In my last post, I wrote about GnRH (gonadotrophin releasing hormone), which stimulates the release of LH and FSH from the anterior pituitary. In this post, I will be talking about kisspeptin, which stimulates the release of GnRH from the hypothalamus.
Effects of kisspeptin on GnRH
Kisspeptin, which is encoded by the Kiss1 gene, comes in several forms, but the most common form is Kisspeptin-54 (a.k.a. metastin). Kisspeptin binds to the GPR54 receptor (a.k.a. Kiss1r), expressed on most GnRH neurons. In fact, GnRH neurons are almost always located next to kisspeptin neurons. Most kisspeptin-releasing neurons are located either in the more rostral AVPV (anteroventral periventricular nucleus) or in the more caudal ARC (arcuate nucleus). The AVPV and ARC neurons are thought to have somewhat different effects.
ARC kisspeptin neurons project to the median eminence, where they may impact the release of GnRH. ARC neurons, in contrast to AVPV neurons, also express neurokinin B and dynorphin, and are thus sometimes known as KNDy neurons (stands for "Kisspeptin, Neurokinin B, Dynorphin"). They also have receptors for these neurotransmitters, so they can act on themselves in an autocrine fashion. Neurokinin B is thought to stimulate pulse generation by KNDy neurons, whereas dynorphin is thought to inhibit it. KNDy neurons may be stimulated by pheromones (chemicals excreted by other animals).
ARC and AVPV kisspeptin neurons are also affected differently by sex steroids, as I will talk about in the next section.
Regulation by sex steroids
Kiss1 cells have receptors for sex steroids (GnRH neurons do not). These sex steroid receptors include ERα (oestrogen receptor α),
ERβ (oestrogen receptor β), PR (progesterone receptor) and AR (androgen receptor). All four receptors are found in ARC kisspeptin neurons, but the AVPV neurons mainly have only ERα and ERβ receptors.
An interesting finding in female mice is that ARC neurons appear to be stimulated by low oestrogen, whereas AVPV neurons appear to be stimulated by high oestrogen. It has been suggested that ARC neurons may be responsible for negative feedback, whereas AVPV neurons may be responsible for positive feedback.
Another interesting finding is that androgen receptors, at least in mice, may be important in Kiss1 expression. Female mice with androgen receptor knockout have reduced Kiss1 expression in the AVPV and increased Kiss1 expression in the ARC relative to wild-type mice.
Puberty
I don't think there's much to say here, other than that puberty is thought to be stimulated by kisspeptin binding to GPR54 receptors. Moving on...
Energy balance
Kisspeptin may also be involved in energy balance and satiety, which is a topic that I've spoken about here and here. The main neurons involved in satiety are Agrp/Npy neurons, which are orexigenic (appetite-stimulating), and Pomc/Cart neurons, which are anorexigenic (appetite-inhibiting). Kiss1r knockout mice have been found to have an increase in Pomc expression, which means that they tend to eat less. Despite this, however, they tend to gain weight. The weight gain may be due to reduced energy expenditure due to less UCP1 expression (a protein I have spoken about here).
Friday, October 13, 2017
Tuesday, October 10, 2017
Antifungal Agents
Yup, it's another post about drugs! I've also written about antifungal drugs here.
Ergosterol Synthesis Inhibitors
Ergosterol is one of the membrane sterols in fungi (analogous to cholesterol in humans). Blocking of sterol formation by azoles or allylamines leads to the accumulation of toxic sterols in the cell membrane, disrupting packing of membrane lipids.
Azoles
Azoles work by inhibiting 14α-sterol-demethylase, which is in the ergosterol biosynthesis pathway. Inhibition of this enzyme leads to accumulation of 14α methylsterols and disrupted packing of membrane lipids.
The two main types of azoles are the imidazoles and triazoles. Imidazoles, which include ketoconazole and clotrimazole, are quite toxic and are generally only used for more superficial mycoses. Triazoles, such as fluconazole (best against Candida but has no mould activity), itraconazole (better than fluconazole at dealing with moulds, but not as good at dealing with yeasts), voriconazole and posaconazole, are less toxic and target a broader spectrum of fungi. Even though triazoles are less toxic, that's not to say that they are non-toxic: they can still cause hepatotoxicity, and around 30% of patients taking voriconazole experience visual symptoms such as blurred vision and light sensitivity. Azoles also have a huge potential for drug-drug interactions, as they are metabolised by and inhibit cytochrome P450 enzymes.
Allylamines
Allylamines, such as terbinafine, inhibit squalene epoxidase, which is an earlier step in the ergosterol synthesis pathway. Inhibition of squalene epoxidase causes accumulation of squalene and deficiency of ergosterol, which again leads to interference with membrane function and fungal death.
Glucan Synthesis Inhibitors (Echinocandins)
Echinocandins, such as caspofungin, anidulafungin and micafungin inhibit glucan formation. As humans don't have glucan, echinocandins have limited toxic effects. They are used in severe Candida infections as they inhibit the growing ends and branches of fungal hyphae (remember, Candida can form true hyphae when it enters tissue). Unfortunately, echinocandins are very expensive, limiting their use.
Polyenes
Polyenes, such as amphotericin B (AMB) and nystatin, associate with ergosterol to form pores. Large amounts of ions can move through the pore, leading to cell death. Polyenes are broad-spectrum and can be quite useful, especially against invasive fungal infections such as invasive aspergillosis, disseminated candidiasis and cryptococcal meningitis.
Unfortunately, conventional AMB (c-AMB) can be very toxic to the kidneys. Liposomal preparations (L-AMB), which have lipid carriers that ensure uptake and transport by macrophages, have similar efficacy but less toxicity than c-AMB. Thus, L-AMBs, such as AmBisome and Abelcet, are the standard of care for patients with severe fungal infections.
Susceptibility testing
Unlike with bacteria, susceptibility testing is rarely performed on fungi as the results are not very reliable. In vitro resistance usually predicts failure, but in vitro sensitivity doesn't predict success. Also, fungi take a long time to grow as compared to bacteria.
Antifungal resistance
Unfortunately, fungi have already developed some resistance mechanisms to fungi. The main resistance mechanisms are alterations or defects in the ergosterol synthesis pathway, increase of efflux pumps, decrease of drug import and alterations to drug processing.
Treatments
There were a bunch of fungi mentioned throughout this lecture with treatments, but I thought it would be more coherent if I stuck them all at the end of this post, so here they are:
Ergosterol Synthesis Inhibitors
Ergosterol is one of the membrane sterols in fungi (analogous to cholesterol in humans). Blocking of sterol formation by azoles or allylamines leads to the accumulation of toxic sterols in the cell membrane, disrupting packing of membrane lipids.
Azoles
Azoles work by inhibiting 14α-sterol-demethylase, which is in the ergosterol biosynthesis pathway. Inhibition of this enzyme leads to accumulation of 14α methylsterols and disrupted packing of membrane lipids.
The two main types of azoles are the imidazoles and triazoles. Imidazoles, which include ketoconazole and clotrimazole, are quite toxic and are generally only used for more superficial mycoses. Triazoles, such as fluconazole (best against Candida but has no mould activity), itraconazole (better than fluconazole at dealing with moulds, but not as good at dealing with yeasts), voriconazole and posaconazole, are less toxic and target a broader spectrum of fungi. Even though triazoles are less toxic, that's not to say that they are non-toxic: they can still cause hepatotoxicity, and around 30% of patients taking voriconazole experience visual symptoms such as blurred vision and light sensitivity. Azoles also have a huge potential for drug-drug interactions, as they are metabolised by and inhibit cytochrome P450 enzymes.
Allylamines
Allylamines, such as terbinafine, inhibit squalene epoxidase, which is an earlier step in the ergosterol synthesis pathway. Inhibition of squalene epoxidase causes accumulation of squalene and deficiency of ergosterol, which again leads to interference with membrane function and fungal death.
Glucan Synthesis Inhibitors (Echinocandins)
Echinocandins, such as caspofungin, anidulafungin and micafungin inhibit glucan formation. As humans don't have glucan, echinocandins have limited toxic effects. They are used in severe Candida infections as they inhibit the growing ends and branches of fungal hyphae (remember, Candida can form true hyphae when it enters tissue). Unfortunately, echinocandins are very expensive, limiting their use.
Polyenes
Polyenes, such as amphotericin B (AMB) and nystatin, associate with ergosterol to form pores. Large amounts of ions can move through the pore, leading to cell death. Polyenes are broad-spectrum and can be quite useful, especially against invasive fungal infections such as invasive aspergillosis, disseminated candidiasis and cryptococcal meningitis.
Unfortunately, conventional AMB (c-AMB) can be very toxic to the kidneys. Liposomal preparations (L-AMB), which have lipid carriers that ensure uptake and transport by macrophages, have similar efficacy but less toxicity than c-AMB. Thus, L-AMBs, such as AmBisome and Abelcet, are the standard of care for patients with severe fungal infections.
Susceptibility testing
Unlike with bacteria, susceptibility testing is rarely performed on fungi as the results are not very reliable. In vitro resistance usually predicts failure, but in vitro sensitivity doesn't predict success. Also, fungi take a long time to grow as compared to bacteria.
Antifungal resistance
Unfortunately, fungi have already developed some resistance mechanisms to fungi. The main resistance mechanisms are alterations or defects in the ergosterol synthesis pathway, increase of efflux pumps, decrease of drug import and alterations to drug processing.
Treatments
There were a bunch of fungi mentioned throughout this lecture with treatments, but I thought it would be more coherent if I stuck them all at the end of this post, so here they are:
- Dermatophyte infections: First try topical therapy with ketoconazole, clotrimazole or terbinafine cream. Oral ketoconazole or terbinafine can be used if treatment is unsuccessful. Tinea capitis can be treated with oral terbinafine.
- Pityriasis versicolor (Malassezia): Treat with topical antifungal shampoos or with oral ketoconazole or itraconazole. Oral terbinafine is ineffective against pityriasis versicolor. (Malassezia itself isn't immune to terbinafine, but the location of the infection may play a role in its ineffectiveness in pityriasis versicolor.)
- Invasive candidasis: Intravenous azoles, such as itraconazole.
- Invasive aspergillosis: Voriconazole. Polyenes may still be used. Treatment should be started as soon as possible to reduce the risk of mortality.
- Cryptococcal meningitis: IV amphotericin plus flucytosine for two weeks, followed by high-dose fluconazole. Fluconazole may be continued to prevent reinfection.
- Penicillum marneffii: Amphotericin B, then high-dose itraconazole, then lifelong suppressive therapy.
Antiviral Agents
Now we're onto discussing antivirals! I've spoken about them a little bit for PHAR2210, but I'll be talking about even more drugs in this post. Yay drugs.
Nucleoside/Nucleotide Analogues
Nucleoside/nucleotide analogues are fairly close to the structure of a real nucleoside/nucleotide, so they get incorporated into viral DNA but cause instability or chain termination. They generally need to be triphosphorylated by viral enzymes or by host enzymes in order to become active.
Nucleoside/nucleotide analogues are mostly active against herpes viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV), though they are also active against HIV and hepatitis viruses. HSV is usually treated with acyclovir or penciclovir cream. Oral antivirals, such as valaciclovir and famciclovir, are more effective. Treatment can reduce the risk of serious sequelae, such as HSV-1 encephalitis. VZV is not usually treated in children, but in adults (who have a more severe form of chickenpox or may have shingles), acyclovir, famciclovir and/or valacyclovir may be given. Hepatitis B can be treated and even occasionally cured with nucleoside analogues, though the main aim is usually to suppress viral replication.
Acyclovir and Valacyclovir
Acyclovir is an analogue of guanosine. It is phosphorylated once by herpes virus thymidine kinase, and then twice more by host enzymes. A prodrug of acyclovir, valacyclovir, has a different side chain that improves its oral bioavailability (3-5x that of oral acyclovir).
Penciclovir and Famciclovir
Penciclovir is pretty similar to acyclovir, but it has a longer half-life. Famciclovir is a prodrug of penciclovir with higher oral bioavailability.
Ganciclovir and Valganciclovir
Ganciclovir is a guanosine analogue with IV, oral and intravitreal formulations. The intravitreal formulation, which is an implant, can be used to treat CMV retinitis (a complication of CMV that mainly occurs in HIV patients). Unfortunately, ganciclovir is very toxic and may suppress the bone marrow. Valganciclovir, the valyl ester of ganciclovir, has higher oral bioavailability and less toxicity.
Ribavirin
Ribavirin is an analogue of both guanine and adenine. It inhibits the RNA polymerase of RNA viruses, and has multiple targets in other viruses. Daily oral ribavirin, in conjunction with weekly interferon injections, are used to treat hepatitis C. Ribavirin is also effective against respiratory syncytial virus (RSV) and Lassa virus. Unfortunately, ribavirin can cause anaemia and thrombocytopaenia, and may have interactions with HIV drugs.
Matrix protein inhibitors
The only matrix protein inhibitor I'll talk about in this post is amantadine, which is only effective against influenza A (and even then has no effect against some strains, such as H1N1 or H3N2). It blocks the ion channel protein M2, which transports hydrogen ions and lowers the pH in the virus core, which in turn results in M1 protein dissociation from the ribonucleoprotein. Treatment with amantadine can shorten the illness and reduce viral shedding. Amantadine also has neurological effects and can be used in nerve pain and Parkinson's disease.
Neuraminidase inhibitors
Neuraminidase inhibitors, such as zanamivir and oseltamivir, block neuraminidase (!), which is a viral enzyme that cleaves receptors containing sialic acid, allowing viral particles to dissociate from the host cell. They are also used to treat influenza.
HIV drugs
See earlier post: Chemotherapy III: Antiviral Drugs
Nucleoside/Nucleotide Analogues
Nucleoside/nucleotide analogues are fairly close to the structure of a real nucleoside/nucleotide, so they get incorporated into viral DNA but cause instability or chain termination. They generally need to be triphosphorylated by viral enzymes or by host enzymes in order to become active.
Nucleoside/nucleotide analogues are mostly active against herpes viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV), though they are also active against HIV and hepatitis viruses. HSV is usually treated with acyclovir or penciclovir cream. Oral antivirals, such as valaciclovir and famciclovir, are more effective. Treatment can reduce the risk of serious sequelae, such as HSV-1 encephalitis. VZV is not usually treated in children, but in adults (who have a more severe form of chickenpox or may have shingles), acyclovir, famciclovir and/or valacyclovir may be given. Hepatitis B can be treated and even occasionally cured with nucleoside analogues, though the main aim is usually to suppress viral replication.
Acyclovir and Valacyclovir
Acyclovir is an analogue of guanosine. It is phosphorylated once by herpes virus thymidine kinase, and then twice more by host enzymes. A prodrug of acyclovir, valacyclovir, has a different side chain that improves its oral bioavailability (3-5x that of oral acyclovir).
Penciclovir and Famciclovir
Penciclovir is pretty similar to acyclovir, but it has a longer half-life. Famciclovir is a prodrug of penciclovir with higher oral bioavailability.
Ganciclovir and Valganciclovir
Ganciclovir is a guanosine analogue with IV, oral and intravitreal formulations. The intravitreal formulation, which is an implant, can be used to treat CMV retinitis (a complication of CMV that mainly occurs in HIV patients). Unfortunately, ganciclovir is very toxic and may suppress the bone marrow. Valganciclovir, the valyl ester of ganciclovir, has higher oral bioavailability and less toxicity.
Ribavirin
Ribavirin is an analogue of both guanine and adenine. It inhibits the RNA polymerase of RNA viruses, and has multiple targets in other viruses. Daily oral ribavirin, in conjunction with weekly interferon injections, are used to treat hepatitis C. Ribavirin is also effective against respiratory syncytial virus (RSV) and Lassa virus. Unfortunately, ribavirin can cause anaemia and thrombocytopaenia, and may have interactions with HIV drugs.
Matrix protein inhibitors
The only matrix protein inhibitor I'll talk about in this post is amantadine, which is only effective against influenza A (and even then has no effect against some strains, such as H1N1 or H3N2). It blocks the ion channel protein M2, which transports hydrogen ions and lowers the pH in the virus core, which in turn results in M1 protein dissociation from the ribonucleoprotein. Treatment with amantadine can shorten the illness and reduce viral shedding. Amantadine also has neurological effects and can be used in nerve pain and Parkinson's disease.
Neuraminidase inhibitors
Neuraminidase inhibitors, such as zanamivir and oseltamivir, block neuraminidase (!), which is a viral enzyme that cleaves receptors containing sialic acid, allowing viral particles to dissociate from the host cell. They are also used to treat influenza.
HIV drugs
See earlier post: Chemotherapy III: Antiviral Drugs
Obesity part 2
Yup, another post about obesity. See my earlier post for BIOC3004 here.
The obesity epidemic-definition and prevalence
See earlier post: Obesity
Health issues associated with obesity
The metabolic syndrome
See earlier post: Metabolic Syndrome and Fat Metabolism
Properties of adipose tissue
Adipose tissue is often simply thought of as a storage organ for fatty acids, but it can do much more than that. Aside from the storage and release of free fatty acids, it can also store and release leptin, adiponectin, renin, angiotensin, glucocorticoids, sex steroids and pro-inflammatory cytokines. Pro-inflammatory cytokines can cause macrophage migration, which is why obesity is sometimes thought of as a "chronic, low-grade inflammatory condition."
Factors contributing to obesity
Thermogenesis
Around 2/3 of our resting metabolic rate is used on maintaining our body temperature. If our core body temperature is higher, we will use more energy for thermogenesis, and vice versa. The next question is this: can we increase thermogenesis to increase energy expenditure?
As mentioned here, children and some adults have brown adipose tissue, which burns energy to create heat. In fact, as little as 50g of brown fat could use up to 20% of our basal energy needs. Interestingly enough, there is an inverse relationship between BMI and detectable brown fat, so brown fat might represent a potential target for obesity treatment. Fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) may both help to stimulate brown fat proliferation. BMP-7 has already had some promising effects in mice, but we need to wait and see if it will have the same effects in humans.
Circadian rhythmicity
You've probably heard of the Circadian rhythm- an adaptation to the 24 hour light-dark cycle that controls many physiological processes. The main controllers of the Circadian rhythm are the "central clock" located in the suprachiasmatic nucleus, directly linked to the retina, as well as several "peripheral clocks" in metabolic organs. There are strong links between the Circadian rhythm and metabolism, as many metabolic hormones such as insulin and leptin display rhythmic secretion patterns. Eating at abnormal hours, when our organs are not "primed" for feeding, may be problematic.
Knocking out "clock genes" in mice has been shown to cause abnormal metabolic phenotypes. Knocking out Clock leads to hyperphagia, obesity and hormonal imbalances associated with metabolic syndrome, whereas knocking out Bmal1 leads to extreme weight loss. Interestingly enough, feeding rodents a high-fat diet appears to alter the activity of hepatic clock genes.
Melatonin, a hormone usually secreted at night by the pineal gland, has been examined as a potential treatment option. It might be able to decrease weight gain, improve lipid profiles and insulin sensitivity, and have anti-oxidative and anti-inflammatory effects. It might also help to "re-set" the Circadian rhythm for shift workers.
Metabolic programming
See earlier post: Developmental programming of adult health and disease. Offspring of rats fed a high-fat diet were more likely to become obese, even if they ate a normal diet throughout their life. In other words: babies born to obese mothers appear to be predisposed to obesity.
Treatment options and directions for the future
Another treatment option that has been examined is omega-3. Omega-3 may help to lower the inflammation that is present in obesity (remember, obesity is considered to be a "chronic low-grade inflammatory condition"). A lot more research is still being done in this area, though.
The obesity epidemic-definition and prevalence
See earlier post: Obesity
Health issues associated with obesity
The metabolic syndrome
See earlier post: Metabolic Syndrome and Fat Metabolism
Properties of adipose tissue
Adipose tissue is often simply thought of as a storage organ for fatty acids, but it can do much more than that. Aside from the storage and release of free fatty acids, it can also store and release leptin, adiponectin, renin, angiotensin, glucocorticoids, sex steroids and pro-inflammatory cytokines. Pro-inflammatory cytokines can cause macrophage migration, which is why obesity is sometimes thought of as a "chronic, low-grade inflammatory condition."
Factors contributing to obesity
Thermogenesis
Around 2/3 of our resting metabolic rate is used on maintaining our body temperature. If our core body temperature is higher, we will use more energy for thermogenesis, and vice versa. The next question is this: can we increase thermogenesis to increase energy expenditure?
As mentioned here, children and some adults have brown adipose tissue, which burns energy to create heat. In fact, as little as 50g of brown fat could use up to 20% of our basal energy needs. Interestingly enough, there is an inverse relationship between BMI and detectable brown fat, so brown fat might represent a potential target for obesity treatment. Fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) may both help to stimulate brown fat proliferation. BMP-7 has already had some promising effects in mice, but we need to wait and see if it will have the same effects in humans.
Circadian rhythmicity
You've probably heard of the Circadian rhythm- an adaptation to the 24 hour light-dark cycle that controls many physiological processes. The main controllers of the Circadian rhythm are the "central clock" located in the suprachiasmatic nucleus, directly linked to the retina, as well as several "peripheral clocks" in metabolic organs. There are strong links between the Circadian rhythm and metabolism, as many metabolic hormones such as insulin and leptin display rhythmic secretion patterns. Eating at abnormal hours, when our organs are not "primed" for feeding, may be problematic.
Knocking out "clock genes" in mice has been shown to cause abnormal metabolic phenotypes. Knocking out Clock leads to hyperphagia, obesity and hormonal imbalances associated with metabolic syndrome, whereas knocking out Bmal1 leads to extreme weight loss. Interestingly enough, feeding rodents a high-fat diet appears to alter the activity of hepatic clock genes.
Melatonin, a hormone usually secreted at night by the pineal gland, has been examined as a potential treatment option. It might be able to decrease weight gain, improve lipid profiles and insulin sensitivity, and have anti-oxidative and anti-inflammatory effects. It might also help to "re-set" the Circadian rhythm for shift workers.
Metabolic programming
See earlier post: Developmental programming of adult health and disease. Offspring of rats fed a high-fat diet were more likely to become obese, even if they ate a normal diet throughout their life. In other words: babies born to obese mothers appear to be predisposed to obesity.
Treatment options and directions for the future
Another treatment option that has been examined is omega-3. Omega-3 may help to lower the inflammation that is present in obesity (remember, obesity is considered to be a "chronic low-grade inflammatory condition"). A lot more research is still being done in this area, though.
Developmental programming of adult health and disease
The Barker hypothesis suggests that early life environmental manipulation (i.e. the environment experienced in utero) can impact later physiological changes and disease risk. Evidence for this hypothesis comes from babies with very low birth weight, as low birth weight suggests that something was not quite right in utero. Babies with low birth weight are at risk of an array of conditions such as hypertension, type 2 diabetes, hyperlipidaemia, metabolic syndrome, ischaemic heart disease, osteoporosis and depression. Since many of these conditions are common and are taking a toll on the health care system, it would be great if we could do a better job at preventing these problems before they occur.
The Predictive Adaptive Response (PAR) hypothesis suggests that the fetus adapts to whatever environment the mother is experiencing. For example, if a mother doesn't have enough to eat and cannot provide sufficient nutrition to her fetus, the fetus may adapt in ways that allow it to thrive without a lot of nutrition. If the baby is born in a similarly nutrition-poor environment, this "thrifty adaptation" could be very helpful. On the other hand, if the baby is born into a nutrient-rich environment, the "thrifty adaptations" might cause it to gain excess weight, leading to obesity, metabolic syndrome, and so on. Aside from diet, maternal stress may also play a role in "programming" the fetus.
The timing of an environmental insult may affect which problems the child has later on in life. In a study involving rats, some rats were fed a low-protein diet during pregnancy. If they were fed a low-protein diet early in pregnancy, their children experienced hypertension and renal failure. If they were fed a low-protein diet later in pregnancy, their children experienced obesity, a preference for high-fat food, decreased activity and glucose intolerance. These results echoed the aftermath of the Dutch Hunger Winter in 1944-45: mothers who experienced famine in their early stages of pregnancy had children with an increased risk of hypertension, and mothers who experienced famine in later stages of pregnancy had children with increased adiposity and glucose intolerance.
It has been suggested that glucocorticoids may play a role in the developmental programming of the fetus. Glucocorticoid levels increase during pregnancy and are essential for fetal maturation in late gestation. They are thought to allow cells to switch to their functional phenotype (i.e. they serve as a maturational signal). This is all well and good if the signals come at the right time, but too many glucocorticoids too early may have detrimental effects on the fetus. Excessive glucocorticoids may also alter the activity of PEP carboxykinase, an enzyme involved in gluconeogenesis, which may lead to some errors in glycaemic control programming.
Glucocorticoids have an active and inactive form, and are activated and inactivated by enzymes called 11β-hydroxysteroid dehydrogenases, or 11β-HSDs. 11β-HSD2 inactivates glucocorticoids, whereas 11β-HSD1 activates them. 11β-HSD2 is abundant in the placenta and developing fetal tissues, which prevents too many active glucocorticoids from getting through. 11β-HSD2 levels decline later in gestation, allowing more glucocorticoids to get through later on. A low-protein diet may decrease 11β-HSD2 levels, leading to the detrimental effects that I outlined earlier on. Indeed, 11β-HSD2 knockout mice have a range of problems, from low birth weight to anxiety-like behaviour. It is possible that 11β-HSD2 might represent a potential target to alter developmental programming in utero.
The Predictive Adaptive Response (PAR) hypothesis suggests that the fetus adapts to whatever environment the mother is experiencing. For example, if a mother doesn't have enough to eat and cannot provide sufficient nutrition to her fetus, the fetus may adapt in ways that allow it to thrive without a lot of nutrition. If the baby is born in a similarly nutrition-poor environment, this "thrifty adaptation" could be very helpful. On the other hand, if the baby is born into a nutrient-rich environment, the "thrifty adaptations" might cause it to gain excess weight, leading to obesity, metabolic syndrome, and so on. Aside from diet, maternal stress may also play a role in "programming" the fetus.
The timing of an environmental insult may affect which problems the child has later on in life. In a study involving rats, some rats were fed a low-protein diet during pregnancy. If they were fed a low-protein diet early in pregnancy, their children experienced hypertension and renal failure. If they were fed a low-protein diet later in pregnancy, their children experienced obesity, a preference for high-fat food, decreased activity and glucose intolerance. These results echoed the aftermath of the Dutch Hunger Winter in 1944-45: mothers who experienced famine in their early stages of pregnancy had children with an increased risk of hypertension, and mothers who experienced famine in later stages of pregnancy had children with increased adiposity and glucose intolerance.
It has been suggested that glucocorticoids may play a role in the developmental programming of the fetus. Glucocorticoid levels increase during pregnancy and are essential for fetal maturation in late gestation. They are thought to allow cells to switch to their functional phenotype (i.e. they serve as a maturational signal). This is all well and good if the signals come at the right time, but too many glucocorticoids too early may have detrimental effects on the fetus. Excessive glucocorticoids may also alter the activity of PEP carboxykinase, an enzyme involved in gluconeogenesis, which may lead to some errors in glycaemic control programming.
Glucocorticoids have an active and inactive form, and are activated and inactivated by enzymes called 11β-hydroxysteroid dehydrogenases, or 11β-HSDs. 11β-HSD2 inactivates glucocorticoids, whereas 11β-HSD1 activates them. 11β-HSD2 is abundant in the placenta and developing fetal tissues, which prevents too many active glucocorticoids from getting through. 11β-HSD2 levels decline later in gestation, allowing more glucocorticoids to get through later on. A low-protein diet may decrease 11β-HSD2 levels, leading to the detrimental effects that I outlined earlier on. Indeed, 11β-HSD2 knockout mice have a range of problems, from low birth weight to anxiety-like behaviour. It is possible that 11β-HSD2 might represent a potential target to alter developmental programming in utero.
GnRH (Gonadotrophin Releasing Hormone)
This week we'll be delving into the details for two reproductive hormones: GnRH and kisspeptin! For the purposes of this post, we'll be discussing GnRH.
GnRH neurons are scattered throughout the hypothalamus, with the highest concentration in the preoptic area of the hypothalamus (the preoptic area is near the optic chiasm). Interestingly enough, GnRH neurons actually originated from the olfactory epithelium in the nose before migrating into the hypothalamus. It is thought that neural cell adhesion molecules and cytokines may help influence axonal outgrowth and brain development.
One of the most important cytokines in GnRH neuron development and migration is probably SDF-1. SDF-1 and its receptor, CXCR4, are highly expressed during development in the cerebellum, hippocampus, neocortex and nasal compartment. CXCR4 and/or SDF-1 gene deletions are embryolethal.
GnRH neurons are very unique in their morphology. They have two long, axonal-like projections that go to the median eminence (the network of blood vessels connecting the hypothalamus and anterior pituitary- see here), but a closer inspection of biotin-stained neurons suggests that these axonal-like projections might actually be more dendritic in nature as they have structures known as "dendritic spines." As such, these projections are sometimes called dendrites or "dendrons."
GnRH neuronal "dendrons" are mostly in close apposition to "dendrons" from other GnRH neurons, forming "dendritic bundles." "Dendrons" also share synapses (i.e. they synapse onto the same axon from another neuron). These features help GnRH neurons to communicate with each other, which might help coordinate the pulsatile release of GnRH. "Dendrons" also extend outside the blood-brain barrier into the OVLT, which might help these neurons to obtain input from external stimuli.
As mentioned before, "dendrons" have dendritic spines. Dendritic spines are areas where neurons receive input, and are usually found in areas with GABAergic or glutamatergic transmission. The number of spines can fluctuate- there is a dramatic increase before puberty, and there are also increases in spine density around the time of the GnRH/LH surge in activated neurons.
Welp, that was a short and sweet post. Less typing! Yay!
GnRH neurons are scattered throughout the hypothalamus, with the highest concentration in the preoptic area of the hypothalamus (the preoptic area is near the optic chiasm). Interestingly enough, GnRH neurons actually originated from the olfactory epithelium in the nose before migrating into the hypothalamus. It is thought that neural cell adhesion molecules and cytokines may help influence axonal outgrowth and brain development.
One of the most important cytokines in GnRH neuron development and migration is probably SDF-1. SDF-1 and its receptor, CXCR4, are highly expressed during development in the cerebellum, hippocampus, neocortex and nasal compartment. CXCR4 and/or SDF-1 gene deletions are embryolethal.
GnRH neurons are very unique in their morphology. They have two long, axonal-like projections that go to the median eminence (the network of blood vessels connecting the hypothalamus and anterior pituitary- see here), but a closer inspection of biotin-stained neurons suggests that these axonal-like projections might actually be more dendritic in nature as they have structures known as "dendritic spines." As such, these projections are sometimes called dendrites or "dendrons."
GnRH neuronal "dendrons" are mostly in close apposition to "dendrons" from other GnRH neurons, forming "dendritic bundles." "Dendrons" also share synapses (i.e. they synapse onto the same axon from another neuron). These features help GnRH neurons to communicate with each other, which might help coordinate the pulsatile release of GnRH. "Dendrons" also extend outside the blood-brain barrier into the OVLT, which might help these neurons to obtain input from external stimuli.
As mentioned before, "dendrons" have dendritic spines. Dendritic spines are areas where neurons receive input, and are usually found in areas with GABAergic or glutamatergic transmission. The number of spines can fluctuate- there is a dramatic increase before puberty, and there are also increases in spine density around the time of the GnRH/LH surge in activated neurons.
Welp, that was a short and sweet post. Less typing! Yay!
Friday, October 6, 2017
Drug Management of Rheumatoid Arthritis
In my last post, I discussed the aetiology and clinical presentation of rheumatoid arthritis, without delving into too many details with regards to treatment. Well, now's the time!
Pathogenesis
The inflammatory process kicks off when a self-reactive T-cell meets its antigen on an antigen-presenting cell, thus activating the T-cell. Activated T-cells can then activate B-cells to produce antibody, and/or activate macrophages to produce prostaglandins and cytokines such as TNFα. Prostaglandins are mainly responsible for pain and swelling, whereas TNFα is responsible for joint tissue damage. Various drugs can target different stages of the inflammatory process.
Methotrexate
Methotrexate (which got a cameo appearance here) is a disease-modifying anti-rheumatoid drug (DMARD) that targets T-cell proliferation. It does this by blocking dihydrofolate reductase (DHFR), which catalyses the conversion of folate into dihydrofolate, and dihydrofolate into tetrahydrofolate. As folate is important in nucleic acid synthesis (as described here), blocking folate regeneration can block T-cell proliferation.
TNFα antagonists
The two main types of TNFα antagonists are anti-TNFα antibodies and soluble TNFα receptors. Both types of antagonists bind to TNFα, preventing it from binding to its receptor.
Since humans can't produce antibodies against their own TNFα, antibodies are produced in other animals, such as mice. The problem is, mice antibodies are viewed as foreign by humans (which is why serum sickness is a thing). Hence, genetic engineering techniques have been made in order to make them more human. Infliximab is an anti-TNFα antibody that has a mixture of human and mouse sequences, whereas adalimumab has a completely humanised sequence. The "lim" in "adalimumab" indicates that the antibody targets a part of the immune system (in this case TNFα).
Glucocorticoids
See previous post: Drugs for asthma. Prednisolone is the most common glucocorticoid used in RA treatment. Since systemic glucocorticoids can have adverse metabolic and CVS effects, inflammatory arthritis is generally treated with local intra-articular injections.
NSAIDs and coxibs
See previous post: Analgesics
Treatment
Usually the first drug of choice is either methotrexate or leflunomide. Low-dose systemic glucocorticoids may also be used. The next drug to be added is usually hydroxychloroquine or sulfasalazine (they haven't been discussed in this blog post since it's still not 100% clear how they work). Next up is a biological agent such as TNFα. Throughout the course of the disease, NSAIDs might be used for analgesia and some anti-inflammatory action, though they do not slow the progression of the disease.
There are also several non-drug treatments for RA. These include joint protection with splints, management of cardiovascular risk and other kinds of support (e.g. assistance with tasks and psychological support).
Pathogenesis
The inflammatory process kicks off when a self-reactive T-cell meets its antigen on an antigen-presenting cell, thus activating the T-cell. Activated T-cells can then activate B-cells to produce antibody, and/or activate macrophages to produce prostaglandins and cytokines such as TNFα. Prostaglandins are mainly responsible for pain and swelling, whereas TNFα is responsible for joint tissue damage. Various drugs can target different stages of the inflammatory process.
Methotrexate
Methotrexate (which got a cameo appearance here) is a disease-modifying anti-rheumatoid drug (DMARD) that targets T-cell proliferation. It does this by blocking dihydrofolate reductase (DHFR), which catalyses the conversion of folate into dihydrofolate, and dihydrofolate into tetrahydrofolate. As folate is important in nucleic acid synthesis (as described here), blocking folate regeneration can block T-cell proliferation.
TNFα antagonists
The two main types of TNFα antagonists are anti-TNFα antibodies and soluble TNFα receptors. Both types of antagonists bind to TNFα, preventing it from binding to its receptor.
Since humans can't produce antibodies against their own TNFα, antibodies are produced in other animals, such as mice. The problem is, mice antibodies are viewed as foreign by humans (which is why serum sickness is a thing). Hence, genetic engineering techniques have been made in order to make them more human. Infliximab is an anti-TNFα antibody that has a mixture of human and mouse sequences, whereas adalimumab has a completely humanised sequence. The "lim" in "adalimumab" indicates that the antibody targets a part of the immune system (in this case TNFα).
Glucocorticoids
See previous post: Drugs for asthma. Prednisolone is the most common glucocorticoid used in RA treatment. Since systemic glucocorticoids can have adverse metabolic and CVS effects, inflammatory arthritis is generally treated with local intra-articular injections.
NSAIDs and coxibs
See previous post: Analgesics
Treatment
Usually the first drug of choice is either methotrexate or leflunomide. Low-dose systemic glucocorticoids may also be used. The next drug to be added is usually hydroxychloroquine or sulfasalazine (they haven't been discussed in this blog post since it's still not 100% clear how they work). Next up is a biological agent such as TNFα. Throughout the course of the disease, NSAIDs might be used for analgesia and some anti-inflammatory action, though they do not slow the progression of the disease.
There are also several non-drug treatments for RA. These include joint protection with splints, management of cardiovascular risk and other kinds of support (e.g. assistance with tasks and psychological support).
Subscribe to:
Posts (Atom)