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[This corrects the article DOI: 10.1371/journal.pone.0237315.].

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The decision to allocate time and energy to find multiple sexual partners or raise children is a fundamental reproductive trade-off. The Strategic Pluralism Hypothesis argues that human reproductive strategies are facultatively calibrated towards either investing in mating or parenting (or a mixture), according to the expression of features dependent on the individual's condition. This study seeks to test predictions derived from this hypothesis in a sample of 242 young men (M ± SD = 22.12 ± 3.08) from Chile's 5th Region (33Ö¯ south latitude). Specifically, two predictions were considered that raise questions about the relationship between traits related to physical and psychological attractiveness (fluctuating facial asymmetry and self-perception of attractiveness) and competitive skills (baseline testosterone and self-perception of fighting ability) with short-term reproductive strategies. Our results indicate that psychological features related to the self-perception of physical attractiveness are related to short-term reproductive strategies. However, no evidence was found that fluctuating facial asymmetry, basal levels of testosterone and self-perception of fighting ability were related to short-term reproductive strategies. These results support the existing evidence of the importance of physical attractiveness in calibrating men's reproductive strategies but cast doubts about the role of fluctuating facial asymmetry. They also suggest that traits related to physical attractiveness, in comparison to competitive capabilities, play a more important role in calibrating men's short-term reproductive strategies.

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Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1α, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2-induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1α signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1α. We found that iPGE2 increases HIF-1α expression through iEP2-dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR-HIF-1α in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1α play a role in PC.

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Microparticles are produced by vesiculation of the cell plasma membrane and serve as vectors of cell-to-cell communication. Co-culture experiments have shown that hypoxia-inducible factor-α (HIF-α)-regulated-genes are up-regulated in human renal proximal tubular HK-2 cells by endothelial cell factors which might be transported inside endothelial microparticles (EMP). Here we aimed to study in HK-2 cells the effect of EMP, produced by activated endothelial cells, on HIF-α and HIF-α-regulated vascular endothelial growth factor-A (VEGF-A). EMP, at a concentration much lower than that found in plasma, increased the expression of HIF-α/VEGF-A in a COX-2/EP2 receptor dependent manner. Since the EMP/cells ratio was ∼1/1000, we hypothesized that paracrine mediators produced by HK-2 cells amplified the initial signal. This hypothesis was confirmed by two facts which also suggested that the mediators were conveyed by particles released by HK-2 cells: (i) HIF-α was up-regulated in HK-2 cells treated with the pellet obtained from the conditioned medium of the EMP-treated HK-2 cells. (ii) In transwell experiments, EMP-treated cells increased the expression of HIF-α in untreated HK-2 cells. Interestingly, we detected these cells, particles that were released by EMP-treated HK-2 cells. Depending on the pathological context, activation of HIF-α and VEGF-A signaling in renal tissue/cells may have either beneficial or harmful effects. Therefore, our results suggest that their presence in the urinary space of EMP produced by activated endothelial cells may influence the outcome of a number of renal diseases.

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UNLABELLED: ETHNO-PHARMACOLOGICAL RELEVANCE: The scientific proof and clinical validation of Chinese herbal medicine (CHM) require a rigorous approach that includes chemical standardization, biological assays, animal studies and clinical trials. AIM OF THE STUDY: To assess the experimental design of animal studies on the activity of CHM by selection and scrutinizing of a series of papers in some major disease areas. MATERIALS AND METHODS: We have analyzed the English publications reported in MEDLINE (ISI web of knowledge). RESULTS: Our data showed that (i) research of CHM during the last 10 years had been highly intensified and become more accessible worldwide through increased publications in English, although still most authors had Chinese names; (ii) English journals publishing animal research of CHM were comparable to those publishing animal studies of non-Chinese phytotherapy in terms of impact factor; and (iii) published data on authentication and quality control of CHM, as well as research design of animal studies were far from sufficient to meet the criteria needed to support their reproducibility and reliability. CONCLUSIONS AND PERSPECTIVES: The recent decade witnessed an increase in CHM research activities and CHM English publications. Based on common problems identified in publications on CHM animal studies, we have proposed a checklist that could help in preliminary selection of publications lacking the most common problems and thus would be useful for a quick search of reproducible CHM regimens that are likely to be effective in a given context. The second application of this checklist is to help avoid the most common problems when designing experiments.

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Hypoxia-inducible factor-1α (HIF-1α) and all-trans retinoic acid (ATRA) afford protection in several experimental models of kidney disease. HIF-1α protein is degraded under normoxia but stabilized by hypoxia, which activates its transcription factor function. ATRA activates another set of transcription factors, the retinoic acid receptors (RAR) α, ß and γ, which mediate its effects on target genes. ATRA also up-regulates the expression of RAR α, ß and γ at the transcriptional level. Here we demonstrate the presence of mutual regulation of hypoxic and retinoic acid related signalling in tubular proximal cells. In human proximal tubular HK-2 cells we have found that: (i) ATRA treatment induces HIF-1α under normoxic conditions and also synergizes with hypoxia leading to the over-expression of HIF-1α and vascular endothelial growth factor-A, a HIF-1α-regulated renal protector. ATRA-induced HIF-1α expression involved stabilization of HIF-1α mRNA but not of HIF-1α protein. (ii) Expression of HIF-1α is an absolute requirement for the transcriptional up-regulation of RARß by ATRA. Transfection with HIF-1α siRNA abolished the induction by ATRA of the expression of both RARß mRNA and protein while treatment with HIF-1α inhibitor YC-1 results in the abolishment of ATRA-induced activity of a retinoic acid-response element (RARE) construct from the RARß promoter. (iii) Hypoxia up-regulates RARß through HIF-1α since this effect was inhibited by HIF-1α knockdown. In contrast to ATRA-induced RARß up-regulation, induction of RARß expression by ATRA did not involve transcriptional up-regulation as hypoxia did not increase the expression of RARß mRNA or the activity of the RARE construct. These results suggest the presence of crosstalk between hypoxia/HIF-1α and ATRA/RARß that may be physiologically and pharmacologically relevant.

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