced membrane disruption leads to endothelial cell damage, increasing vascular permeability and promoting hemorrhage. Depending on the context, PLA2s can either promote or inhibit platelet aggregation, contributing to coagulopathies. This is mediated through the production of eicosanoids and direct interactions with platelet membranes.
PLA2s interfere with synaptic transmission at neuromuscular junctions, leading to paralysis. This effect is due to the disruption of presynaptic membrane integrity and inhibition of neurotransmitter release. The inflammatory mediators produced by PLA2 activity can induce neuroinflammation, exacerbating neuronal damage and dysfunction.
PLA2s cause direct damage to muscle cell membranes, leading to necrosis and inflammation. This results in severe pain, swelling, and loss of muscle function. The release of inflammatory mediators further exacerbates muscle damage, promoting edema and prolonged tissue destruction. PLA2-derived eicosanoids activate immune cells, promoting the release of pro-inflammatory cytokines and chemokines. This enhances the inflammatory response and contributes to tissue damage.
Potential Therapeutic Applications
Despite their toxic effects, PLA2s from Lachesis venom have potential therapeutic applications, particularly in anti-inflammatory and antimicrobial therapy.
Inhibitors of PLA2 can reduce the production of inflammatory mediators, providing a potential therapeutic strategy for treating inflammatory conditions such as arthritis and asthma.
The membrane-disrupting activity of PLA2s can be harnessed to develop novel antimicrobial agents, particularly against antibiotic-resistant bacteria.
The ability of PLA2s to induce apoptosis in cells can be explored for developing anti-cancer therapies. Targeting PLA2s to tumor cells may selectively induce cell death in malignant tissues.
Phospholipases A2 (PLA2s) in Lachesis venom are potent enzymes that exert their toxic effects through the hydrolysis of membrane phospholipids, induction of oxidative stress, and modulation of inflammatory responses. These effects lead to significant damage to various physiological systems, including the cardiovascular, nervous, and muscular systems. Despite their toxicity, PLA2s hold potential for therapeutic applications, particularly in anti-inflammatory, antimicrobial, and anti-cancer therapies. Continued research into the molecular mechanisms of PLA2 action will enhance our understanding of venom biology and contribute to the development of innovative medical treatments.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF SERINE PROTEINASES IN LACHESIS VENOM
Serine proteinases are a major component of Lachesis muta (bushmaster) venom, contributing significantly to its overall toxicity. These enzymes target various physiological pathways, primarily involving blood coagulation and fibrinolysis, leading to complex toxic effects. This article delves into the molecular mechanisms by which serine proteinases in Lachesis venom exert their toxic effects, highlighting their impact on the hemostatic system, tissue damage, and potential therapeutic implications.
Serine proteinases are enzymes characterized by a serine residue at their active site, which plays a critical role in their catalytic mechanism.
The catalytic activity of serine proteinases is mediated by a triad of amino acids: serine, histidine, and aspartate. These residues work together to hydrolyze peptide bonds in protein substrates. Serine proteinases exhibit specificity for certain peptide bonds in their substrates, which is determined by the structure of their active site. Many serine proteinases are produced as inactive zymogens that require proteolytic cleavage for activation.
The toxic effects of serine proteinases are primarily mediated through their actions on blood coagulation and fibrinolysis, leading to complex hemostatic disturbances.
Some serine proteinases in Lachesis venom can activate prothrombin to thrombin, a key enzyme in the coagulation cascade. Thrombin then converts fibrinogen to fibrin, leading to clot formation. Certain serine proteinases activate coagulation factors V and VIII, which enhance the generation of thrombin and promote clot formation. Serine proteinases can degrade natural anticoagulants such as protein C and protein S, reducing their ability to inhibit clot formation and thereby promoting a hypercoagulable state.
Some serine proteinases can activate plasminogen to plasmin, an enzyme that degrades fibrin clots. This can lead to a paradoxical effect where excessive fibrinolysis results in bleeding. By degrading antiplasmin, serine proteinases reduce the inhibition of plasmin, further enhancing fibrinolytic activity and contributing to hemorrhage.
Serine proteinases can activate matrix metalloproteinases (MMPs), which degrade extracellular matrix components such as collagen and elastin. This leads to tissue damage and hemorrhage. The degradation products generated by serine proteinases can stimulate the release of pro-inflammatory cytokines and chemokines, enhancing the inflammatory response and contributing to tissue damage.
Serine proteinases can cleave key proteins involved in apoptotic pathways, leading to programmed cell death. This effect is particularly relevant in endothelial cells, contributing to vascular damage.
The primary targets of serine proteinases in Lachesis venom are the hemostatic system, vascular system, and various tissues. The toxic effects manifest through several pathological processes. The activation of procoagulant factors and inhibition of natural anticoagulants lead to a hypercoagulable state, resulting in widespread clot formation. Concurrently, the activation of fibrinolytic pathways and degradation of clotting inhibitors can lead to excessive bleeding and hemorrhage. The degradation of extracellular matrix components and endothelial cell apoptosis increase vascular permeability, leading to edema and hemorrhage. The inflammatory response induced by serine proteinases exacerbates vascular damage, contributing to increased permeability and hemorrhage.
The degradation of extracellular matrix proteins by activated MMPs leads to local tissue necrosis and damage. The release of inflammatory mediators enhances tissue damage and prolongs the healing process. The activation of inflammatory pathways by serine proteinases can lead to a cytokine storm, causing widespread inflammation and tissue damage.
Potential Therapeutic Applications
Despite their toxic effects, serine proteinases from Lachesis venom have potential therapeutic applications, particularly in thrombolytic therapy and cancer treatment. The ability of serine proteinases to activate plasminogen to plasmin can be harnessed to develop thrombolytic agents for the treatment of conditions such as myocardial infarction and stroke. The matrix-degrading activity of serine proteinases can be exploited to disrupt the tumor microenvironment, inhibiting tumor growth and metastasis.
Understanding the role of serine proteinases in inflammatory pathways could lead to new strategies for controlling excessive inflammation in conditions such as autoimmune diseases.
Serine proteinases in Lachesis venom are potent enzymes that exert their toxic effects through the disruption of blood coagulation and fibrinolysis, induction of tissue damage, and modulation of inflammatory responses. These effects lead to significant damage to various physiological systems, including the hemostatic and vascular systems, and contribute to local tissue necrosis. Despite their toxicity, serine proteinases hold potential for therapeutic applications, particularly in thrombolytic and anti-cancer therapies. Further research into the molecular mechanisms of serine proteinase action will enhance our understanding of venom biology and contribute to the development of innovative medical treatments.
MOLECULAR MECHANISM OF TOXIC EFFECTS OF METALLOPROTEINASES IN LACHESIS VENOM
Metalloproteinases are a significant component of Lachesis muta (bushmaster) venom, playing a crucial role in its overall toxicity. These enzymes target extracellular matrix (ECM) components and various physiological pathways, leading to complex toxic effects such as hemorrhage, tissue necrosis, and inflammation. This article delves into the molecular mechanisms by which metalloproteinases in Lachesis venom exert their toxic effects, highlighting their impact on hemostasis, tissue integrity, and potential therapeutic implications.
Lachesis muta, known as the bushmaster snake, produces venom that is a complex mixture of proteins, enzymes, and peptides. Among these, metalloproteinases are particularly noteworthy for their role in disrupting the extracellular matrix (ECM) and affecting various physiological processes. These enzymes contribute to the venom’s overall toxicity by inducing hemorrhage, promoting tissue necrosis, and modulating inflammatory responses. This article explores the molecular mechanisms underlying the toxic effects of metalloproteinases in Lachesis venom, focusing on their interactions with cellular targets and signaling pathways.
Metalloproteinases in snake venom, particularly those in Lachesis venom, belong to the class of zinc-dependent endopeptidases. The catalytic domain contains a zinc ion, coordinated by three histidine residues, essential for the proteolytic activity. Hemopexin-like Domain aids in substrate binding and determines substrate specificity, contributing to the enzyme’s ability to target various ECM components. Some metalloproteinases contain disintegrin-like domains, which can inhibit platelet aggregation and affect cell adhesion. Many metalloproteinases are synthesized as inactive zymogens with a pro-domain that must be cleaved for activation. The toxic effects of metalloproteinases are mediated through several key mechanisms, primarily involving the degradation of ECM components, modulation of blood coagulation, and induction of inflammatory responses.
Metalloproteinases hydrolyze collagen, elastin, fibronectin, laminin, and other ECM components. This degradation compromises the structural integrity of tissues, leading to hemorrhage and tissue necrosis. The degradation of basement membrane components by metalloproteinases leads to increased vascular permeability and bleeding.
Some metalloproteinases possess disintegrin-like domains that bind to integrins on platelets, inhibiting their aggregation and promoting bleeding. Metalloproteinases can degrade fibrinogen, preventing its conversion to fibrin and thereby impairing clot formation. This action contributes to coagulopathy and increased bleeding tendency.
The degradation products generated by metalloproteinases can stimulate the release of pro-inflammatory cytokines and chemokines from immune cells, enhancing the inflammatory response and contributing to tissue damage.
Metalloproteinases can activate host MMPs, amplifying the breakdown of ECM components and promoting inflammation. By degrading ECM components and disrupting cell-ECM interactions, metalloproteinases induce anoikis, a form of apoptosis caused by cell detachment. The disruption of integrin signaling and cellular stress induced by ECM degradation can activate the mitochondrial apoptotic pathway, leading to cytochrome c release and caspase activation.
The primary targets of metalloproteinases in Lachesis venom are the vascular, muscular, and immune systems. The toxic effects manifest through various pathological processes. The degradation of basement membrane and ECM components by metalloproteinases increases vascular permeability, leading to extravasation of blood and hemorrhage. Metalloproteinases cause direct damage to endothelial cells, further contributing to hemorrhage and vascular leakage. The degradation of ECM components in muscle tissue by metalloproteinases leads to muscle cell necrosis and inflammation. This results in severe pain, swelling, and loss of muscle function. The release of pro-inflammatory cytokines and chemokines exacerbates muscle damage and prolongs tissue destruction.
Metalloproteinase activity stimulates the activation of immune cells, promoting the release of pro-inflammatory mediators and enhancing the inflammatory response.
Potential Therapeutic Applications
Despite their toxic effects, metalloproteinases from Lachesis venom have potential therapeutic applications, particularly in oncology and wound healing. The matrix-degrading activity of metalloproteinases can be exploited to disrupt the tumor microenvironment, inhibiting tumor growth and metastasis. Understanding the role of metalloproteinases in ECM remodeling could lead to new strategies for enhancing wound healing and tissue regeneration. Targeting metalloproteinase activity could provide new approaches for controlling excessive inflammation in conditions such as arthritis and autoimmune diseases.
Metalloproteinases in Lachesis venom are potent enzymes that exert their toxic effects through the degradation of extracellular matrix components, modulation of blood coagulation, and induction of inflammatory responses. These effects lead to significant damage to various physiological systems, including the vascular and muscular systems, and contribute to local tissue necrosis. Despite their toxicity, metalloproteinases hold potential for therapeutic applications, particularly in oncology, wound healing, and anti-inflammatory therapies. Further research into the molecular mechanisms of metalloproteinase action will enhance our understanding of venom biology and contribute to the development of innovative medical treatments.
INTRODUCTION TO MIT EXPLANATIONS OF SCIENTIFIC HOMEOPATHY
Similia similibus curentur means, if symptoms expressed in an individual during a disease condition and the symptoms produced by a drug when applied in healthy individuals appear similar, that particular drug substance could work as a curative agent for that particular patient.
Symptoms expressed in an individual during a disease condition and the symptoms produced by a drug when applied in healthy individuals appear similar when the disease-causing substance and the particular drug substance contain similar chemical molecules with similar functional groups, which can bind to similar biological targets, producing similar molecular inhibitions and leading to errors in the same biochemical pathways. These similar chemical molecules can compete each other to bind to the same molecular targets, by their similar molecular conformations or functional groups.
Disease-causing molecules produce disease by competitively binding with some biological targets in the body, mimicking as natural ligands of those targets due to their conformational similarity. Drug molecules having conformational similarity with disease-causing molecules, can displace them through competitive relationships, thereby alleviating the pathological inhibitions they cause. Modern biochemistry says, if the functional groups of the disease-causing molecules and drug molecules are similar, they can bind to similar molecular targets and elicit similar symptoms.
Homeopathy utilizes this phenomenon in identifying the similarity between pathogenic molecules and drug molecules by observing the symptoms they produce. Through “Similia Similibus Curentur,” Hahnemann tried to harness this phenomenon of molecular mimicry and molecular competitions to develop into a novel therapeutic method. He theorized that if symptoms produced in healthy individuals by a particular drug when taken in its molecular form are similar to those appearing in a diseased individual, applying the drug in molecular imprinted form could potentially cure the disease.
Molecular imprints of similar chemical molecules can act as artificial binding pockets for similar substances, neutralizing them due to their mutually complementary conformations. It is evident that Hahnemann observed this competitive relationship between substances affecting living organisms by producing similar symptoms. Due to historical limitations of scientific knowledge available during his time, he could not fully explain this phenomenon in scientific terms.
Now we are able to explain the ‘similarity’ between drug-induced symptoms and disease-induced symptoms in terms of ‘similarity’ of molecular inhibitions caused by drug molecules and disease-causing molecules arising from the ‘similarity’ of their functional groups. Samuel Hahnemann, the pioneer of homeopathy, formulated his principles during a time when modern biochemistry had not yet emerged. This historical context explains why Hahnemann was unable to describe his observations using contemporary biochemical concepts. Despite these limitations, his foresight into their therapeutic implications was nothing short of genius.
Homeopathy, or “Similia Similibus Curentur,” is a therapeutic approach grounded in the identification of drug molecules that, due to their similar functional groups, are capable of competing with disease-causing molecules for binding to biological targets. This methodology relies on observing the similarity of symptoms produced by the disease and those the drug can induce in healthy individuals, thereby deactivating the disease-causing molecules through the binding action of molecular imprints derived from the drug. The future recognition of homeopathy as a scientific discipline hinges on our ability to demonstrate to the scientific community that “Similia Similibus Curentur” is based on the naturally occurring phenomenon of competitive relationships between chemically similar molecules, as explained in modern biochemistry. Once this connection is clearly established, homeopathy’s status as a scientific practice will inevitably be recognized.
Only way the medicinal properties of a drug substance could be transmitted to and preserved in a medium of water-ethanol mixture during homeopathic ‘potentization’ without any single drug molecule remaining in it is by preserving the conformational details of its functional groups by a process of ‘molecular imprinting’, since the conformational properties of functional groups of drug molecules play a decisive role in biomolecular interactions.
Active principles of homeopathy drugs potentized above 12 c are molecular imprints of ‘functional groups’ of drugs molecules used as templates for potentization process. When introduced into living system as therapeutic agent, these molecular imprints act as artificial binding pockets for the pathogenic molecules having functional groups that are similar to the template molecules used for potentization. As we know, a state of pathology arises when some endogenous or exogenous molecules having functional groups similar to those of natural ligands of a biological target competitively bind to that target and produce molecular inhibitions. Removing these molecular inhibitions amounts to cure. Once you understand this biological mechanism, you will realize that molecular imprints of natural ligands also can act as therapeutic agents by binding to pathogenic molecules that compete with the natural ligands.
Biological ligands are molecules that bind specifically to a target molecule, typically a larger protein. This interaction can regulate the protein’s function or activity in various biological processes. Ligands can be of different types, including small molecules, peptides, nucleotides, and others. In biochemistry and pharmacology, understanding ligands and their interactions with proteins is crucial for drug design and for understanding cellular signalling pathways.
Biological ligands can interact with a variety of molecular targets in the body, each playing a critical role in influencing physiological processes. Ligands can activate or inhibit enzymes, which are proteins that catalyze biochemical reactions. For example, many drugs act as enzyme inhibitors to slow down or halt specific metabolic pathways that contribute to disease.
According to MIT homeopathic perspective, biological ligands potentized above 12c will contain molecular imprints of constituent functional groups. Molecular imprints of drugs that compete with natural biological ligands for same biological targets also could be used, as both of their functional groups will be similar. These molecular imprints could be used as artificial binding pockets to deactivate any pathogenic molecule that create biomolecular inhibitions by binding to the biological target molecules by their functional groups. As per this approach, therapeutics involves identifying the biological ligands implicated in a particular disease condition, preparing their molecular imprints by homeopathic potentization, and administering those molecular imprints as disease-specific formulations.
Endogenous or exogenous pathogenic molecules mimic as authentic biological ligands by conformational similarity and competitively bind to their natural target molecules producing inhibition of their functions, thereby creating a state of pathology. Molecular imprints of such biological ligands as well as those of any molecule similar to the competing molecules can act as artificial binding pockets for the pathogenic molecules and remove the molecular inhibitions, and produce a curative effect. This is the simple biological mechanism involved in Molecular Imprints Therapeutics or homeopathy. Potentization is the technique of preparing molecular imprints, and ‘similarity of symptoms’ is the tool used for identifying the biological ligands, their competing molecules, and the drug molecules ‘similar’ to them.
SYMPTOMATOLOGY OF LACHESIS FROM HANDBOOK OF HOMEOPATHIC MATERIA MEDICA BY WILLIAM BOERICKE
- ·Like all snake poisons, Lachesis decomposes the blood, rendering it more fluid; hence a haemorrhagic tendency is marked.
- ·Purpura, septic states, diphtheria, and other low forms of disease, when the system is thoroughly poisoned and the prostration is profound.
- ·The modalities are most important in guiding to the remedy.
- ·Delirium tremens with much trembling and confusion.
- ·Very important during the climacteric and for patients of a melancholic disposition.
- ·Ill effects of suppressed discharges.
- ·Diphtheritic paralysis (Botulinum).
- ·Diphtheria carriers.
- ·Sensation of tension in various parts.
- ·Cannot bear anything tight anywhere.
Mind.
- ·Great loquacity.
- ·Amative.
- ·Sad in the morning; no desire to mix with the world.
- ·Restless and uneasy; does not wish to attend to business; wants to be off somewhere all the time.
- ·Jealous (Hyos).
- ·Mental labor best performed at night.
- ·Euthanasia.
- ·Suspicious; nightly delusion of fire.
- ·Religious insanity (Verat; Stram).
- ·Derangement of the time sense.
Head.
- ·Pain through head on awaking.
- ·Pain at root of nose.
- ·Pressure and burning on vertex.
- ·Waves of pain; worse after moving.
- ·Sun headaches.
- ·With headache, flickerings, dim vision, very pale face.
- ·Vertigo.
- ·Relieved by onset of a discharge (menses or nasal catarrh).
Eyes.
- ·Defective vision after diphtheria, extrinsic muscles too weak to maintain focus.
- ·Sensation as if eyes were drawn together by cords which were tied in a knot at root of nose.
Ears.
- ·Tearing pain from zygoma into ear; also with sore throat.
- ·Ear-wax hard, dry.
Nose.
- ·Bleeding, nostrils sensitive.
- ·Coryza, preceded by headache.
- ·Hay asthma; paroxysms of sneezing (Silica; Sabad).
Face.
- ·Pale.
- ·Trifacial neuralgia, left side, heat running up into head (Phos).
- ·Tearing pain in jaw-bones (Amphisbaena; Phos).
- ·Purple, mottled, puffed; looks swollen, bloated, jaundiced, chlorotic.
Mouth.
- ·Gums swollen, spongy, bleed.
- ·Tongue swollen, burns, trembles, red, dry and cracked at tip, catches on teeth.
- ·Aphthous and denuded spots with burning and rawness.
- ·Nauseous taste.
- ·Teeth ache, pain extends to ears.
- ·Pain in facial bones.
Throat.
- ·Sore, worse left side, swallowing liquids.
- ·Quinsy.
- ·Septic parotiditis.
- ·Dry, intensely swollen, externally and internally.
- ·Diphtheria; membrane dusky, blackish; pain aggravated by hot drinks; chronic sore throat, with much hawking; mucus sticks, and cannot be forced up or down.
- ·Very painful; worse slightest pressure, touch is even more annoying.
- ·In diphtheria, etc, the trouble began on the left side.
- ·Tonsils purplish.
- ·Purple, livid color of throat.
- ·Feeling as if something was swollen which must be swallowed; worse, swallowing saliva or liquids.
- ·Pain into ear.
- ·Collar and neck-band must be very loose.
Stomach.
- ·Craving for alcohol, oysters.
- ·Any food causes distress.
- ·Pit of stomach painful to touch.
- ·Hungry, cannot wait for food.
- ·Gnawing pressure made better by eating, but returning in a few hours.
- ·Perceptible trembling movement in the epigastric region.
- ·Empty swallowing more painful than swallowing solids.
Abdomen.
- ·Liver region sensitive, cannot bear anything around waist.
- ·Especially suitable to drunkards.
- ·Abdomen tympanitic, sensitive, painful (Bell).
Stool.
- ·Constipated, offensive stool.
- ·Anus feels tight, as if nothing could go through it.
- ·Pain darting up the rectum every time be sneezes or coughs.
- ·Haemorrhage from bowels like charred straw, black particles.
- ·Haemorrhoids protrude, become constricted, purplish.
- ·Stitches in them on sneezing or coughing.
- ·Constant urging in rectum, not for stool.
Female.
- ·Climacteric troubles, palpitation, flashes of heat, haemorrhages, vertex headache, fainting spells; worse, pressure of clothes.
- ·Menses too short, too feeble; pains all relieved by the flow (Eupion).
- ·Left ovary very painful and swollen, indurated.
- ·Mammae inflamed, bluish.
- ·Coccyx and sacrum pain, especially on rising from sitting posture.
- ·Acts especially well at beginning and close of menstruation.
Male.
- ·Intense excitement of sexual organs.
- Respiratory.
- ·Upper part of windpipe very susceptible to touch.
- ·Sensation of suffocation and strangulation on lying down, particularly when anything is around throat; compels patient to spring from bed and rush for open window.
- ·Spasm of glottis; feels as if something ran from neck to larynx.
- ·Feels he must take a deep breath.
- ·Cramp-like distress in praecordial region.
- ·Cough; dry, suffocative fits, tickling.
- ·Little secretion and much sensitiveness; worse, pressure on larynx, after sleep, open air.
- ·Breathing almost stops on falling asleep (Grind).
- ·Larynx painful to touch.
- ·Sensation as of a plug (Anac) which moves up and down, with a short cough.
Heart.
- ·Palpitation, with fainting spells, especially during climacteric.
- ·Constricted feeling causing palpitation, with anxiety.
- ·Cyanosis.
- ·Irregular beats.
Back.
- ·Neuralgia of coccyx, worse rising from sitting posture; must sit perfectly still.
- ·Pain in neck, worse cervical region.
- ·Sensation of threads stretched from back to arms, legs, eyes, etc.
Extremities.
- ·Sciatica, right side, better lying down.
- ·Pain in tibia (may follow sore throat).
- ·Shortening of tendons.
Sleep.
- ·Patient sleeps into an aggravation.
- ·Sudden starting when falling asleep.
- ·Sleepiness, yet cannot sleep (Bell; Op).
- ·Wide-awake in evening.
Fever.
- ·Chilly in back; feet icy cold; hot flushes and hot perspiration.
- ·Paroxysm returns after acids.
- ·Intermittent fever every spring.
Skin.
- ·Hot perspiration, bluish, purplish appearance.
- ·Boils, carbuncles, ulcers, with bluish, purple surroundings.
- ·Dark blisters.
- ·Bed-sores, with black edges.
- ·Blue-black swellings.
- ·Pyemia; dissecting wounds.
- ·Purpura, with intense prostration.
- ·Senile erysipelas.
- ·Wens.
- ·Cellulitis.
- ·Varicose ulcers.
Modalities.
- ·Worse, after sleep, (Kali bich). Lachesis sleeps into aggravation; ailments that come on during sleep (Calc); left side, in the spring, warm bath, pressure or constriction, hot drinks. Closing eyes.
- ·Better, appearance of discharges, warm applications.
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REDEFINING HOMEOPATHY 