AJ WELLNESS IPACE CAPSULES

Indications

• Selenium deficiency
• Supportive therapy in conditions requiring antioxidant support
• Potential adjunct in cancer prevention strategies

Dosage

Children: Refer to BNF for Children for specific dosing information.

Adults: Initially 100–500 micrograms daily, adjusted according to response and serum levels.

Mechanism of action

Selenium is metabolized to selenophosphate and selenocysteine, which are essential for the synthesis of selenoproteins. This process involves the incorporation of selenium into proteins through a specialized tRNA that recognizes the RNA sequence UGA, which is facilitated by SECIS structures and SBP-2 proteins. Key selenoproteins, like glutathione peroxidases, help protect cells from oxidative damage, thus playing a significant role in reducing the risk of diseases such as atherosclerosis and certain cancers.

Pharmacodynamics

Selenium is incorporated into various selenoproteins that perform essential functions, including antioxidant activity, redox balance, and regulation of thyroid hormones. Its role in antioxidant defense mechanisms is particularly important for protecting cells against reactive oxygen species (ROS). Selenium supplementation has been linked to improved immune function and potential cancer prevention.

Pharmacokinetics

Selenium is absorbed through the gastrointestinal tract, and its bioavailability can vary based on the source and form of selenium. Once absorbed, it is distributed to various tissues, where it is incorporated into selenoproteins. Selenium is primarily excreted through urine, and its half-life can depend on dietary intake and individual metabolism. Selenium status can be assessed through blood levels of selenoproteins and selenium itself.

Adverse effects

• Nausea
• Anaemia
• Aplastic anaemia
• Skin reactions
• Gastrointestinal disorders

Precautions

• Selenium supplementation should not be given unless there is good evidence of deficiency.
• Use caution in patients with a history of hypersensitivity to selenium or its compounds.

Pregnancy

Limited information is available regarding selenium supplementation during pregnancy. Consult specialist sources for guidance.

Breast-feeding

Limited information is available; the effect of selenium on copper levels in milk is conflicting, and its impact on the infant is unknown.

Storage

After opening, store in a refrigerator (2–8°C).

Formulations

• Tablets (e.g., L-Selenomethionine 200 micrograms, SelenoPrecise 100 micrograms)
• Capsules (e.g., Trientine dihydrochloride 250 mg)
• Injection solutions (e.g., Sodium selenite 50 micrograms per 1 ml)

Indications

• Improvement of visual function
• Support for eye health
• Management of diabetic retinopathy
• Enhancement of microcirculation
• Support for cardiovascular health

Dosage

Children: Consult a healthcare provider for appropriate dosing in children, as specific pediatric dosing may not be established.

Adults: Refer to specific product guidelines or consult a healthcare provider for dosing information, as it can vary based on formulation.

Mechanism of action

Bilberry is thought to exert its effects primarily through the action of anthocyanins, which have been shown to improve visual function and circulation. These compounds may enhance the integrity of the vascular system, inhibit oxidative stress, and improve microcirculation, particularly in the retina, thus potentially aiding in conditions like night blindness and age-related macular degeneration.

Pharmacodynamics

The pharmacodynamic effects of bilberry are largely attributed to its antioxidant properties, which help to scavenge free radicals and reduce oxidative damage in tissues. The anthocyanins in bilberry may also modulate inflammatory responses and improve endothelial function, contributing to better blood flow and reduced risk of cardiovascular complications.

Pharmacokinetics

Bilberry extracts are typically administered orally, and the active constituents are absorbed in the gastrointestinal tract. The bioavailability of anthocyanins can be influenced by factors such as food intake and gastrointestinal pH. Once absorbed, these compounds are metabolized in the liver and excreted primarily through urine. The half-life of bilberry components varies and is influenced by the specific anthocyanins and the formulation used.

Adverse effects

• Gastrointestinal upset
• Allergic reactions
• Headache
• Dizziness

Interactions

• Anticoagulants
• Antiplatelet drugs
• Diabetes medications

Precautions

• Use with caution in individuals with bleeding disorders
• Caution in patients undergoing surgery due to potential bleeding effects

Pregnancy

Bilberry is classified as safe for use during pregnancy, but it should be used under the guidance of a healthcare provider.

Breast-feeding

There is insufficient reliable information regarding the safety of bilberry during breastfeeding, thus caution is advised.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Dried berries
• Powdered extract
• Capsules
• Liquid extract

Indications

• Type 2 diabetes mellitus
• Insulin resistance
• Impaired glucose tolerance
• Metabolic syndrome
• Hyperlipidemia

Dosage

Children: Refer to the BNF for Children for specific dosage recommendations suitable for pediatric patients.

Adults: Refer to the BNF for specific dosage recommendations based on the condition being treated.

Mechanism of action

Chromium enhances insulin signaling by upregulating insulin receptor-mediated pathways. It affects downstream effector molecules after insulin binds to its receptor, leading to the activation of phosphatidylinositol 2-kinase (PI3K) and protein kinase B (Akt). This process promotes the translocation of glucose transporter-4 (Glut4) to the cell membrane, facilitating increased glucose uptake. Additionally, chromium can promote GLUT-4 transporter translocation independently of insulin receptor activity under insulin-resistant conditions and aids in cholesterol efflux by increasing membrane fluidity.

Pharmacodynamics

Trivalent chromium is essential for the glucose tolerance factor, which activates insulin-mediated pathways. It enhances insulin binding to cells, increases the density of insulin receptors, and activates insulin receptor kinase, all of which contribute to improved insulin sensitivity. Chromium deficiency can lead to impaired glucose metabolism, and supplementation can normalize glucose tolerance in individuals exhibiting diabetic-like characteristics due to deficiency.

Pharmacokinetics

Chromium absorption occurs primarily in the intestines, but its bioavailability is influenced by various dietary factors, such as the presence of other minerals and vitamins. The mineral is transported in the bloodstream bound to transferrin and is predominantly stored in the liver, spleen, and bone. The elimination of chromium occurs mainly through urine, with small amounts excreted in feces. The half-life and exact metabolic pathways for chromium can vary based on its form and the individual's nutritional status.

Pregnancy

Chromium is generally considered safe during pregnancy when taken in appropriate amounts, but it is advisable to consult a healthcare provider.

Breast-feeding

Chromium is excreted in breast milk, and while it is deemed safe in moderate amounts, consultation with a healthcare provider is recommended.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Indications

• Copper deficiency
• Occipital Horn Syndrome
• Menke's disease
• Contraception (via copper IUD)

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: Refer to the relevant clinical guidelines and BNF for specific dosing information.

Mechanism of action

Copper is absorbed from the gastrointestinal tract via high affinity copper uptake proteins and low affinity copper uptake proteins, likely being reduced to the Cu1+ form prior to transport. Inside enterocytes, it binds to the copper transport protein ATOX1, which facilitates its transport to copper transporting ATPase-1 on the Golgi membrane for incorporation into the Golgi apparatus. Once in systemic circulation, copper binds primarily to ceruloplasmin, albumin, and alpha 2-macroglobulin. It acts as a cofactor in a variety of oxidase enzymes and also influences sperm motility when released from copper IUDs, contributing to its contraceptive effect.

Pharmacodynamics

Copper is essential for the activity of many enzymes and plays a vital role in processes such as iron metabolism, neurotransmitter synthesis, and antioxidant defense. Copper ions, particularly when released from intrauterine devices, have been shown to decrease sperm viability, thereby impacting fertility.

Pharmacokinetics

Copper is absorbed from the gut and is predominantly transported in the plasma bound to proteins such as ceruloplasmin and albumin. The absorption efficiency can vary; however, a significant portion of dietary copper is usually absorbed. The body regulates copper levels through hepatic excretion and storage mechanisms, ensuring homeostasis. Excess copper can lead to toxicity, while deficiency results in various health issues.

Pregnancy

Copper is considered essential during pregnancy, but excessive intake should be avoided due to potential toxicity.

Breast-feeding

Copper is excreted in breast milk, and adequate maternal intake is important for infant development.

Storage

Store in a cool, dry place, away from moisture and heat.

Indications

• General wellness support
• Anti-inflammatory effects
• Antioxidant activity
• Digestive aid
• Support for immune function

Dosage

Children: Paediatric dosing should be determined based on the specific extract and its intended use. Consultation with a healthcare provider is recommended for accurate dosing.

Adults: Dosage varies widely depending on the specific extract and formulation. It is essential to follow the manufacturer's instructions or consult a healthcare professional for appropriate dosing.

Mechanism of action

The mechanism of action of herbal extracts can vary significantly based on their constituents. Commonly, they exert their effects through multiple pathways including modulation of neurotransmitter systems, interference with inflammatory processes, or direct antioxidant activity. Some extracts may activate certain receptors or inhibit enzymes related to disease processes.

Pharmacodynamics

The pharmacodynamics of extracts is complex due to the presence of multiple active compounds which can have synergistic or antagonistic effects. These compounds may influence cellular signaling pathways, alter gene expression, or modulate immune response. The overall pharmacological profile is determined by the specific composition of the extract, its concentration, and the biological target it interacts with.

Pharmacokinetics

The pharmacokinetics of extracts involves absorption, distribution, metabolism, and excretion of the active compounds. Generally, herbal extracts are absorbed in the gastrointestinal tract, with bioavailability influenced by factors such as formulation, the presence of food, and individual metabolic differences. Compounds may undergo hepatic metabolism, and elimination can occur through urine or feces, depending on their chemical nature.

Pregnancy

Consult a healthcare professional before use, as the safety of the extract during pregnancy has not been established.

Breast-feeding

Consult a healthcare professional before use, as the safety of the extract during breastfeeding has not been established.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Folate deficiency
• Megaloblastic anemia
• Prevention of neural tube defects in pregnancy
• Supplementation in patients on certain medications (e.g., methotrexate)

Dosage

Children: Refer to the BNF for Children for appropriate pa

Adults: Refer to specific guidelines or the BNF for appropriate adult dosing based on the indication.

Mechanism of action

Folate functions as a coenzyme in the conversion of homocysteine to methionine, a process that is vital for DNA synthesis and repair. It is involved in the one-carbon metabolism pathway, where it acts as a carrier of one-carbon units necessary for the synthesis of purines and thymidylate, thus supporting the production of nucleotides and DNA. This mechanism is particularly important in rapidly dividing cells.

Pharmacodynamics

Folate is critical for the formation of red blood cells and the proper functioning of the nervous system. It aids in the production of nucleic acids, which are essential for cell proliferation. Folate deficiency can lead to impaired DNA synthesis, resulting in megaloblastic anemia characterized by the presence of large, immature red blood cells in the bloodstream. Adequate folate levels are also associated with reduced risk of neural tube defects in developing fetuses.

Pharmacokinetics

Folate is absorbed in the proximal part of the small intestine, primarily in the jejunum, and is transported in the bloodstream bound to plasma proteins. It undergoes hepatic metabolism and is stored mainly in the liver. The elimination half-life varies, but dietary folate can be retained in the body for several weeks. Excess folate is excreted through the urine. The bioavailability of folate from food sources is lower compared to synthetic folic acid found in supplements.

Interactions

• folates+fluorouracil: Severe (increases risk of toxicity)
• folates+antiepileptics: Moderate (decreases concentration)
• folates+fosphenytoin: Moderate (decreases concentration)
• folates+phenobarbital: Moderate (decreases concentration)
• folates+phenytoin: Moderate (decreases concentration)
• folates+primidone: Moderate (decreases concentration)
• sulfasalazine+folates: Unknown (decreases absorption)

Pregnancy

Folate is essential for fetal development and is often recommended to prevent neural tube defects.

Breast-feeding

Folate is generally safe during breastfeeding, as it is important for both maternal and infant health.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Tablets
• Injection

Indications

• Dietary supplement for antioxidant support
• Potential risk reduction for prostate cancer
• Potential risk reduction for lung cancer

Dosage

Children: Refer to specific guidelines as dosing can vary based on the formulation and purpose of use.

Adults: Refer to specific guidelines as dosing can vary based on the formulation and purpose of use.

Mechanism of action

Lycopene functions as a very potent antioxidant, trapping singlet oxygen and reducing mutagenesis. It inhibits cancer cell growth by disrupting growth factor receptor signaling and cell cycle progression. Lycopene upregulates connexin 43, enhancing gap junctional communication which is often deficient in tumors. Furthermore, it exhibits synergistic effects on cell proliferation and differentiation when combined with 1,25-dihydroxyvitamin D3, indicating interactions at a nuclear or subcellular level.

Pharmacodynamics

Lycopene's antioxidant properties play a critical role in protecting cells from oxidative stress. By trapping reactive oxygen species, it lessens cellular damage and may help to prevent the initiation and progression of cancer. Its ability to modulate cell signaling pathways and improve gap junction communication contributes to its anticancer effects. The interactions with vitamin D3 suggest a complex role in regulating cellular functions.

Pharmacokinetics

Lycopene is absorbed in the intestine and can be detected in the serum and various tissues. Its bioavailability can be influenced by dietary factors, including fat intake, which enhances absorption. Once in the body, lycopene is stored in adipose tissue and the liver. The elimination half-life and exact metabolic pathways are not well defined, but it is believed to undergo some conversion into other metabolites before excretion.

Pregnancy

There is insufficient reliable information regarding the safety of lycopene during pregnancy. Caution is advised.

Breast-feeding

Lycopene is considered safe during breastfeeding, but data on its excretion in human milk is limited.

Storage

Store in a cool, dry place, away from light.

Indications

• Manganese deficiency
• Bone health and development
• Antioxidant support
• Enzyme cofactor in metabolic processes

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations.

Adults: Refer to specific clinical guidelines or the BNF for appropriate dosing recommendations.

Mechanism of action

Manganese serves as a cofactor for several enzymes, including manganese superoxide dismutase (MnSOD), which protects cells from oxidative stress by catalyzing the dismutation of superoxide radicals into oxygen and hydrogen peroxide. It also participates in the activation of enzymes involved in carbohydrate, fat, and protein metabolism.

Pharmacodynamics

Manganese plays a role in various biochemical pathways, particularly in the metabolism of amino acids, cholesterol, glucose, and carbohydrates. It is crucial for bone formation and the maintenance of cartilage. Manganese also aids in the synthesis of glycosyltransferases, which are important for the formation of glycoproteins and proteoglycans.

Pharmacokinetics

Manganese is absorbed primarily in the small intestine, with absorption efficiency influenced by dietary factors and the presence of competing minerals. It is transported in the bloodstream bound to proteins such as alpha-2-macroglobulin and transferrin. Manganese is stored in the liver, pancreas, and bones, and is excreted primarily through bile and to a lesser extent in urine. Its half-life in the human body is not well defined due to its trace nature and variable absorption.

Pregnancy

Manganese is classified as a dietary mineral that is essential for human health, but excessive intake should be avoided during pregnancy as it may affect fetal development.

Breast-feeding

Manganese is present in breast milk, and normal dietary intake is considered safe during breastfeeding. However, excessive supplementation should be avoided.

Storage

Store in a cool, dry place, away from direct light and moisture.

Indications

• Herpes simplex virus infections
• Potential cardiovascular benefits
• Anti-inflammatory conditions
• Cancer prevention

Dosage

Children: For paediatric dosing and recommendations, please refer to the BNF for Children.

Adults: For specific dosing recommendations, please refer to the BNF as they can vary based on indications and formulations.

Mechanism of action

Resveratrol suppresses NF-kappaB activation in HSV infected cells, which is essential for the replication of the virus. It acts as a mixed agonist/antagonist for estrogen receptors alpha and beta, binding both with lower affinity than estradiol. It decreases the expression of cell cycle regulatory proteins and anti-apoptotic proteins while increasing p21WAF1/CIP1. Additionally, resveratrol interferes with an ERalpha-associated PI3K pathway, contributing to its anti-proliferative effects.

Pharmacodynamics

As a phytoalexin, resveratrol inhibits the replication of herpes simplex virus types 1 and 2 in a dose-dependent manner. Its antioxidant properties help in scavenging free radicals, while its anti-inflammatory effects contribute to its therapeutic potential. Resveratrol's modulation of estrogen receptors and its ability to affect cell cycle regulation highlight its complex pharmacological profile, with implications for cancer prevention and cardiovascular health.

Pharmacokinetics

Resveratrol is absorbed in the gastrointestinal tract, but its bioavailability is relatively low due to extensive first-pass metabolism. It is metabolized primarily in the liver, with metabolites being excreted via urine. The pharmacokinetic profile can be influenced by factors such as food intake and the presence of other substances in the gastrointestinal tract.

Adverse effects

• Nausea
• Diarrhea
• Abdominal pain
• Headache
• Rash

Interactions

• May interact with anticoagulants and antiplatelet drugs, increasing the risk of bleeding
• Can interfere with the metabolism of certain medications due to its effects on cytochrome P450 enzymes

Precautions

• Use caution in patients with bleeding disorders
• Monitor patients on antidiabetic medications due to potential blood sugar-lowering effects

Pregnancy

Resveratrol is not recommended during pregnancy due to insufficient safety data.

Breast-feeding

Limited data is available; consult a healthcare provider before use.

Storage

Store in a cool, dry place, protected from light.

Formulations

• Capsules
• Tablets
• Powder

Indications

• Antioxidant support
• Anti-inflammatory therapy
• Supportive treatment in cardiovascular diseases
• Hepatoprotective agent
• Nephroprotective agent

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing guidelines.

Adults: Refer to the BNF for specific adult dosing recommendations as they may vary based on the condition being treated.

Mechanism of action

Rutin exerts its protective effects through several mechanisms, including enhancement of antioxidant enzymes and activation of the Nrf2/HO-1 pathway, leading to increased levels of glutathione (GSH) and reduced malondialdehyde (MDA). It also exhibits anti-inflammatory actions by inhibiting pro-inflammatory cytokines such as IL-1β, IL-6, and TGF-β1, as well as enzymes like COX-2 and iNOS. Furthermore, rutin has antiapoptotic effects by inhibiting free radicals and various caspases, while promoting the expression of the antiapoptotic protein Bcl-2.

Pharmacodynamics

Rutin demonstrates various pharmacodynamic effects, particularly its ability to modulate oxidative stress and inflammation. It enhances the body's endogenous antioxidant defenses, contributing to cellular protection against oxidative damage. Additionally, the anti-inflammatory properties of rutin help in reducing tissue inflammation, which may be beneficial in conditions characterized by excessive inflammatory responses.

Pharmacokinetics

The pharmacokinetics of rutin are characterized by its absorption in the gastrointestinal tract, followed by metabolism primarily in the liver, where it is converted into various metabolites. These metabolites are then excreted mainly via the urine. The bioavailability of rutin can be influenced by factors such as food intake and individual metabolic variations.

Pregnancy

Rutin is generally considered safe in pregnancy, but consult a healthcare provider for specific recommendations.

Breast-feeding

Rutin is likely safe during breastfeeding, yet it is advisable to discuss with a healthcare professional.

Storage

Store in a cool, dry place away from direct sunlight.

Indications

• Age-related macular degeneration
• Eye health supplementation
• Antioxidant support

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations.

Adults: Refer to the BNF for specific dosing recommendations.

Mechanism of action

Zeaxanthin acts as a light filter in the retina, protecting the eyes from harmful high-energy light waves like ultraviolet rays. It is believed to neutralize free radicals and reduce oxidative stress, which can contribute to various ocular diseases. Additionally, zeaxanthin is involved in the carotenoid biosynthesis pathways, including its conversion from violaxanthin and its role in various biosynthetic processes.

Pharmacodynamics

Zeaxanthin exhibits antioxidant activity, which helps protect cells from oxidative damage. It is selectively deposited in the macula of the eye, where it contributes to visual acuity and may prevent photochemical damage caused by light exposure. Its presence in the retina aids in filtering blue light and supports overall retinal health.

Pharmacokinetics

Zeaxanthin is absorbed in the gastrointestinal tract after dietary intake, with peak plasma concentrations occurring several hours post-ingestion. It is transported in the bloodstream bound to lipoproteins, and its bioavailability can vary based on dietary fat presence. The half-life of zeaxanthin in the body is not well established but is believed to be several days, as it is stored in the retina and other tissues.

Pregnancy

There is insufficient data on the safety of zeaxanthin during pregnancy. Consult a healthcare provider for advice.

Breast-feeding

Limited data is available on the excretion of zeaxanthin in human milk. Consult a healthcare provider for guidance.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Dietary supplements
• Ophthalmic preparations

Mechanism of action

Selenium is first metabolized to selenophosphate and selenocysteine. Selenium incorporation is genetically encoded through the RNA sequence UGA. This sequence is recognized by RNA ste loop structures called selenocysteine inserting sequences (SECIS). These structures require the binding of SECIS binding proteins (SBP-2) to recognize selenocystiene. The specialized tRNA is first bound to a serine residue which is then enzymatically processed to a selylcysteyl-tRNA by selenocystiene sythase using selenophosphate as a selenium donor. Other unidentified proteins are required as part of the binding of this tRNA to the ribosome. Selenoproteins appear to be necessary for life as mice with the specialized tRNA gene knocked out exhibited early embryonic lethality. The most important selenoproteins seem to be the glutathione peroxidases and thioredoxin reductases which are part of the body's defenses againts reactive oxygen species (ROS). The importance of selenium in these anti-oxidant proteins has been implicated in the reduction of atherosclerosis by preventing the oxidation of low density lipoprotein. Selenium supplementation is also being investigated in the prevention of cancer and has been suggested to be beneficial to immune function. Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. Prior to occurrence of apoptosis, Se compounds alter the expression and/or activities of signaling molecules, mitochondria-associated factors, transcriptional factors, tumor suppressor genes, and cellular reduced glutathione. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess of selenoprotein synthesis can lead to DNA single-strand breaks. To elucidate the effects of Se on cytotoxic events, it should be remembered that the chemical forms and the dose of Se, and the experimental system used, are determinants of its biological activities. This mini-review focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic approach. /Selenium/ Selenium status can also influence thyroid hormone function via the deiodinase enzymes. Selenium is a critical component of the deiodinase enzymes, including iodothyronine 5'-deiodinases, which convert the prohormone thyroxine (T4) to the active circulating form, triiodothyronine (T3). Selenium is also a component of GPX, the main enzyme responsible for protecting thyroid cells against oxidative damage. GPX is involved in the detoxification of hydrogen peroxide, which is produced in the thyroid during the conversion of T4 to T3. /Selenium/ Selenium readily substitutes for sulfur in biomolecules and in many biochemical reactions, especially when the concentration of selenium is high and the concentration of sulfur is low in the organism. Inactivation of the sulfhydryl enzymes necessary for oxidative reactions in cellular respiration, through effects on mitochondrial and microsomal electron transport, might contribute to acute selenium toxicity. Selenium may have a role in hepatic heme metabolism that is related to GPX or lipid peroxidation. Selenocysteine is specifically found in some proteins (e.g., glutathione peroxidase); selenomethionine appears to randomly substitute for methionine in protein synthesis. This appears to be an additional mechanism for intermediate- or chronic-duration toxicity. Skin, hair, and nail damage are significant indicators of chronic selenium overexposure. The mechanism causing these integumentary effects is unclear, but could be related to the high selenium concentrations in these tissues as a consequence of the substitution of selenium for sulfur in certain amino acids, including the disulfide bridges that pr

Pharmacodynamics

Selenium is incorporated into many different selenoproteins which serve various functions throughout the body.

Mechanism of action

Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules. Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake. Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt. Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein. As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells. Chromium attenuates the activity of PTP-1B _in vitro,_ which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling. Transient upregulation of AMPK by chromium also leads to increased glucose uptake. While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders.

Pharmacodynamics

Trivalent chromium is part of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Chromium increases insulin binding to cells, increases insulin receptor density and activates insulin receptor kinase leading to enhanced insulin sensitivity. In chromium deficiency, intravenous administration of chromium resulted in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency.

Mechanism of action

Copper is absorbed from the gut via high affinity copper uptake protein and likely through low affinity copper uptake protein and natural resistance-associated macrophage protein-2. It is believed that copper is reduced to the Cu1+ form prior to transport. Once inside the enterocyte, it is bound to copper transport protein ATOX1 which shuttles the ion to copper transporting ATPase-1 on the golgi membrane which take up copper into the golgi apparatus. Once copper has been secreted by enterocytes into the systemic circulation it remain largely bound by ceruloplasmin (65-90%), albumin (18%), and alpha 2-macroglobulin (12%). Copper is an essential element in the body and is incorporated into many oxidase enzymes as a cofactor. It is also a component of zinc/copper super oxide dismutase, giving it an anti-oxidant role. Copper defiency occurs in Occipital Horn Syndrome and Menke's disease both of which are associated with impaired development of connective tissue due to the lack of copper to act as a cofactor in protein-lysine-6-oxidase. Menke's disease is also associated with progressive neurological impairment leading to death in infancy. The precise mechanisms of the effects of copper deficiency are vague due to the wide range of enzymes which use the ion as a cofactor. Copper appears to reduce the viabilty and motility of spermatozoa. This reduces the likelihood of fertilization with a copper IUD, producing copper's contraceptive effect. The exact mechanism of copper's effect on sperm are unknown. The reason for the less severe reaction when the foreign body is at a distance from the retina has been proposed to be ... that near the retina & its blood vessels there is greater oxygen tension than at a distance, which causes metallic copper to oxidize to toxic copper compounds more rapidly close to or in contact with the retina than at a distance. Furthermore, the abscess formation that is characteristic of copper undergoing oxidation close to the retina & choroiod can be attributed to attraction of polymorphonuclear leukocytes from these nearby vascular tissues, which become heavily infiltrated. Liquefaction & disorganization of the vitreous body has been explained on the basis of copper catalysis of oxidation of ascorbic acid, leading to depolymerization of the hyaluronic acid of the vitreous humor. Changes in protein & hexosamine content have also been related to decrease in viscosity of the vitreous humor. Increased content of amino acids in the vitreous humor has been consistent with proteolysis of the vitreous body, but decreased concentration in the aqueous humor has suggested suppression of secretion of amino acids by the ciliary body under the influence of copper.

Pharmacodynamics

Copper is incorporated into many enzymes throughout the body as an essential part of their function. Copper ions are known to reduce fertility when released from copper-containing IUDs.

Mechanism of action

Serum and tissue lycopene levels have been inversely related to the risk of lung and prostate cancers. Lycopene functions as a very potent antioxidant, and it can trap singlet oxygen and reduce mutagenesis in the Ames test. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression. Studies using human and animal cells identified connexin 43, a gene whose expression is upregulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or upregulation is associated with decreased proliferation. The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on cell proliferation and differentiation, and an additive effect on cell cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level.

Mechanism of action

Resveratrol suppresses NF-kappaB (NF-kappaB) activation in HSV infected cells. Reports have indicated that HSV activates NF-kappaB during productive infection and this may be an essential aspect of its replication scheme [PMID: 9705914]. ... Resveratrol appears to act as a mixed agonist/antagonist for estrogen receptors alpha and beta. It has been found to bind estrogen receptor beta and estrogen receptor alpha with comparable affinity but with 7000-fold lower affinity than estradiol. Resveratrol differs from other phytoestrogens, which bind estrogen receptor beta with higher affinity than they bind estrogen receptor alpha. Resveratrol also shows estradiol antagonistic behavior for estrogen receptor alpha with some estrogen receptors. It does not show estradiol antagonistic activity with estrogen receptor beta ... The anti-proliferative effects of resveratrol were shown to be modulated by cell cycle regulatory proteins ... Resveratrol decreased the expression of cyclins D1 and D2, Cdk 2, 4 and 6, and proliferating cell nuclear antigen (PCNA) whereas p21WAF1/CIP1 was increased. Furthermore there was inhibited expression of anti-apoptotic proteins, such as survivin, and markers of tumor promotion, cyclooxygenase (COX)-2, and ornithine decarboxylase (ODC) were observed ... ... In addition to its antioxidant scavenging of free radicals and modulating estrogen receptor (ER) activity ... resveratrol can interfere with an ERalpha-associated PI3K pathway, following a process that could be independent of the nuclear functions of the ERalpha ... and acts as an agonist for the cAMP/kinase-A system ... It also promotes the accumulation of growth inhibitory/pro-apoptotic ceramide ... and induction of quinone reductase (QR, a phase II detoxification enzyme) ... and induces caspase-independent apoptosis through Bcl-2 downregulation ... It has been shown to suppress Src tyrosine kinase activity ... nitric oxide generation, and the NFkappaB pathway ...

Pharmacodynamics

Resveratrol, a phytoalexin, has been found to inhibit herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) replication in a dose-dependent, reversible manner, although this is only one of its many pharmaceutical properties. In some countries where there is higher consumption of red wine, there appears to be a lower incidence of heart disease. Other benefits of resveratrol include its anti-inflammatory and antioxidant effects. In preclinical studies, Resveratrol has been found to have potential anticancer properties.

Mechanism of action

A 2022 review of Rutin focused on its protective effects on the heart, liver, and kidneys against various chemical and natural toxins. The antioxidant effects involve enhancement of various antioxidant enzymes, Nrf2/HO-1 pathway activation, Glutathione (GSH) elevation, and malondialdehyde (MDA) reduction. The anti-inflammatory effects involve inhibition of IL-1β, IL-6, TGF-β1, COX-2, iNOS, TLR4, and XO. The antiapoptotic effects involve inhibition of free radicals, caspase-3/-7/-9, hsp70, HMGB1, and p53, and elevation of antiapoptotic protein Bcl-2.