Several skin diseases are caused by POMC peptides. Research studies indicate that skin diseases like severe atopic dermatitis, psoriasis, scarring alopecia, and inflammatory keloids are on account of the abnormal expression of these peptides. It was also established that nodular-type, metastatic melanomas and basal cell carcinoma occur due to abnormal expressions of POMC peptides (Slomanski, Wortsman, Mazurkiewicz, Matsuoka, Dietrich, & Lawrence, 1993).
Alaluf et al. showed that variation in skin pigmentation is chiefly on account of biological pigments in the skin tissues, though there are several other factors that can regulate the process of melanogenesis in the melanocyte – namely, cytokines and hormones. Research on pigmentation has principally concentrated on α – melanocyte peptides, which originate from the POMC, that stimulate α – MSH and the relevant adrenocorticotrophic hormone or ACTH (Alaluf, Barrett, Blount, & Carter, 2003, P36). Likewise, cortocotropins play a major role in the pathobiology and physiology of skin. Corticotropin-releasing hormone stimulates pituitary secretion and, as such, acts as a crucial mediator in the neuro-immunoendocrine axis. It also engenders degranulation of the skin mast cells, thereby enhancing vascular permeability. All the same, it serves as an anti-inflammatory agent when skin is thermally injured (Zbytek, Pfeffer, & Slominski, 2004). Moreover, the vasoactive intestinal peptide is well known for its neuro-immunomodualation function. This peptide, which is similar to cytokine, is characterised by wide ranging anti-inflammatory properties in humans (Gonzalez-Rey & Delgado, October 27, 2005).
POMC peptides are expressed by adnexal epithelial cells, Langerhans cells, mast cells, and the macrophages and monocytes (which constitute immune cells). In this was, hair follicles provide a wide array of intermediaries (Ito, et al., 2005).
An example of such mediators is β-endorphin, which is intimately associated with a number of pathophysiological and physiological skin conditions (Slominski A. , Beta-endorphin/mu-opiate receptor system in the skin, 2003). This mediator’s stimulation in human keratinocytes can be brought about by employing UV radiation to activate the μ-opioid receptors (Kauser, Schallreuter, Thody, Gummer, & Tobin, 2003). β-endorphin has also been found to be an active agent in pain reduction. The process involves the activation of endothelin-B receptor and the related rectifying potassium channels on afferent neurons (Khodorova, et al., 2003); for example, it effects acne (Zouboulis & Bohm, 2004) and is assumed to be a cause of atopic dermatitis (though there is no direct evidence to this) (Bigliardi, Buchner, Rufli, & Bigliardi-Qi, 2002).
Furthermore, Farooqui et al., examined POMC and ACTH expression in some dendritic cells. They conducted a Northern blot analysis, employing a 30 – mer oligonucleotide probe in dendritic cells. Their analysis disclosed the presence of messenger RNA transcripts that resembled that of POMC. On the basis of this research, the authors believe that POMC epidermal presence and synthesis is directly related to several mucocutaneous disorders (Farooqui, Medrano, Boissy, Tigelaar, & Nordlund, 2006).
The POMC gene engenders the encoding of a polypeptide hormone precursor. The latter utilises prohormone convertases in order to exhibit widespread post-translational processing; the gene undergoes cleavage during such processing and the resulting peptides affect, among other things, pain, energy homeostasis, and immunity modulation (proopiomelanocortin, 2009).
Gendelman and Ikezu have stated that immune function modification is possible only for α-MSH; to date, however, such functionality has not been shown with β-MSH and γ-MSH actuated receptors (Gendelman & Ikezu, Neuroimmune Pharmacology, 2008. P 485). Thus, α-MSH apparently has exclusive control over immune functions. In addition, Luger et al. established that α-MSH diminishes inflammation and reduces the severity of the effect of proinflammatory cytokines and molecules (Luger, Scholzen, Brzoska, & Bohm, 2003), due in part to NFκB activity; this is because B-cell antibody production increases and decreases in response α-MSH concentrations. In 2006, Manna et al. conducted also noted α-MSH’s anti-inflammatory properties, through research regarding IL-8 regulation (Manna, Sarkar, & Sreenivasan, 2006). From this research, it is also reasonable to assume that α-MSH possesses biphasic abilities.
POMC peptides, initially recognised as neurohormones in the pituitary gland, were subsequently found to originate in several of the extra-neural body tissues. (Slomanski, Wortsman, Mazurkiewicz, Matsuoka, Dietrich, & Lawrence, 1993) Research studies have shown that the epidermal keratinocytes in humans express MC 1R variants. In addition, subsequent work has indicated that there are a number of stimuli, which have the capacity to increase POMC expression in keratinocytes. In the epidermis cells, the stimuli for POMC mRNA and expression for peptides increases on exposure to UVR (Schiller, et al., February 2004, P 469). As expected, POMC peptides are present in a number of body tissues.
Bicknell states in a review that a mere three decades ago, POMC was conclusively identified. In addition to the pituitary gland, the compound is expressed in the skin, placenta, and central nervous tissue Subsequent to synthesis, the POMC experiences widespread processing that produces several peptides, which are biologically active. The production of these peptides is in combinations that depend on the tissue in which the process takes place (Bicknell, June 2008). In addition, Coll et al. have identified an array of biologically active peptides derived from POMC; in order to generate these peptides, the compound undergoes an extensive posttranslational process. Previously, the most well-known role of these peptides had related to the regulating of adrenal steroidogenesis that is controlled by ACTH of corticotroph origin and pigmentation of the skin by α-MSH. Subsequent research has shown that peptides derived from the POMC,
which are synthesised in the neurons of the hypothalamus, are crucial in energy homeostasis control (Coll, Farooqi, Challis, Yeo, & O'Rahilly, 2004, P 2557-2562). Thus, Coll et al. have stated that POMC peptides are indispensable in controlling metabolic equilibrium.
In a 2008 article, Clement et al. described the five peptides derived from POMC; of these, the two most important are ACTH (produced in the anterior pituitary gland) and α-MSH (produced in the hypothalamus). The study also discovered that POMC gene nullification creates a pleiotropic syndrome that changes pigmentation of the hair and skin, and promotes severe obesity and secondary hypocortisolism. They even recommend that patients suffering from a combination obesity/early-onset adrenal insufficiency should be tested for POMC abnormalities, even if the skin and hair pigmentation depict no abnormalities (Clement, et al., December 2008).
Creemers et al. suggested that these mutations impair POMC’s ability to generate bioactive products. Specifically, mutations affect the trafficking pathway because the compound mutates in its N-terminal sequence (Creemers, et al., Nov 2008, Pp 4494-4499). As such, Valverde et al. emphasised the direct association between the MC 1R gene derivatives, red hair, and reduced skin-tanning ability (Valverde, Healy, Jackson, Rees, & Thody, 1995). Furthermore, the MCI receptor has been shown to be responsible for melanoma, basal cell carcinoma, and squamous cell carcinoma diseases.
In, Suzuki et al., have stated that the Agouti Signalling Protein or ASIP inhibits the combination process of a-MSH and MC1 receptor. This results in the inhibition of melanogenesis (Suzuki, Tada, Ollmann, Barsh, Im, & Lamoreux, 1997).
It was established that the process of polymorphism in the ASIP gene at position 8818 is directly associated with human pigmentation and that it produces dark hair and brown eyes among humans (Kanetsky, Swoyer, Panossian, Holmes, Guerry, & Rebbeck, 2002). However, the role of Agouti related protein or AGRP in human pigmentation is unclear. All the same, researchers are of the opinion that as the AGRP hinders the binding of α-MSH to MC receptors; as such, it is potentially associated with human pigmentation (Yang, Thompson, Dickinson, Wilkin, Barsh, & Kens, 1999). In addition, several studies have established the presence of ACTH, α – MSH, β – MSH and β – endorphin peptides in the melanosome of melanocytes pertaining to the epidermis and hair follicles. Interestingly, POMC processing machinery, in its entirety (the PC1 and PC2 prohormone convertases and the regulatory protein 7B2) are also isolated inside these melanocytes (Spencer, Chavan, Marles, Kauser, Rokos, & Schallreuter, 2005).
The Importance of POMC-derived Peptides
The POMC products play an important role in several ways. These peptides, whether produced systemically (like ACTH in humans) or locally (like α–MSH) behave as important cutaneous mediators. For example, the MC 1R receptor is believed to be the mediator for the hormones of α–MSH and ACTH. On the other hand, the MC 5R receptor regulates the activity of the sebaceous gland. Still, other products, like c-MSH and β–endorphin have undefined (as of now) roles in the skin, seemingly substituting the affects of α–MSH and ACTH (Millington G. , May 2006, P 407-412). Finally, research has shown that, together, these POMC products act as the principal controllers of the hair follicle pigmentation (Kauser, Thody, Schallreuter, Gummer, & Tobin, Beta-endorphin as a regulator of human hair follicle melanocyte biology, 2004).
The immune cells expression is via α-MSH, whose actions are through the MC-1R or meleanocortin-1 receptors. Moreover, the β-MSH and γ-MSH, which act via other melanocortin receptors, have not been located in the immune cells. Hence, it can be safely concluded that immune function regulation is the sole preserve of the α-MSH (Gendelman & Ikezu, 2008. P. 485). In 2003, Luger et al. showed that α–MSH has the capacity to transform the function of the immune system in addition to making changes to skin (Luger, Scholzen, Brzoska, & Bohm, 2003). They also established that α-MSH diminishes inflammation and reduces the severity of the effect of proinflammatory cytokines and molecules (Luger, Scholzen, Brzoska, & Bohm, 2003).
The inhibition of the NFκB activity is thought to be partially responsible for the aforementioned effects. In addition, it can be surmised that α-MSH possesses biphasic effects. This is on account of the fact that B-cell antibody production registers an increase or decrease, corresponding to the low or high concentration of α-MSH. However, in 2006, Manna et al. conducted research on IL-8 regulation and concluded that α-MSH acts as an anti-inflammatory (Manna, Sarkar, & Sreenivasan, 2006). To show this, the team used liquid chromatography and mass spectroscopy, in order to identify ACTH and α-MSH in cutaneous extracts. However, the desired information on epidermal cell types was not forthcoming, on account of the fact that these peptides were also secreted by the dermal fibroblasts (Rousseau, et al., 2006).
POMC and Pigmentation
Proopiomelanocortin is the forerunner of melanocortins. Melanocytes and keratinocytes in skin tissues synthesise Proopiomelanocortin. This indicates that these melanocortins behave as paracrine or autocrine factors for melanocytes (Kadekaro & Abdel-Malek, 2007, P150). The cutaneous POMC gene’s molecular characterisations generate forms of mRNA that resemble the mRNA forms in the pituitary. The skin expressions of the POMC peptide receptors are functional in nature. Some of these receptors are MC1R, MC5R, and µ-opiate. The peptides belonging to the MC1R class are found to be more predominant than the other classes. POMC and CRH peptides cause pigmentation of the skin (Slominski, Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ). They affect the immune and adnexal systems; these systems are responsible for stress by acting as neutralising agents in the maintenance of skin integrity. Moreover, such activity is in consonance with stress neutralising activity that curtails disruptions to internal homeostasis. The cutaneous expression of the CRH/POMC system is highly integrated with mediators and receptors. It is analogous to the hypothalamic, pituitary, adrenal, or HPA axis (Slominski, Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ). Furthermore, the skin system of POMC and CRH seems to produce a function, which appears to be the similar to the HPA axis; specifically, both systems neutralise harmful stimuli and other accompanying immune reactions (Slominski, Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ). Human skin contains the POMC processing mechanisms (Slominski & Wortsman, 2000). The colour of the human skin is regulated by peptides that are derived from POMC (Slominski, Tobin, Shibahara, & Wortsman, 2004). The location of POMC processing is also predominantly in one’s skin and hair, since the necessary mechanisms to enable this process are found there.
Melanogenesis is regulated by the skin POMC peptides; α–MSH peptides and MC 1 receptors. The vehicle for these peptides is the cAMP pathway. The research done recently in this field reveals that other factors including β – endorphin and µ - opiate receptors are also responsible for the regulation of the melanogenesis process and for the formation of melanin in human skin cells (Spencer, Chavan, Marles, Kauser, Rokos, & Schallreuter, 2005, P 293).
Human skin contains the POMC processing mechanisms (Slominski & Wortsman, 2000). The colour of the human skin is regulated by peptides that are derived from POMC (Slominski, Tobin, Shibahara, & Wortsman, 2004).
A number of research studies have indicated that the human skin responds to the tanning process via mRNA levels; genes are regulated by the melanocortin peptides derived from the POMC, where these peptides (like α-MSH and ACTH) play a key role in the transcriptional regulation at the gene level (Suzuki, Kato, Motokawa, Tomita, Nakamura, & Katagiri, January 2002, P 77). Research has also established that the skin and hair follicles are local sources for peptides derived from POMC. Furthermore, the skin and hair follicles serve as major sources of ACTH, α–MSH, β–MSH and β–endorphin. It was detected quite recently that β–endorphin can also bring about skin pigmentation and proliferation; this is accomplished through use of the μ–opiate receptor of epidermis and hair follicle melanocytes . In addition, the β – endorphin peptide alters cell dendricity (Kauser, Thody, Schallreuter, Gummer, & Tobin, 2005).
The human skin mast cells express POMC protein and gene and serve as proof for the additional processing of the α–MSH secretory molecule. The level of intracellular content of α–MSH is reduced appreciably on adding the anti-IgE antibody molecules. At the same time, such addition increases the level of extracellular presence of α–MSH, which signifies the secretion of neuropeptides due to IgE intervention (Slominski A. T., Sep 2006, P 1934 - 1936).
Slominski et al. (2004) contend that skin integrity is the outcome of the POMC’s efficient organisation. In conjunction with the distinctive connections between signal transduction systems and the encoding mediators and receptors, the cutaneous POMC system curtails stress related disturbances to internal homeostasis, which has latent effect on global homeostasis (Slominski, Tobin, Shibahara, & Wortsman, 2004).
POMC and Pathology
Neuropeptides are inflammation inhibitors also act as immunosuppressants by producing contra-effects during tumorigenesis. Some of these neuropeptides are corticotrophin, α–melanocyte (a stimulating hormone), α–MSH, and β–endorphin. It is important to note that POMC helps reduce melanoma activity; as such, the POMC gene delivery occurs via the α–MSH induced inhibition of the NFκB/COX-2 pathway. This provides an innovative cure for melanoma (Liu, et al., 2006, P 440).
It has been established that the Ultra Violet B radiation induces Melanogenesis that is amenable to partial mediation, brought about by MC receptor upregulation. Moreover, in both the production of receptors and peptides and in the expression of POMC; Ultra Violet Radiation constitutes a cardinal determinant (Chakraborty, et al., October 1999).
In 2006, Kim et al. investigated the effect of the corticotropin releasing POMC axis in different types of skin tumours. They found that CRH, ACTH, and α-MSH exhibited strong expression the cell lines of malignant tumours (Kim, et al., November 2006). Thus, this axis related hormones are of significance in the malignancy of skin tumours. POMC gene transcription and translation, accompanied by the production of ACTH by means of cAMP dependent pathways, is brought about by the stimulation generated by ex vivo CRF in hair follicles, dermal fibroblasts, and melanocytes of the epidermis. CRF1 activation was essential in determining the temporal and dose dependency of such activation. Furthermore, the CRF stimulates the MSH and its POMC precursor’s extracellular release, in addition to the stimulation of the production of α-MSH; they enact the role of melanocyte differentiation programme regulators. Likewise, the expression of CRF and POMC can be inhibited in the human skin on account of glucucorticoids and some growth factors (Slominski, Wortsman, Paus, Elias, Tobin, & Fenigold, 2008).
Moreover, Hyperpigmentation had been noticed in patients with Addison’s disease and Nelson’s syndrome where excess concentrations of POMC had been detected. In addition, POMC peptides have been found to stimulate melanogenesis and melanocyte tyrosinase in humans. The estimation of cutaneous POMC, in relation to ACTH and α-MSH, has proved to be a daunting task (if recourse is taken only in the form of immunochemistry) (Rousseau, et al., 2006). This difficulty arises because ACTH and α-MSH antibodies are not specific and, therefore, unable to detect the exact extent of POMC presence. Another difficulty is occasioned by the inability to test the cross-reactivity of many antibodies with POMC because of the difficulty inherent in procuring purified or synthesised POMC (Rousseau, et al., 2006).
Mutations of the POMC gene are very important in skin and hair pigmentation. These mutations cause red hair, pale skin, early-onset obesity, and adrenal insufficiency. Specific to pigmentation, ACTH and α-MSH produced eumelanin bring about darker skin colours; in addition, hyperpigmentation is a result of ACTH presence for prolonged intervals of time (Rousseau, et al., 2006).
The POMC gene, which is expressed in the skin, requires MSH peptide processing. In effect, skin pigmentation is controlled by these peptides.
In addition to the pituitary gland, POMC is expressed in the skin, placenta, and central nervous tissue. The peptides derived from the POMC are truly versatile; their functions range from skin and hair pigmentation to food ingestion (specifically, how much as absorbed). It is also the source of a number of skin diseases.
Disorders like psoriasis, atopic dermatitis, scarring alopecia, and inflammatory keloids are caused by the abnormal expression of POMC derived peptides. The various peptide functions in the cutaneous cells are principally those that relate to immune activity, melanin pigmentation, hair follicles, sebaceous glands and secretory activities. The location of these compounds in the body varies; however, they are concentrated in hair and skin cells. Keratinocytes, which constitute the principal cell type, are the main source of POMC peptides. Melanocortin signalling is chiefly brought about by the POMC peptides and its cutaneous processing.
The expression of the relevant receptors and the POMC system’s stimulation is engendered by Ultra Violet Radiation. Skin integrity is preserved by the POMC mechanism, which controls the immune, pigmentary, and other defence systems of the skin; however, local epidermal paracrine and autocrine effects are affected by POMC gene mutations that, themselves, are affected by UV radiation.
Melanocortin systems, a collection of which are extremely effective in responding to internal as well as external stress syndromes. Some of the mechanisms through which the skin controls these stress syndromes are local pigmentation of the skin, vascular systems and immune structures. Modifications in the POMC results in the red hair phenotype; as such, the phenotypes of skin and hair are determined by the levels of melanocortin components in the skin. As such, it can be surmised that the POMC derived peptides enact multifarious biological roles that have a significant effect of cell functions, especially in the context of cell pigmentation.
The POMC peptides derived from keratinocytes are very effective in causing melanogenesis in human melanocytes. The MC1R is significant in regulating cutaneous pigmentation. In addition, melanocyte function is controlled by the activation of the melanocortin receptor, and the relevant agonist is the α-MSH. A very important source of the α-MSH is the human skin. Thus, the chief controller of human skin pigmentation is the α-MSH that had been produced locally. Moreover, the α-MSH behaves like an autocrine or paracrine mediator of pigmentation that has been induced by UVR (Tsatmali, Ancans, Yukitake, & Thody, 2000).
POMC peptides obtained from keratinocytes are effectual in engendering melanogenesis in human melanocytes. Pigmentation of the skin is controlled to a great extent by the MC1R. Moreover, locally produced α-MSH has been deemed to be the cardinal controller of the cutaneous pigmentation in humans.
The cutaneous profiling of POMC peptides and its determination by proteolytic processing of POMC are of great significance in melanocortin signalling. In addition, they constitute major controlling factors that govern pigmentation of the skin. Consequently, the manner in which cutaneous processing of the POMC transpires is of great significance in regulation of pigmentation. α-MSH and ACTH peptides constitute the principal moderators of skin pigmentation in humans. These POMC derived peptides actively participate in the controlling of melanogenesis in the human epidermis, dendricity, and proliferation by means of action that transpires at the melanocortin 1 receptor.
Subsequent to the observation and analysis of inactivating mutations of the POMC gene in humans, it was surmised that the POMC peptides were central to the control of pigmentation in human hair. As such, null mutation of the POMC in humans produces sallow skin and the red hair phenotype. It is believed that these results indicate the absence of ligands for melanocortin 1 receptor. Analogously, fair skin and red hair have been correlated to polymorphisms of the melanocortin 1 receptor that diminish MC1R activity. Therefore, it can be concluded that the POMC-derived peptides regulate several physiological functions, including skin pigmentation, inflammation, energy homeostasis, and exocrine secretion.
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Instead of talking about PMOC, you need to focus on the purpose of this paper. The last portion on the abstract should relate your thesis, methodology, and findings.
So far, you’ve not introduced your thesis statement, the purpose of the study, the methodology, or the paper’s structure. The introduction is the place for each of these things. The text that precedes this comment is, instead, better suited for the literature review.
Again, you’ve yet to introduce this term.
Again, I feel as if this paper lacks basic structure. You’ve simply launched into rapid-fire facts; instead, you should have mapped your discussion early in the section.
“This section discusses the properties of POMC peptides. Essentially, they can affect a range of cells, from [insert] to [insert]. Specifically, they are:
Insert – briefly explain why/how
Insert – “ “
Insert – “ “
Then, you should begin a detailed explanation of this outline (i.e. use what you've already written).
Cite this info.
This is out of place; however, I do not know of a better spot, since I don’t really know the purpose of the sentence. It doesn’t seem to directly correspond with anything; rather, it seems to be an afterthought.
Again, this seems as if you’re trying to show that you’ve read articles, as opposed to advancing (forward) a concept. This line just begs more questions, instead of answering any.
Why is it here? How does it contribute to the summation of this paragraph/section?
By neutralising what?
Briefly note what this is, here.
This paragraph was actually an example of how you should be writing.
The first sentence stated a fact that also pertained to the subject of this paragraph. The second backed the first with a fact. The last provided an ancillary fact. Most importantly, the reader knew what would be discussed in the body of the paragraph because the first sentence gave the heads-up.
You were using British spelling before – is this supposed to follow?
This is a better introduction than the one that your currently have. It is straightforward, concise, and flows well. Most importantly, it lays-out the paper’s chief concerns and mirrors its format.
I would suggest that you adapt your Intro (and take notes from your Summary when doing so).
Again, briefly describe this here.
This paragraph does not flow from the last. How did we get here? Why is this one relevant/building upon the last?
Again, you need to provide linking thoughts, so your paper doesn’t seem to jump/be a cobbled jumble of other people’s articles.