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Abdul Kader Mohiuddin, Assistant Professor
Department of Pharmacy, World University of Bangladesh
151/8, Green Road, Dhanmondi, Dhaka – 1205, Bangladesh

Skin is the barrier that segregates the body from the outer environment. Besides protecting the body from water loss and microorganism infection, it has an important cosmetic role. Young and beautiful appearance may have a positive influence on people’s social behavior and reproductive status. Cleopatra, the Egyptian queen is said to have indulged in daily donkey-milk baths, a practice which apparently required over 700 donkeys to accomplish. The alpha hydroxy acids in the milk is believed to be anti-aging and skin-softening agents. Tang-dynasty ruler and sole female emperor of China, Wu Zetian, maintained a lifelong interest in skincare formulas. She mixed her “fairy powder” (made of carefully harvested and prepared Chinese motherwort) with cold water in order to wash her face each morning. The empress was a famed beauty well into her old age. The most hair-raising entrant in this list, 16th century Hungarian countess Elizabeth Báthory is infamous for being one of the world’s first documented female serial killers. Most of her life is shrouded in mystery and legend—the most famous story being that she would regularly bathe in the blood of her female victims. Mary, Queen of Scots, the ill-fated and attractive adversary of Elizabeth I, spent her sixteenth-century happier days on her estate in Edinburgh, Scotland, where her beauty regimen was said to include white-wine baths. In addition to wine’s antiseptic alcohol content, it was also was thought to improve complexion in general. Crème Céleste, a favorite product of empress Elisabeth (Sisi) of Austria, was a concoction of spermaceti (a wax found in the head of sperm whales), sweet almond oil, and rosewater. She would apply this daily and at night, she was known to coat her face in raw veal and crushed strawberries, kept in place with a custom-made leather mask. The skin folds are indicative of an aged personality, but not youthfulness. So, everyone wants to look younger for whole of the life, which lead to the discovery of many surgical and non-surgical treatment modalities to improve the youthfulness. Since the introduction of Botox in 2002 after FDA approval more aesthetic procedures using Botox were performed by aestheticisms involving plastic surgeons and dermatologists. However, many scientists are now starting to view physical aging as a disease process. The cellular and molecular mechanisms involved in aging reveal an intricate series of signals, markers, and pathways, all of which are programmed to monitor and control the lifespan of a cell as it ages. By studying these molecular events and pathways, the field of anti-aging will be furthered by the use of more and more cosmetics.

As the most voluminous organ of the body that is exposed to the outer environment, the skin suffers from both intrinsic and extrinsic aging factors. Skin aging is characterized by features such as wrinkling, loss of elasticity, laxity, and rough-textured appearance. This aging process is accompanied with phenotypic changes in cutaneous cells as well as structural and functional changes in extracellular matrix components such as collagens and elastin. With intrinsic aging, structural changes occur in the skin as a natural consequence of the biological changes over time and produce a certain number of histological, physiological, and biochemical modifications. Intrinsic aging is determined genetically (influence of gender and ethnic group), variable in function of skin site, and also influenced by hormonal changes. Visually it is characterized by fine wrinkles. By comparison, “photoaging” is the term used to describe the changes occurring in the skin, resulting from repetitive exposure to sunlight. The histological, physiological, and biochemical changes in the different layers of the skin are much more drastic. From a mechanical point of view, human skin appears as a layered composite containing the stiff thin cover layer presented by the stratum corneum, below which are the more compliant layers of viable epidermis and dermis and further below the much more compliant adjacent layer of subcutaneous white adipose tissue. Upon exposure to a strain, such a multi-layer system demonstrates structural instabilities in its stiffer layers, which in its simplest form is the wrinkling. These instabilities appear hierarchically when the mechanical strain in the skin exceeds some critical values. Their appearance is mainly dependent on the mismatch in mechanical properties between adjacent skin layers or between the skin and subcutaneous white adipose tissue, on the adhesive strength and thickness ratios between the layers, on their bending and tensile stiffness as well as on the value of the stress existing in single layers. Gradual reduction of elastic fibers in aging significantly reduces the skin’s ability to bend, prompting an up to 4-fold reduction of its stability against wrinkling, thereby explaining the role of these fibers in skin aging. Anti-aging medicine is practiced by physicians, scientists, and researchers dedicated to the belief that the process of physical aging in humans can be slowed, stopped, or even reversed through existing medical and scientific interventions. This specialty of medicine is based on the very early detection and prevention of age-related diseases. Physicians practicing anti-aging medicine seek to enhance the quality of life as well as its length, limiting the period of illness and disability toward the end of one’s life. Anti-aging medicine encompasses lifestyle changes (diet and exercise); hormone replacement therapies, as needed, determined by a physician through blood testing (DHEA, melatonin, thyroid, human growth hormone, estrogen, testosterone); antioxidants and vitamin supplements; and testing protocols that can measure not only hormone levels and blood chemistry but every metabolic factor right down to the cellular level.

Reference Id: PHARMATUTOR-ART-2675

Evergreen Monica Bellucci

Figure 1. Evergreen Monica Bellucci (Goenka, 2017;Monica Bellucci Beauty Secrets) . One of the hottest Italian beauties, although she is 54 years old, starts taking a cold shower to the day. Cold shower, the skin maintains the elasticity and argues that tightens. She uses thermal water and revitalizing spray for her face. The actress is totally against all sorts of plastic surgery, but don’t forget to constantly clean and moisturize the skin. She says, noting that eating and drinking can be anything, the main thing in small amounts and never blame themselves for the food. She never denied that sport is important for health and toned figure. Drinking plenty of water is another good thing that Bellucci follows as her regular activities.

Skin aging is a complex biological process influenced by a combination of endogenous or intrinsic and exogenous or extrinsic factors. Because of the fact that skin health and beauty is considered one of the principal factors representing overall “well-being” and the perception of “health” in humans, several anti-aging strategies have been developed during the last years. In contrast to thin and atrophic, finely wrinkled and dry intrinsically aged skin, premature photoaged skin typically shows a thickened epidermis, mottled discoloration, deep wrinkles, laxity, dullness and roughness. Gradual loss of skin elasticity leads to the phenomenon of sagging. Slowing of the epidermal turnover rate and cell cycle lengthening coincides with a slower wound healing and less effective desquamation in older adults. This fact is important when esthetic procedures are scheduled. On the other side, many of these features are targets to product application or procedures to accelerate the cell cycle, in the belief that a faster turnover rate will yield improvement in skin appearance and will speed wound healing. A marked loss of fibrillin-positive structures as well as a reduced content of collagen type VII (Col-7), may contribute to wrinkles by weakening the bond between dermis and epidermis of extrinsically age skin. Sun-exposed aged skin is characterized by the solar elastosis. The sparse distribution and decrease in collagen content in photoaged skin can be due to increased collagen degradation by various matrix metalloproteinases, serine, and other proteases irrespective of the same collagen production. The overall collagen content per unit area of the skin surface is known to decline approximately 1%/year. Glycosaminoglycans (GAGs) are among the primary dermal skin matrix constituents assisting in binding water. In photo-aged skin, GAGs may be associated with abnormal elastotic material and thus be unable to function effectively. The total hyaluronic acid (HA) level in the dermis of skin that age intrinsically remains stable; however, epidermal HA diminishes markedly. Decreased estrogen levels may play a role in skin aging in women and compounds stimulating estrogen receptors could potentially counteract some of the visible signs of aging. As people live longer, women spend a larger portion of their lives in a post-menopausal state, with a deficiency of estrogen as compared to their younger selves. Changes in diet and increasing exercise, together with a regimen of antioxidants, nutritional supplements, and growth factors, can alter how the genes express themselves. Both factors can greatly enhance the healing capability of the skin and can improve the results of cosmetic surgeries.

Desired effect of anti-aging treatment

Figure 2. Desired effect of anti-aging treatment (Ganceviciene, 2012; Posição da FEBRASGO, 2018) The desired therapeutic anti-aging effect of the skin is continuous, step-by step process, which combines various methods of the skin bio-revitalization and rejuvenation, augmentation, restoration of each skin layer individually and in the light of many other factors—from a style of the life to the immune, genetic, emotional and health status in general.

The aging processes
Aging can be viewed as the accumulation of changes in cells and tissues resulting from a greater disorderliness of regulatory mechanisms that result in reduced robustness of the organism to encountered stress and disease. The notion of greater disorderliness in aging is illustrated by the erosion of the orderly neuroendocrine feedback regulation of the secretion of luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) and growth hormone (GH). These changes are manifested as menopause, andropause, adreno-pause, and somato-pause. Skin aging is part of the slow decline in appearance and function that appears to be attributed in large part to the drastic decline of hormones in the body after adulthood. At the cellular level, several processes are involved in the physiology of aging and the development of some age-related diseases. The process of apoptosis signifies the process of nontraumatic and noninflammatory cell death. Dysregulation of apoptosis has been implicated in the increased incidence of cutaneous malignancies that are more prevalent in older individuals, such as basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Cell senescence limits cell divisions in normal somatic cells and may play a central role in age-related diseases. Telomeres are thought to play a role in cellular aging and might contribute to the genetic background of human aging and longevity. It has been speculated that the limited proliferation potential of human cells is a result of the telomere shortening that occurs during DNA synthesis at each cell division. Photoaging may accelerate the shortening of telomeres and push cells into senescence sooner. That could be the reason why various growth factors may affect the speed and quality of wound healing. Biochemical insults also arise within aging cells, in part from the action of reactive oxygen species generated and scavenged incompletely throughout the cell cycle. Aging-associated changes also occur between and among cells via alterations in the intercellular matrix, the intercellular exchange of trophic factors, the release of inflammatory cytokine mediators, and the degree of infiltration by other associated cell types. In addition, the quantity and distribution of various growth factors may affect wound healing. Decline of DNA repair in combination with loss of melanin increases the risk of photo-carcinogenesis and can also cause the decline of enzymatically active melanocytes (10–20% each decade) that contributes to increased sensitivity to UV radiation. However, it is not known why free radical damage does not adversely affect all of the body’s cells (e.g., gonadal germ cells) (Quiroga, 2005).

Schematic representation of pathogenesisFigure 3. Schematic representation of pathogenesis of premature/extrinsic skin aging (Kim, 2016). ROS: reactive oxygen species, AhR: arylhydrocarbon receptor, NF-kB: nuclear factor kappa‐B, IL-1: interleukin‐1, TNF-α: tumor necrosis factor, CCN1: cysteine-rich protein 61, MAPK: mitogen‐activated protein kinase, AP‐1: activator protein 1, and MMPs: matrix metalloproteinases.

Factors involved in skin aging
Skin aging is a complex biological process influenced by combination of endogenous or intrinsic (genetics, cellular metabolism, hormone and metabolic processes) and exogenous or extrinsic (chronic light exposure, pollution, ionizing radiation, chemicals, toxins) factors. These factors lead together to cumulative structural and physiological alterations and progressive changes in each skin layer as well as changes in skin appearance, especially, on the sun-exposed skin areas (Ganceviciene, 2012). Facial skin wrinkles can be considered as a marker for intrinsic aging (See wrinkle classification in Exhibit 1). The major perceived risk factors are unhealthy eating habits, stress, less exercise, dehydration, diseased state and sleeping habits. Though the main factor responsible for extrinsic aging is UVR (Bhatt, 2019). Beyond sun damage factors such as smoking and atmospheric pollution have also been studied and considered in extrinsic aging. Studies have shown a clear correlation between these factors and the appearance of melanosis and wrinkles. Both of these factors contribute to aging through a common mechanism called oxidative stress that has a negative impact on cellular processes, such as DNA replication. In addition to the UV region of solar radiation that contributes to cellular injury, visible radiation has an oxidative effect similar to that of infrared radiation via heat generation. The effects of comorbidities, such as metabolic illnesses common in the elderly, nutritional deficiencies, and the use of drugs such as corticosteroids, and even cancer treatments, should be assessed by dermatologists attending to skin conditions associated with aging (Addor, 2019). Good skin condition can be maintained to some extent by changes in modifiable lifestyle factors such as smoking and sunscreen use (Asakura, 2009). Human skin cells respond to instructions from highly specialized proteins or hormones referred to as growth factors. The growth differentiation factor GDF11, a TGF-β family member, has been associated with the maintenance of youth phenotypes in different human tissues and organs, and in the skin has been related to an inhibition of the inflammatory response. The production of elastin and collagen dermal connective fibers slows, and, with age, the regenerative rates of GAGs become delayed (Tito, 2019; Barone, 2019).

Exhibit 1. Pierard Classification of Wrinkles (Anson, 2016)
• Atrophic wrinkles develop in exposed and non-exposed skin, disappear with skin traction, change in orientation with body posture, and are due to atrophy of the extracellular matrix.
• Elastotic wrinkles develop in sun exposed skin, exhibit solar elastosis, become progressively permanent, and do not disappear with perpendicular traction.
• Expressional wrinkles due to subdermal muscle contraction, become permanent with repeated wrinkling.
• Gravitational wrinkles due to skin sagging in response to gravitational forces and inelasticity.

Chronic repetitive exposure of human skin to solar UV rays causes marked morphological, histological, biochemical, and biophysical changes that are described as photoaging. the clinical signs of photoaging are fine and coarse wrinkles, actinic keratoses, solar elastosis, yellowing, pigmentation disorders and premalignant lesions, skin atrophy, senile purpura, freckles, solar comedones, telangiectasia, laxity, roughness, and extreme dryness (Clarys, 2014). UV damage can also cause significant changes in some of the mechanical properties of the stratum corneum, reducing its cell cohesion and mechanical integrity; the UV radiation also affects the molecular structure of cell proteins and lipids (Addor, 2018). According to Leccia, 2019, at the cellular level DNA damage is the main event following UV exposure. The kind of lesions produced depends on the wavelength and the energy profile of the radiation, with different photoproducts being formed as a result. Although endogenous DNA repair mechanisms are somewhat effective in repairing DNA, some DNA damage persists and can accumulate with chronic exposure. Through ROS formation, UVB induces activator protein-1 (AP-1) overexpression along with the upregulation of collagen-degrading enzymes like matrix metalloproteinases (MMPs) (Figure 4). Overall, UVB stimulates collagen degradation and inhibits procollagen biosynthesis resulting in loss of collagen content and wrinkle formation, thus inducing skin photoaging, as reported by Karapetsas, 2019. Sun damage also creates a state of chronic inflammation, with the release of proteolytic enzymes by the inflammatory system, disrupting the dermal matrix (Clarys, 2014). UV protection strategies, such as sunscreen use, are important in limiting further DNA damage (Leccia, 2019). Exposure to UV radiation is the primary factor of extrinsic skin aging; it accounts for about 80% of facial aging (Zhang, 2018).

mechanism of inflammaging in skin

Figure 4. A model proposed to explain the mechanism of inflammaging in skin (Zhang, 2018). (A) UV radiation induces oxidative stress in epidermal cells, resulting in damaged cells with oxidized lipids. Oxidation-specific epitopes on damaged cells and oxidized lipids activate complement systems and cause inflammation, leading to infiltration and activation of macrophages. Activated macrophages release MMPs to degrade extracellular matrix. (B) Repeated UV radiation over-activates the complement system, causing damage to the dermis–epidermis junction, on which they deposit, and macrophages are overburdened with oxidized lipids. Overburdened macrophages release proinflammatory cytokines and ROS, the former of which cause chronic inflammation and long-term damage to the dermis, while the latter triggers the oxidative stress-induced damages to the dermal extracellular matrix.

Effects of UVR on the Dermal white adipose tissue (dWAT) in vitro: UVR can significantly modulate sWAT metabolism. This effect is observable not only in chronically sun-damaged human skin, but even after a single UV exposure of a non-damaged skin. Free fatty acid and triglyceride content in sWAT of sun-exposed skin (forearm) is significantly lower than in the buttocks (sun-protected area) of the same subjects. At the same time, young subjects did not demonstrate such differences, which points to the UV-induced effect and not just to the regional variations in fat metabolism. Additionally, both chronic and single UVR exposure significantly reduces master adipogenic factors such as peroxisome proliferator-activated receptor γ (PPARγ); this reduction was rapid and remained stable for at least 72 h after acute UVR exposure. From this point of view dWAT content correlates with a much more pronounced extrinsic aging process in the dorsal hand comparing to the palm area. Chronological skin aging demonstrates similar but not as pronounced differences in aging processes in palmar and dorsal regions of the hand. This can be an indication that UVR accelerates the processes of skin aging, whereas their basic components are determined by some other factors, one of which could be the local dWAT content. This can make skin aging not only body area dependent, but also spatially heterogeneous in the same body area, since dWAT can have a spatially heterogeneous structure (Kruglikov, 2016).



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