Pachydermoperiostosis: A Rare Masquerader of Acromegaly and Thyroid Acropachy

Background: Pachydermoperiostoasis is a rare disease of prostaglandin metabolism that presents with extensive clubbing, skin thickening, and enlargement of hands and feet, often misdiagnosed as acromegaly or thyroid acropachy. Clinical Case: A 29-year-old male presented with progressive enlargement of hands and feet for the past three years, with increased sweating, seborrhea, acne, arthralgia, and photophobia. On examination, facial furrowing and severe clubbing in all fingers and toes was noticed, with palmoplantar hyperhidrosis, tenderness and widening around distal forearms, and increased heel pad thickness. He had nodulocystic acne, injected right eye with ptosis, normal pupil, and visual field. Slit-lamp examination showed extensive pannus formation, with yellow nodules, suggestive of phlyctenular conjunctivitis, secondary to a systemic inflammatory process. No prominent supraorbital ridge, prognathism, proptosis, goiter, or pretibial myxedema. No family history of a similar condition. Labs showed normal cell counts and metabolic panel. Normal IGF-1 (112 ng/mL, n 84-250 ng/ml), TSH (3.82 mIU/L, n 0.27-4.2 mIU/L), fT4 (1.19 ng/dL, n 0.93-1.7 ng/dL), Testosterone (354 ng/dL, n 249-836 ng/dL) and Prolactin (15.2 ng/mL, n 2.1-17.7 ng/mL). Inflammatory markers were elevated with ESR of 54 mm/hr (n 0-15 mm/hr) and CRP of 12.45 mg/L (n 1-4 mg/L). ANA, RF, anti-CCP, and HLA-B27 were negative. C3 and C4 levels were normal as well. Interferon-gamma release assay was negative. Imaging showed a normal chest X-ray. Brain MRI showed normal pituitary gland and increased scalp skin thickness with cutis verticis gyrata “undulating skin sign.” X-ray of hands and feet showed diffuse periosteal reaction. A diagnosis of pachydermoperiostosis (PDP) was made based on clinical criteria (thickened skin, periosteal reaction, and finger clubbing). PDP is a genetic disorder of prostaglandin metabolism with variable expression and incomplete penetrance. It manifests after puberty and affects males more than females with a 7:1 ratio. PDP has been recently shown to go through an inflammatory phase, in which patients may benefit from immunosuppressants or NSAIDs. PDP should be distinguished from hypertrophic pulmonary osteoarthropathy, thyroid acropachy, and acromegaly. Our patient had a normal chest radiograph and normal hormone levels (TSH, T4, and IGF-1). The patient received topical steroids and antibiotics with artificial tears for his eyes, which resulted in a good response, and was referred to a rheumatology clinic for further management. Clinical Lesson: PDP can be mistaken for acromegaly or thyroid acropachy and should be considered in any patient with acromegaloid features with normal IGF-1 and no evident pituitary pathology. Awareness of this condition can help in reaching the diagnosis promptly.

A New Trick for an Old Dog? Myocardial-Specific Roles for Prostaglandins as Mediators of Ischemic Injury and Repair

The small lipid-derived paracrine signalling molecules known as prostaglandins have been recognized for their ability to modulate many facets of cardiovascular physiology since their initial discovery more than 85 years ago. While the role of prostaglandins in the vasculature has gained significant attention across time, a handful of historical studies have also directly implicated the cardiomyocyte in both prostaglandin synthesis and release. Recently our understanding of how prostaglandin receptor modulation impacts and contributes to myocardial structure and function has gained attention while leaving most other components of myocardial prostaglandin metabolism and signalling unexplored. This mini-review highlights both the key historical studies that underpin modern prostaglandin research in the heart, while concurrently presenting the latest findings related to how prostaglandin metabolism and signalling impact myocardial injury and repair.

Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155

Background Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it’s function in prostaglandin metabolism is largely unknown. Methods A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production. Results We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients’ survival. Conclusions Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.

Analysis of drosophila stress resistance at pharmacological inhibition of prostaglandins metabolism

Inhibition of inflammatory processes in the model organisms using non-steroidal anti-inflammatory drugs (NSAIDs) can be an effective geroprotective method. The mechanisms of NSAIDs action in insects have not been studied enough. It is assumed that they are similar to those in mammals and are based on the inhibition of cyclooxygenase 2, which leads to a decrease in the synthesis of prostaglandins. Prostaglandins are central signaling molecules for mediated coordinated cellular immunity of insects and control the imago eclosion, egg production and oogenesis of Drosophila. Obviously, signaling pathways exist where the role of prostaglandins has not yet been shown. In our work, the resistance to starvation of Drosophila melanogaster of wild type stock Canton-S under pharmacological inhibition of prostaglandin metabolism at different stages of ontogenesis was analyzed. In the experiments, nimesulide was used in three different concentrations – 0.1, 0.05, and 0.025 mg/ml. The results of the experiments have shown, that the development of larvae in the medium containing NSAID nimesulide leads to a decrease in resistance to stress factor – starvation on average by 19.2% in females and by 7.4% in males. Resistance to starvation of the most stress-resistant (10% of individuals with the longest life span) females decreases during the development of larvae in the medium containing nimesulide in concentrations 0.1 and 0.05 mg/ml. The consumption of nimesulide by imago at a concentration of 0.025 mg/ml during the first days of life increases stress resistance and life span at starvation in females by 12.4% and in males in all variants of the experiment on average by 17.8%. Under the same experimental conditions, life span during starvation increased in the most stress-resistant females Canton-S. Thus, pharmacological inhibition of prostaglandin metabolism leads to an increase of resistance to starvation if virgin adults are exposed to nimesulide during the first day after eclosion, and stress resistance decreases if nimesulide is consumed by larvae. This is obviously, due to that somatic tissues of the adult flies are almost entirely composed of postmitotic cells, while intensive processes of cell division are characteristic of growing larvae. The data obtained indicate that the action of nimesulide on postmitotic imago cells promotes transition of cells to increased stress tolerance, while the impact on actively dividing cells of larvae leads to a decrease in the resistance of the adults.