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Ehlers–Danlos syndrome spondylodysplastic type 3 is caused by impaired collagen production due to ZIP13 dysfunction. (a) ZIP13 supplies zinc (brown circle) to SMAD proteins for their nuclear translocation. Phosphorylatoin is depicted as circled P. (b) The elder affected sib is shown at age 22 years. Patient exhibits short stature with mildly shortened trunk, antimongoloid eye slant with lack of periorbital tissue, thin and finely wrinkled skin on the palms of the hands. BMPR/TGFβR, BMP receptor/TGF-β receptor; Col, collagen. Modified from Fukada et al. [38].
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The first manifestations that appear under zinc deficiency are skin defects such as dermatitis, alopecia, acne, eczema, dry, and scaling skin. Several genetic disorders including acrodermatitis enteropathica (also known as Danbolt-Closs syndrome) and Brandt's syndrome are highly related to zinc deficiency. However, the zinc-related molecular mechan...
Citations
... It occurs due to mutation in SLC39A4 gene located on chromosome 8q24.3 and is expressed in duodenum and jejunum which carries trans membrane proteins essential for zinc absorption (Zip4) [37] . ...
... Proper absorption of zinc occurs in the small intestine firstly in the jejunum by the zinc transporting protein ZIP4. So, mutation in gene carrying this protein can affect intestinal absorption of zinc causing zinc deficiency [37] . ...
... Zinc homeostasis is maintained by a balance in the expression of two kinds of zinc ion transporters. The SLC39 family, also known as the Zip family, can import zinc ions into the cytoplasm, and the SLC30 family (known as the Znt family) functions as a zinc exporter [65]. LPS stimulation in DCs altered the expression patterns of zinc transporters and thereby decreased intracellular zinc levels. ...
Dendritic cells (DCs) are specialized antigen‐presenting cells (APCs) that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.
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... Participates in the activation of immune cells Increases susceptibility (211,212) Vitamin C may protect humans from SARS-CoV-2 by limiting viral entry into human small alveolar epithelial cells, stimulating oxygen free radical scavenging activity in the skin, and improving epithelial barrier function (204,205). Vitamin B12 can suppress the NSP12 polymerase activity of SARS-CoV-2 (208). ...
... Zinc supplementation has been reported to reduce infection, while its deficiency lead to humoral and cell-mediated immune dysfunction and increase susceptibility (209,213). Iron is an important component of enzymes involved in immune cell activation, and its deficiency cause increased susceptibility to infection, especially with intracellular pathogens (211,212). ...
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others are still associated with severe and even fatal clinical outcomes. Innate and adaptive immunity are important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization of the innate and adaptive immune response to COVID-19 is still lacking and the mechanisms underlying immune pathogenesis and host predisposing factors are still a matter of scientific debate. Here, the specific functions and kinetics of innate and adaptive immunity involved in SARS-CoV-2 recognition and resultant pathogenesis are discussed, as well as their immune memory for vaccinations, viral-mediated immune evasion, and the current and future immunotherapeutic agents. We also highlight host factors that contribute to infection, which may deepen the understanding of viral pathogenesis and help identify targeted therapies that attenuate severe disease and infection.
... Skin is the third most zinc-abundant tissue in our body (skeletal muscle 60%, bones 30%, liver 5%, and skin 5%) [13]. It is involved in epidermal keratinocyte differentiation and growth as well as in antiin ammatory processes and wound healing [14] and is crucial for epidermal stem cells [15]. Knowing its roles, it's clear that a zinc de ciency can cause various clinical manifestations, which can involve every organ and system. ...
Background: Acrodermatitis enteropathica is a rare disorder characterized by the triad composed by dermatitis, alopecia and diarrhoea. Its acquired form can be caused by inadequate zinc intake, malabsorptive processes, excessive renal or intestinal loss. A rare cause of acquired zinc deficiency is iatrogenic nutritional deficiency due to parenteral nutrition.
The diagnosis can be really difficult because the early clinical signs are non-specific and patient’s eventual comorbidities can often mask symptoms.
Case presentation: A 5-years-old child affected by several comorbidities, consequent to C. Koserimeningo-encephalitis occurred in the neonatal period, was admitted to Pediatric ward for acute pancreatitis and he had been fed via total parenteral nutrition for one month. Symptoms started approximately 15 days after the start of a standardised standardized parenteral nutrition mixture. The child presented with diarrhoea, alopecia and erythematous bullous skin lesions, distributed predominantly in acral and periorificial sites and not responsive to topical treatments. Zinc serum dosage were very low (10 µg/dL, with normal values 68-107 µg/dL). Clinical improvement was very fast after oral zinc supplementation (5mg/daily), with a rapid regularisation in the intestinal habits and re‐epithelialization of the skin lesions.
Conclusion: Trace elements are an essential component of parenteral nutrition. The supplementation of trace elements is a complex and important part of the parenteral nutrition prescription. Even few days of zinc shortage, especially in frail patients, may cause a severe dermatitis that can be easily prevented. Despite its rarity, acrodermatitis enteropathica should be strongly considered in the differential diagnosis of skin lesions for these patients.
... A study suggested that ZIP transporters act as a zinc-selective channel that transports zinc ions into the cytoplasm based on zinc concentration gradients [75]. ZIP family was found to be directly involved in maintaining skin homeostasis [76]. In the epidermis, ZIP1, ZIP2, ZIP4, and ZIP10 are linked to epidermal morphogenesis and abnormalities [23,[77][78][79], whereas ZIP7 and ZIP13 are required for normal dermal development and collagen metabolism [80]. ...
... In the epidermis, ZIP1, ZIP2, ZIP4, and ZIP10 are linked to epidermal morphogenesis and abnormalities [23,[77][78][79], whereas ZIP7 and ZIP13 are required for normal dermal development and collagen metabolism [80]. Although zinc transporters play a major role in maintaining cellular homeostasis, metallothioneins (MT) accumulating in the epidermal layer, binding heavy metal ions such as zinc are found to be associated with increased zinc concentrations in the tissues which implies the significance of not only ZIP but also MTs in maintaining high concentrations of zinc required for normal proliferation and differentiation of the epidermis [76,81]. Acrodermatitis enteropathica (AE) is a zinc metabolism disorder that can be inherited or acquired, and it is caused by dysfunction of ZIP4 protein leading to impaired zinc absorption [82]. ...
... ZIP2 aids in the differentiation of keratinocytes in the epidermis and the knock-down of ZIP2 leads to immortalizing human keratinocytes and inhibiting their differentiation [23] (Figure 2). metallothioneins (MT) accumulating in the epidermal layer, binding heavy metal ions such as zinc are found to be associated with increased zinc concentrations in the tissues which implies the significance of not only ZIP but also MTs in maintaining high concentrations of zinc required for normal proliferation and differentiation of the epidermis [76,81]. Acrodermatitis enteropathica (AE) is a zinc metabolism disorder that can be inherited or acquired, and it is caused by dysfunction of ZIP4 protein leading to impaired zinc absorption [82]. ...
Zinc is an important trace mineral in the human body and a daily intake of zinc is required to maintain a healthy status. Over the past decades, zinc has been used in formulating topical and systemic therapies for various skin disorders owing to its wound healing and antimicrobial properties. Zinc transporters play a major role in maintaining the integrity of the integumentary system by controlling zinc homeostasis within dermal layers. Mutations and abnormal function of zinc-transporting proteins can lead to disease development, such as spondylocheirodysplastic Ehlers–Danlos syndrome (SCD-EDS) and acrodermatitis enteropathica (AE) which can be fatal if left untreated. This review discusses the layers of the skin, the importance of zinc and zinc transporters in each layer, and the various skin disorders caused by zinc deficiency, in addition to zinc-containing compounds used for treating different skin disorders and skin protection.
... Although this gene has not been associated with any skin-related traits, the known role of SLC30A1 in the cellular transport of Ca 2+ and Zn 2+ could be relevant for skin biology. 50,51 In particular, Ca 2+ levels impact on cell proliferation and differentiation, and in the mobility and viability of melanoma cells, and Zn 2+ can induce apoptosis in melanoma cells in vitro. 52 SLC30A1 could therefore be involved in the emergence of skin moles, which result from melanocyte neoplasia and hyperplasia, 53,54 by affecting melanocyte proliferation and viability. ...
Background:
Genome-wide association studies (GWAS) have identified genes influencing skin ageing and mole count in Europeans but little is known about the relevance of these (or other genes) in non-Europeans.
Objective:
To conduct a GWAS for facial skin ageing and mole count in adults < 40 years old, of mixed European, Native American and African ancestry, recruited in Latin America.
Methods:
Skin ageing and mole count scores were obtained from facial photographs of >6,000 individuals. After quality control checks, three wrinkling traits and mole count were retained for genetic analyses. DNA samples were genotyped with Illumina's Omni Express chip. Association testing was performed on ~8,703,729 SNPs across the autosomal genome.
Results:
Genome-wide significant association was observed at four genome regions: two were associated with wrinkling (in 1p13.3 and 21q21.2), one with mole count (in 1q32.3), and one with both wrinkling and mole count (in 5p13.2). Associated SNPs in 5p13.2 and in 1p13 are intronic within SLC45A2 and VAV3, respectively, while SNPs in 1q32.3 are near the SLC30A1 gene, and those in 21q21.2 occur in a gene desert. Analysis of SNPs in IRF4 and MC1R are consistent with a role of these genes in skin ageing.
Conclusions:
We replicate the association of wrinkling with variants in SLC45A2, IRF4 and MC1R reported in Europeans. We identify VAV3 and SLC30A1 as two novel candidate genes impacting on wrinkling and mole count, respectively. We provide the first evidence that SLC45A2 influences mole count, in addition to variants in this gene affecting melanoma risk in Europeans.
... Zinc deficiency resulting in reduced wound healing is well established, and correspondingly, the application of zinc creams enhances the wound healing process, as reviewed in [129]. Skin, as well as other proliferating tissues, contains a lot of zinc, suggesting a physiologically important role for it, and zinc transporters have been shown to have an essential role in skin formation [130]. GPR39 was shown to be activated by Zn 2+ released from human keratinocytes (HaCaT) upon injury, and treatment of the keratinocytes with Zn 2+ induced a Ca 2+ response, which was eliminated when GPR39 expression was inhibited [14]. ...
The G-protein coupled receptor GPR39 is abundantly expressed in various tissues and can be activated by changes in extracellular Zn2+ in physiological concentrations. Previously, genetically modified rodent models have been able to shed some light on the physiological functions of GPR39, and more recently the utilization of novel synthetic agonists has led to the unraveling of several new functions in the variety of tissues GPR39 is expressed. Indeed, GPR39 seems to be involved in many important metabolic and endocrine functions, but also to play a part in inflammation, cardiovascular diseases, saliva secretion, bone formation, male fertility, addictive and depression disorders and cancer. These new discoveries offer opportunities for the development of novel therapeutic approaches against many diseases where efficient therapeutics are still lacking. This review focuses on Zn2+ as an endogenous ligand as well as on the novel synthetic agonists of GPR39, placing special emphasis on the recently discovered physiological functions and discusses their pharmacological potential.
... Melanocytes, Langerhans cells, Merkel cells, and epidermal-resident memory T cells, are also present in the epidermis [101]. Although not available in dogs, studies in other mammals showed that zinc transporters are present in skin cells of the epidermis, having an important role in health and skin homeostasis [102]. For instance, ZIP4 and specially ZIP2 are highly expressed in keratinocytes and are involved in their proliferation [103]. ...
Zinc is an essential trace element, required for enzymatic, structural, and regulatory functions. As body reserves are scarce, an adequate zinc status relies on proper dietary supply and efficient homeostasis. Several biomarkers have been proposed that enable the detection of poor zinc status, but more sensitive and specific ones are needed to detect marginal deficiencies. The zinc content of commercial dry dog foods has great variability, with a more frequent non-compliance with the maximum authorized limit than with the nutritional requirement. The bioavailability of dietary zinc also plays a crucial role in ensuring an adequate zinc status. Despite controversial results, organic zinc sources have been considered more bioavailable than inorganic sources, albeit the zinc source effect is more evident after a restriction period of dietary zinc. Many disorders have been associated with inadequate zinc status, not being clear whether the occurrence of the disease is the consequence or the cause. This review presents data on zinc requirements and biomarkers for zinc status, that can be applied for the development of supplementation strategies of zinc in complete pet foods. Moreover, it provides an understanding of the role zinc plays in the health of dogs, and how altered zinc status affects diseases in dogs.
... In those considerations particularly in recent years, there are some research and review articles mentioned why Zn 2+ -transporters are important for several organ proper functions in mammalians through being responsible for the re-distribution of subcellular labile Zn 2+ levels at cell levels. For instance, in the last 5 years, it is published over 200 articles focused on the impact of Zn 2+ -transporters in health and disease [47,48,102,[175][176][177][178][179][180][181][182][183][184][185][186][187][188]. ...
An important energy supplier of cardiomyocytes is mitochondria, similar to other mammalian cells. Studies have demonstrated that any defect in the normal processes controlled by mitochondria can lead to abnormal ROS production, thereby high oxidative stress as well as lack of ATP. Taken into consideration, the relationship between mitochondrial dysfunction and overproduction of ROS as well as the relation between increased ROS and high-level release of intracellular labile Zn²⁺, those bring into consideration the importance of the events related with those stimuli in cardiomyocytes responsible from cellular Zn²⁺-homeostasis and responsible Zn²⁺-transporters associated with the Zn²⁺-homeostasis and Zn²⁺-signaling. Zn²⁺-signaling, controlled by cellular Zn²⁺-homeostatic mechanisms, is regulated with intracellular labile Zn²⁺ levels, which are controlled, especially, with the two Zn²⁺-transporter families; ZIPs and ZnTs. Our experimental studies in mammalian cardiomyocytes and human heart tissue showed that Zn²⁺-transporters localizes to mitochondria besides sarco(endo)plasmic reticulum and Golgi under physiological condition. The protein levels as well as functions of those transporters can re-distribute under pathological conditions, therefore, they can interplay among organelles in cardiomyocytes to adjust a proper intracellular labile Zn²⁺ level. In the present review, we aimed to summarize the already known Zn²⁺-transporters localize to mitochondria and function to stabilize not only the cellular Zn²⁺ level but also cellular oxidative stress status. In conclusion, one can propose that a detailed understanding of cellular Zn²⁺-homeostasis and Zn²⁺-signaling through mitochondria may emphasize the importance of new mitochondria-targeting agents for prevention and/or therapy of cardiovascular dysfunction in humans.
... Etiology of acquired disease is akin to other nutritional deficiencies including insufficient intake due to restricted diet or parenteral nutrition, malabsorption secondary to gastrointestinal disease or surgery, and increased requirement as in pregnant or elderly individuals [51]. Inherited disease, instead, is due to genetic mutations in the SLC39A family of zinc transporters, most notably ZIP4 [52,53]. Frequently, skin changes are the presenting signs of zinc deficiency with the typical triad of disease including acral, periorificial, and perianal dermatitis, alopecia, and diarrhea [51,54]. ...
... Frequently, skin changes are the presenting signs of zinc deficiency with the typical triad of disease including acral, periorificial, and perianal dermatitis, alopecia, and diarrhea [51,54]. Due to compromised skin barrier integrity and immune mechanisms associated with zinc deficiency, secondary bacterial and fungal infections of lesions are common [53]. Additionally, patients may develop stomatitis, glossitis, and cheilitis [24]. ...
... As compared with other micronutrients, there has been a substantial amount of new literature regarding zinc deficiency and its relation to dermatologic disease. While a few case reports [55][56][57][58][59] have highlighted clinical variants of AE demonstrating the importance of heightened suspicion for nutritional deficiency in the setting of discordant clinical presentation and histopathologic report, there have also been valuable literature reviews [51,54,60,61], biochemical mechanistic investigations [52,53], and original research and reviews with novel focuses [37, 62•, 63•, 64•] all investigating zinc's role in skin disease. Discussed below are selected studies that have utmost impact on clinical implications of zinc deficiency. ...
Dermatologic manifestations of systemic diseases provide distinctive and reliable diagnostic clues that hasten time to intervention and improve overall outcomes. Notably, nutritional deficiencies are a class of diseases with representative and well-established dermatologic associations. Nutritional deficiencies can be primary or secondary and genetic or acquired; however, mucocutaneous findings remain characteristic irrespective of etiology.
Purpose of Review
This review will summarize the major classifications of nutritional deficiencies with a focus on conditions relevant and of greatest impact to the geriatric population.
Recent Findings
Recent literature has largely supported the well-known, pathognomonic mucocutaneous findings associated with nutritional deficiencies as well as displayed atypical clinical presentations and elucidated pathophysiologic mechanisms, which increases awareness and expands the breadth of knowledge of these disorders.
Summary
Total and specific micronutrient deficiencies can produce a vast array of mucocutaneous findings. These dermatologic manifestations of nutritional deficiencies are critical for all clinicians to recognize to enable prompt diagnosis and treatment. The geriatric population is specifically at-risk and attentiveness towards subtle signs of disease may substantially improve overall health outcomes.
