Cell Biology: Research & TherapyISSN: 2324-9293

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Editorial, Cell Biol Henderson Nv Vol: 5 Issue: 2

Phosphorylase Kinase Inhibition with Curcumin in Psoriasis

Madalene CY Heng*
Professor of Medicine and Dermatology, UCLA School of Medicine, USA
Corresponding author : Madalene CY Heng, MD, FRACP, FACD, FAAD
Professor of Medicine and Dermatology, UCLA School of Medicine, USA
Tel: (310) 825-6911
E-mail: [email protected]
Received: August 31, 2016 Accepted: August 31, 2016 Published: September 02, 2016
Citation: Heng MCY (2016) Phosphorylase Kinase Inhibition with Curcumin in Psoriasis. Cell Biol (Henderson, NV) 5:2. doi:10.4172/2324-9293.1000e115

Abstract

Psoriasis is an inflammatory disease with a genetic component. The disease activity is characterized by unique epidermal proliferative kinetics, with specific clinical, histological and immunohistochemical markers of psoriatic hyper proliferation, including the expression of proliferating cell nuclear antigen (PCNA) as shown by the Ki-67 immunohistochemical marker, Observations of depletion of glycogen granules in active psoriasis has led to the identification of elevated Phosphorylase kinase (PhK) activity in psoriasis, with elevated PhK levels correlating with the presence of specific markers of psoriatic hyper proliferation.

Keywords: Psoriasis

Editorial

Psoriasis is an inflammatory disease with a genetic component. The disease activity is characterized by unique epidermal proliferative kinetics, with specific clinical, histological and immunohistochemical markers of psoriatic hyper proliferation, including the expression of proliferating cell nuclear antigen (PCNA) as shown by the Ki- 67 immunohistochemical marker, Observations of depletion of glycogen granules in active psoriasis has led to the identification of elevated Phosphorylase kinase (PhK) activity in psoriasis, with elevated PhK levels correlating with the presence of specific markers of psoriatic hyper proliferation. Suppression of PhK levels with its inhibitor, Curcumin, has been shown to correlate with resolution of clinical psoriasis as well as resolution of the specific markers of psoriatic proliferation including the de-expression of PCNA/Ki-67 antigen. In a proof-of-principle clinical investigation in a large series of consecutive psoriatic patients treated with a protocol aimed at inhibiting PhK activity using topical Curcumin, topical steroids and eliminating antigens and super antigens (contact allergens, bacterial, viral, fungal and lipopolysaccharides), clearance was achieved in over 70% within 16 weeks, with 60% of patients achieving long- term remission without the need for maintenance therapy.
Psoriasis is a common and distressing chronic skin disease that causes significant morbidity. The search for a treatment that is safe, effective and economical has to date been largely unsuccessful because the etiology and mechanisms of psoriasis have been baffling and elusive. It is generally accepted that psoriasis is a prototypical chronic inflammatory skin disorder with a strong genetic component, but associated with many environmental aggravating factors that trigger recurring episodes of clinical relapse. The active clinical disease is characterized by rapid and excessive growth of epidermis secondary to an abnormally high turnover of epidermal cells [1]. This is associated with specific clinical and pathologic manifestations unique to psoriatic hyperproliferation. Clinically, patients show welldefined plaques with coarse silver scaling. Histology demonstrates pathognomonic changes with parakeratosis and elongated thin rete ridges with suprapapillary thinning. Histochemistry shows expression of proliferating cell nuclear antigen (PCNA) as demonstrated by positive Ki-67 immunohistochemical marker [2]. The active disease is associated with a non-specific inflammatory response driven predominantly by T cell subsets (CD3, CD4, CD8, among others), but frequently may also involve neutrophils and macrophages. While the epidermal proliferative changes are most marked in involved skin of active psoriasis, the role of the underlying genetic component is apparent when similar changes, albeit less severe, are also observed in uninvolved skin.
The plethora of therapy for psoriasis at present reflects the current uncertainty about the etiology of the disease. The range includes numerous topical agents with largely inflammatory and epidermal suppressive properties (topical corticosteroid preparations, coal tar ointment, anthralin, vitamin D3 preparations). The frequently used phototherapy with psoralens (PUVA), suppresses both epidermal proliferation and inflammatory cells. Phototherapy with psoralens (PUVA), which produces DNA cross-links and monoadducts are highly toxic to actively proliferating cells and suppresses epidermal proliferation and inflammatory cells. However, these DNA cross-links promote a higher risk of skin malignancy. Systemic treatment with the anti-metabolite, methotrexate inhibits cell proliferation by inhibition of dihydrofolate reductase, thus resulting in inhibiting the synthesis of purines and pyrimidines involved in both DNA and RNA synthesis. Oral etretinate functions to inhibit ornithine decarboxylase, which is important in cell cycling. Anti-psoriatic treatment also includes a host of treatment targeting the T cell population, their function, migration, and the cytokines secreted by these inflammatory cells. These include cyclosporine A (anti-IL2/T cell growth factor), and a host of monoclonal antibodies against inflammatory cytokines such as TNFα (etanercept and adalimumab), IL-12/23 (ustekinumab), as well as anti LFA-1 (efalizumab) which blocks T cell migration. However, because these therapies are essentially symptomatic, none of these therapies seem to result in long-term remission and psoriasis frequently recurs after treatment is stopped.
For a number of years, we have been investigating a hypothesis that psoriasis is due to a failure of regulating mechanisms to inhibit the epidermal cellular turnover and proliferation in the skin of susceptible individuals. Specifically, our studies suggest that the enzyme phosphorylase kinase (PhK) may be central to the pathophysiologic mechanism mentioned above. We found much higher levels of PhK in active psoriasis compared to other diseases such as active eczema [3]. When psoriatic lesions healed, PhK levels declined significantly [2,3]. The elevated PhK activity correlated with the known specific markers of psoriatic hyperproliferation, and in particular, with the expression of PCNA/Ki-67 antigen, parakeratosis and elongated rete ridges in active and healing psoriasis compared to active non-psoriatic controls [3]. To our knowledge, this is the only enzyme which has been linked to the specific markers of psoriatic hyperproliferation. We were initially led to the discovery that PhK levels are elevated in psoriasis from electron microscopic observations that glycogen granules were depleted in active psoriatic epidermis [3]. The enzyme functions to break down glycogen by phosphorylating glycogen phosphorylase, and elevated PhK activity results in depletion of glycogen granules from cells. In our personal clinical experience, we have not observed depletion of glycogen granules of this degree in any other skin disease.
Phosphorylase kinase is a cAMP-dependent dual specificity kinase [4] capable of breaking down glycogen [3], and phosphorylating multiple kinases required for activation of NF-kB, a transcription regulator [2-5]. In the non-activated state, NF-kB exists as a pair of dimers (p50/p65). When NF-kB is activated by injurious stimuli [5], two events occur: (a) phosphorylation of several serine specific sites, and (b) removal of the inhibitory molecule, IkBα though phosphorylation by its kinase, IkBα kinase, resulting in translocation of the subunits to DNA, where it binds to the kB binding site with eventual activation of over 200 genes involved in inflammation, cell cycling and cell proliferation. It is important to note that the activation of IkBα kinase (without which NF-kB cannot achieve full activity) requires phosphorylation at multiple sites of different specificities (serine and tyrosine) – a function achieved by the dual specificity property of PhK. Normally, a protein kinase can only transfer high energy phosphate bonds from ATP to either serine or tyrosine specific sites but not both because the substrate binding site of most protein kinases only allows for one configuration. Phosphorylase kinase achieves its dual specificity function through the presence of a hinge joint between the subunits, which allows for changes in size of the substrate binding site. In addition, the shape of the substrate binding site can be altered in one plane or another by binding to either Mn or Mg ions [4].
Our studies and findings mentioned above have shown that elevated PhK activity correlates closely with psoriatic activity [2,3]. First, elevated PhK activity is associated with depletion of glycogen granules in active psoriasis. Second, elevated PhK is found in active psoriasis but not in active eczema and other proliferative skin conditions. Third, elevated PhK activity correlates with presence of the specific markers of psoriatic proliferation, including expression of PCNA/Ki-67 antigen, presence of parakeratosis, thin elongated rete pegs and suprapapillary thinning. Fourth, PhK activity returns to normal in the healing phase of psoriasis, correlating with resolution of the specific markers of psoriatic proliferation, including deexpression of PCNA/Ki-67 antigen. We have further observed that normalization of these markers appears to be important in the induction of long-term clinical remission.
Phosphorylase kinase is a large molecule consisting of a tetramer of four subunits each (αβγδ). The δ subunit is calmodulin, a calciumbinding protein which is involved in antigen- and superantigenactivated T cell responses, thus identifying the target for activation of the molecule by the aggravating and precipitating factors for psoriasis in our study. The γ subunit is a catalytic subunit, with α and β subunits are involved in activation and deactivation of the molecule, catalyzed by Types I- and II- cyclic AMP dependent protein kinases respectively. Genes for familial psoriatic susceptibility and susceptibility loci have been mapped to 17q and 16q [6-8] corresponding to the ligand (Type II cAMP-dependent protein kinase; 17q) [9] and β unit of PhK, 16q [10], which contains the receptor for the switch-off mechanism for PhK. These findings are consistent with our postulate that a defective switch-off mechanism for PhK activity may be important in the basic pathophysiology of psoriasis.
We reported a proof of principle clinical investigation in a large series of personal but consecutive psoriatic patients [11] treated with a protocol aimed at inhibiting PhK activity using topical curcumin, a PhK inhibitor [12], topical corticosteroids [13], and elimination of PhK-generating antigens and superantigens. These antigens and superantigens (contact allergens, bacterial, yeast, fungal and viral infections, and lipopolysaccharides associated with lactose intolerance) are thought to activate calmodulin-dependent T cell responses through the calmodulin-containing δ subunit of PhK. Clearance was achieved in over 70% of patients within 16 weeks, with 60% of patients achieving long-term remission during the duration of the study and subsequent follow up without need for maintenance therapy [11].
There has been recent interest in the use of phosphodiesterase inhibitors, in particular anti-PDE4 (apremilast), in the treatment of psoriasis - a phase III trial [14] has reported that adds to the increased focus to the role of protein kinases in psoriasis [15]. Phosphodiesterase hydrolyzes cAMP and affects the function of cAMP protein kinasedependent processes. The phosphodiesterase-4 inhibitor, anti-PDE-4 (apremilast), has been shown to have anti-inflammatory activity in psoriasis. Whether this drug has anti-PhK activity, through its effect on cAMP-dependent protein kinase, remains to be seen since it has not yet been reported to have activity against the specific markers of psoriatic hyper proliferation.
Figure 1: Representative signals of AIMS sum signal and humidity of the exhaled breath sample measured with ChemPro®100 and multicapillary column used. The AIMS spectrum from the maximum point of the AIMS sum signal was analyzed further.
Table 1: Dietary content,physical activity, weight and blood parameters in 2x1 week diet intervention with low (LFD) and high fibre (HFD) diets in seven healthy men1.

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