Cell proliferation and apoptosis are hormone-dependent physiological processes involved in endometrial growth and regression. The aims of the present study were: (1) to evaluate endometrial cell proliferation using proliferating cell nuclear antigen (PCNA) expression; (2) to evaluate the induction of endometrial cell death by the expression of active caspase-3 and the apoptotic phenotype visualised by DNA fragmentation; and (3) to relate these observations to endometrial tissue dynamics in the equine endometrium throughout the oestrous cycle. Endometria were assigned to follicular and luteal phases based on ovarian structures and plasma progesterone. Cell proliferation and active caspase-3-mediated apoptosis were expressed in both phases of the oestrous cycle. In the luteal phase, PCNA expression was higher than in the follicular phase. Highest PCNA activity was noted in the luminal and glandular structures. Active caspase-3 staining was increased in luminal epithelium and deep glandular cells during the luteal phase. However, in the follicular phase, stromal cells showed greater active caspase-3 expression. Only a few apoptotic endometrial cells were detected by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) and these cells were mostly present in luminal and glandular structures. A simultaneous increase in DNA, cell proliferation and protein synthesis was observed in the endometrium during the mid-luteal phase. This suggests that cell hyperplasia occurs at the time the histotroph is needed for eventual embryo nourishment.

in Buerger's disease there is an impairment of sympathoadrenal function with an altered peripheral adrenergic response to cigarette smoking. Patients submitted to sympathectomy have high pAD, but this benefit is reversed after smoking. This might be clinically relevant given the association between cigarette smoking and the manifestations of Buerger's disease and the controversy on the effectiveness of sympathectomy in the management of the disease.

The use of cannabinoids to treat fibrotic skin diseases is an emergent issue. Therefore, we aimed to evaluate systemic and skin endocannabinoid responses in the wound-healing process in humans. A prospective study was performed in 50 patients who underwent body-contouring surgery. Anandamide (N-arachidonoylethanolamine, AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified using LC-MS/MS. Ten (20%) patients developed hypertrophic (HT) scars. No significant changes were observed between the normal (N) scar and HT scar groups in terms of plasma and skin endocannabinoids. Nevertheless, a positive correlation between plasma and skin AEA concentrations was found in the N group (r = 0.38, p = 0.015), which was absent in the HT group. Moreover, the AEA concentration was significantly lower in HT scar tissue than in normal scar tissue (0.77 ± 0.12 ng/g vs 1.15 ± 0.15 ng/g, p < 0.001). Interestingly, in all patients, the surgical intervention produced a time-dependent effect with a U shape for AEA, PEA and OEA plasma concentrations. In contrast, 2-AG plasma concentrations increased 5 days after surgery and were reduced and stabilized 3 months later. These results suggest crosstalk between systemic and local skin endocannabinoid systems during human wound healing. AEA appears to be the most likely candidate for this link, which is deficient in patients with HT scars. Endocannabinoids are the endogenous ligands for cannabinoid receptors CB1 and CB2, which are two G-protein coupled receptors that have a widespread distribution throughout the body 1,2. The most studied endocannabinoids are the arachidonic acid derivatives N-arachidonoylethanolamine (AEA) 3 and 2-arachidonoylglycerol (2-AG) 4. Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are N-acylethanolamines (NAEs) that act by influencing AEA metabolism and binding to peroxisome proliferator-activated receptor alpha (PPAR-α) and to transient receptor potential cation channel subfamily V member 1 (TRPV1) 5-7. Endocannabinoids and related NAEs play an essential role in many physiological central and peripheral processes. These include emotional responses, cognition, memory, motor behaviour, immune function, feeding, energy consumption and metabolic regulation at the systemic and cellular levels 8-13. Endocannabinoids are present in human blood, and their concentrations are dynamic. Food consumption, obesity, exercise, sleep pattern, time of the day, stress, anxiety, inflammation and pain are known to modify the endocannabinoid concentrations in the circulation 14. They have also been quantified in other biological samples obtained from humans, including saliva 15 , hair 16 , semen 17 , breast milk, and amniotic fluid 18 .

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Endometrial growth of vascular tissues during the estrous cycle may be coordinated with development of nonvascular tissue. Estrogen and progesterone may play a role in regulation of uterine growth and angiogenesis.

There is a different systemic inflammatory profile response in the patients during the formation of hypertrophic scars. Vitamin D plasma levels are marked reduced in these patients. Considering the powerful anti-inflammatory effect of vitamin D, these findings could be related.

Previous studies showed that cannabinoid 2 (CB2) receptor is involved in skin inflammation, fibrogenesis and re-epithelialization in mice, indicating that this receptor may be implicated in wound healing. Thus, topical use of cannabinoids may have a role in local fibrotic and wound healing diseases such as scars or keloids. We investigate the effect of the CB2 selective receptor agonist (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran (JWH133) and the CB2 selective receptor antagonist ( 6, on primary cultures of human fibroblasts. Primary cultures of adult human fibroblasts were obtained from abdominal human skin samples. Fibroblasts pretreated with JWH133 and/or AM630 were stimulated with TGF-β (10 ng/ml). Fibroblast activation into myofibroblasts was quantified by the expression of alpha-smooth muscle actin (α-SMA) using Immunocytochemistry and Western Blot assays. Collagen content was quantified with the Sirius red staining assay. Upon human fibroblasts stimulation with TGF-β, a significant increase on α-SMA and CB2 receptor expression was observed. In these cells, JWH133 decreased α-SMA expression and collagen content. However, this effect was not observed in resting human fibroblasts. AM630 decreased α-SMA expression and collagen content in both resting and activated fibroblasts. This effect was time-and concentration-dependent with an IC 50 value of 11 μM. The CB2 receptor appears to be involved in fibroblast repair during skin wound healing in humans, as TGF-β increases CB2 receptor expression and JWH133 produces an anti-fibrotic effect in human fibroblasts. AM630 also showed an anti-fibrotic effect hypothesizing that other cannabinoid receptors, such as TRPV, may be involved in this response.

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