Aldo-keto reductase family member C3(AKR1C3)promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α

Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.

Effects of prostaglandin F_(2α) on small intestinal interstitial cells of Cajal

AIM：To explore the role of prostaglandin F2α（PGF2α） on pacemaker activity in interstitial cells of Cajal（ICC）from mouse small intestine. METHODS：In this study,effects of PGF2αin the cultured ICC cells were investigated with patch clamp technology combined with Ca 2＋ image analysis. RESULTS：Externally applied PGF2α（10μmol/L）produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode.The application of flufenamic acid（a non-selective cation channel inhibitor）or niflumic acid（aCl channel inhibitor）abolished the generation of pacemaker currents but only flufenamic acid inhibited the PGF2α-induced tonic inward currents.In addition,the tonic inward currents induced by PGF2αwere not inhibited by intracellular application of 5’-[-thio]diphosphate trilithium salt.Pretreatment with Ca 2＋ free solution, U-73122,an active phospholipase C inhibitor,and thapsigargin,a Ca 2＋ -ATPase inhibitor in endoplasmic reticulum,abolished the generation of pacemaker currents and suppressed the PGF2α-induced tonic inward currents.However,chelerythrine or calphostin C,protein kinase C inhibitors,did not block the PGF2α-induced effects on pacemaker currents.When recording intracellular Ca 2＋ （[Ca 2＋ ]i）concentration using fluo-3/AM,PGF2α broadly increased the spontaneous[Ca 2＋ ]i oscillations. CONCLUSION：These results suggest that PGF2αcan modulate pacemaker activity of ICC by acting non-selective action channels through phospholipase C-dependent pathway via[Ca2＋]i regulation

Prospects of diagnostic and prognostic biomarkers of pyometra in canine

Pyometra is one of the most common uterine pathologies of intact bitch at middle to advanced age. In the early stages, the disease shows subtle changes, making diagnosis a challenge. In contrast, at later stages, it manifests as potentially life-threatening systemic inflammatory response syndrome. Ultrasonographic examination of the uterus aids in the diagnosis, although it has limitation in ascertaining the clinical severity of pyometra. Moreover, differentiation of cystic endometrial hyperplasia from pyometra could not be discerned with greater accuracy. Therefore, false negative diagnosis of pyometra patients leads to development of systemic inflammatory response, which delays administration of therapies and results in deaths during early course of treatment. Further, indiscriminate use of broad-spectrum antimicrobials at higher dose in false positive cases considerably contributes to the rising pool of drug resistant pathogens, thereby increasing the risk of case fatality due to sepsis in a long-term. Monitoring the circulating pro-inflammatory cytokines, acute phase proteins, endotoxin, growth factors and inflammatory mediators is the current trend in pyometra research, especially for developing diagnostic and prognostic biomarkers. The present review deals with the prospects of developing diagnostic and prognostic biomarkers in the canine pyometra.

Pregnancy recognition signaling mechanisms in ruminants and pigs

Maternal recognition of pregnancy refers to the requirement for the conceptus（embryo and its associated extraembryonic membranes） to produce a hormone that acts on the uterus and/or corpus luteum（CL） to ensure maintenance of a functional CL for production of progesterone;the hormone required for pregnancy in most mammals.The pregnancy recognition signal in primates is chorionic gonadotrophin which acts directly on the CL via luteinizing hormone receptors to ensure maintenance of functional CL during pregnancy.In ruminants,interferon tau（IFNT） is the pregnancy recognition signal.IFNT is secreted during the peri-implantation period of pregnancy and acts on uterine epithelia to silence expression of estrogen receptor alpha and oxytocin receptor which abrogates the oxytocin-dependent release of luteolytic pulses of prostaglandin F2-alpha（PGF） by uterine epithelia;therefore,the CL continues to produce progesterone required for pregnancy.Pig conceptuses secrete interferon delta and interferon gamma during the peri-implantation period of pregnancy,but there is no evidence that they are involved in pregnancy recognition signaling.Rather,pig conceptuses secrete abundant amounts of estrogens between Days 11 to 15 of pregnancy required for maternal recognition of pregnancy.Estrogen,likely in concert with prolactin,prevents secretion of PGF into the uterine venous drainage（endocrine secretion）,but maintains secretion of PGF into the uterine lumen（exocrine secretion） where it is metabolized to a form that is not luteolytic.Since PGF is sequestered within the uterine lumen and unavailable to induce luteolysis,functional CL are maintained for production of progesterone.In addition to effects of chorionic gonadotrophin,IFNT and estrogens to signal pregnancy recognition,these hormones act on uterine epithelia to enhance expression of genes critical for growth and development of the conceptus.

Effects of wrist-ankle acupuncture on associated factors in uterus tissue and serum in rats with primary dysmenorrhea

Objective：To observe effects of wrist-ankle acupuncture （WAA） onβ-endorphin （EP）, nitric oxide （NO） in uterus tissue and prostaglandin F2α （PGF2α）, substance P （SP） in serum of rats with primary dysmenorrhea. Methods：A total of 45 non-pregnant Wistar rats were randomly divided into a control group, a model group and a WAA group, 15 rats in each group. Rats in the model group and the WAA group received continuous abdominal subcutaneous injection of Diethylstilbestrol to establish dysmenorrhea rat models. On the first day after modeling, rats in the WAA group began to receive acupuncture on Point Lower 1 and Point Lower 2, once a day for 10 d. The control group and the model group didn’t receive any treatment. Writhing latencies and frequencies were recorded.β-EP and NO in uterus tissue homogenates and PGF2α, SP in serum were detected. Results：In the model group,β-EP and NO levels were the lowest among the groups, the serum PGF2α level was the highest, and serum SP level was the lowest. These measurements showed significantly difference between the model group and the control group （P〈0.05）. PGF2α in the WAA group was lower than that in the model group;β-EP, NO and SP levels were higher than those in the model group, with inter-group statistically significant differences （P〈0.05）. Conclusion： WAA may achieve analgesic effect through decreasing PGF2α, increasingβ-EP, NO and SP to relieve uterine cramps, increase blood flow and promote functional improvement.

Effects of electroacupuncture on uterine prostaglandin F2α,cyclooxygenase 2 and nuclear factorκB in rats with primary dysmenorrhea

Objective:To observe the effects of electroacupuncture(EA)on uterine prostaglandin F2α(PGF2α),cyclooxygenase 2(COX-2)and nuclear factorκB(NF-κB)in rats with primary dysmenorrhea(PD)and to discuss the possible mechanism in EA intervening PD.Methods:Forty Sprague-Dawley female rats were randomly divided into a blank group,a model group,an EA group and an ibuprofen group,with 10 rats in each group.The PD model was established using estradiol benzoate combined with oxytocin in the model group,EA group and ibuprofen group.At the same time of modeling,rats in the EA group were given EA at Guanyuan(CV 4)and Sanyinjiao(SP 6)once a day for 20 min each time for 10 consecutive days.Ibuprofen was intragastrically administered once a day for 10 consecutive days in the ibuprofen group.The same amount of normal saline was intragastrically administered once a day for 10 consecutive days in the blank group and model group.The number of writhing of rats in each group within 30 min was compared on the 11th day just after the interventions.The uterine homogenate supernatant was separated and the PGF2αlevel was detected by enzyme-linked immunosorbent assay.Western blot was applied for the detection of the expression levels of COX-2,phospho-NF-κB p65 and NF-κB p65 proteins in uterine tissues.Results:Compared with the blank group,the number of writhing in the model group increased significantly(P<0.01),and the expression levels of PGF2α,COX-2,phospho-NF-κB p65 and NF-κB p65 proteins in uterine tissues were significantly increased(all P<0.01).Compared with the model group,the number of writhing in the EA group and ibuprofen group were significantly reduced(both P<0.01),and the expression levels of PGF2αand COX-2 protein in uterine tissues were significantly reduced(both P<0.01).Compared with the model group,the phospho-NF-κB p65 level in uterine tissues in the EA group was significantly reduced(P<0.01).Compared with the ibuprofen group,the phospho-NF-κB p65 level in the EA group was significantly reduced(P<0.01).Conclusion:The mechanism of EA for PD rats may be related to inhibiting the phosphorylation of NF-κB and reducing the levels of COX-2 and PGF2αin uterine tissues.

Synchronization of ovulation in goats using prostaglandin F2α based protocols during the breeding season

The main aim of this review was to describe the feasibility of prostaglandin F2α(PGF2α)based protocols used as a tool for ovulation synchronization in cycling goats.There is a reproductive seasonality in small ruminants.However,from latitudes 45°towards equator,the intensity of anoestrus progressively decreases and tends to disappear in local breeds.Consequently,PGF2α or their synthetic analogues as luteolytic substances can assume a great importance in reproductive management of flocks from these regions.However,a single or double(9–11 days apart)PGF2α administration provokes a good induction but a moderate synchronization of ovulations if timed artificial insemination is considered,and a significant short oestrous cycle can occur with detrimental effects on fertility rate when compared with conventional progesterone-based protocols.In order to minimize this constraint,some gonadotropinreleasing hormone-PGF2α-gonadotropin-releasing hormone(Ovsynch)-based protocols and their modifications,manipulating the dominant follicles and corpora lutea,were successfully tested in goats.Similar to cows,these PGF2αbased protocols seem to be a promising and more cost-effective tool for reproductive management in cycling goats.