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Pharmacological self-management of osteoarthritis (OA) with over the counter (OTC) drugs remains challenging. To compare the safety, tolerability, and efficacy of a finished phytotherapeutic product (FPP; 2-propanolic dry extract from stinging nettle leaves, Hox alpha [HOXA]) with conventional non-steroidal anti-inflammatory drugs (NSAIDs) used as OTC self-medication in OA. Retrospective, longitudinal exploratory analysis of depersonalized data from the German Pain e-Registry. Two propensity score-matched cohorts of 1073 OA patients each, reporting at least 3 months of continuous OTC treatment with HOXA or NSAIDs, were evaluated. The composite primary endpoint was the proportion of patients who did not discontinue due to an adverse drug reaction (ADR) AND achieved a clinically relevant reduction in average 24‑h pain intensity at the end of the evaluation period. Secondary endpoints included improvements in pain intensities, pain‑related disability, and physical/mental quality of life; safety analyses assessed ADR frequency, number of affected patients, and ADR‑related discontinuations. Both treatments were associated with significant relief of OA-related symptoms compared to baseline, with greater improvements observed for HOXA across all evaluated domains (all p < 0.001). The frequency of ADRs (789 vs 152), the proportion of patients with ADRs (46.8 vs 13.1%) and ADR-related discontinuations (25.2 vs 2.1) were all significantly higher with NSAIDs compared to HOXA (all p < 0.001). The composite primary endpoint was achieved by 96.2% (HOXA) vs 73.2% (NSAIDs; p < 0.001; OR 9.23; RR 7.02; effect size 0.319). In this real‑world OTC setting, HOXA use was associated with fewer ADRs and more favorable multidimensional outcomes compared with NSAID. Given the retrospective design, these findings should be interpreted as exploratory and hypothesis‑generating and confirmed in randomized controlled trials. HMA‑EMA Catalogues of real‑world data sources and studies; EU PAS number 1000000564 (encepp.europa.eu).

In vertebrates, including humans, the relative length of the second to the fourth digit correlates with sex hormone-dependent behavioural, psychological and physiological traits. However, despite a decade of research, the underlying mechanism linking digit ratio to these sex hormone-dependent traits remains unclear. Previous work suggests that during embryo development, circulating levels of plasma androgens or oestrogens may act through their receptors to affect transcription levels of posterior HOX genes in the developing digits, thereby possibly influencing their relative length. The correlation between digit ratio and sex hormone-dependent traits might thus stem from variation in expression or sensitivity of the sex hormone receptors, or from variation in sex hormone levels in the embryo. Here, we show that in a population of 1156 zebra finches Taeniopygia guttata, a polymorphism in the oestrogen receptor α gene (ESR1) explains 11.3 per cent of the variation in digit ratio, and is also associated with male and female-mating behaviour. By contrast, we found no associations between digit ratio or mating behaviours and polymorphisms in the androgen receptor gene. Thus, our results (i) provide an explanation for the observed significant genetic covariance between digit ratio and male and female mating behaviour and (ii) strongly confirm the indicator function of digit ratio through the oestrogen pathway. Finally, we note that the commonly invoked effect of foetal testosterone on human digit ratio seems to be substantially weaker than the effect described here.

Homeodomain-containing transcription factors are important regulators of stem cell behavior. HOXB4 mediates expansion of adult and embryo-derived hematopoietic stem cells (HSCs) when expressed ectopically. To define the underlying molecular mechanisms, we performed gene expression profiling in combination with subsequent functional analysis with enriched adult HSCs and embryonic derivatives expressing inducible HOXB4. Thereby, we identified a set of overlapping genes that likely represent \"universal\" targets of HOXB4. A substantial number of loci are involved in signaling pathways important for controlling self-renewal, maintenance, and differentiation of stem cells. Functional assays performed on selected pathways confirmed the biological coherence of the array results. HOXB4 activity protected adult HSCs from the detrimental effects mediated by the proinflammatory cytokine TNF-α. This protection likely contributes to the competitive repopulation advantage of HOXB4-expressing HSCs observed in vivo. The concept of TNF-α inhibition may also prove beneficial for patients undergoing bone marrow transplantation. Furthermore, we demonstrate that HOXB4 activity and FGF signaling are intertwined. HOXB4-mediated expansion of adult and ES cell-derived HSCs was enhanced by specific and complete inhibition of FGF receptors. In contrast, the expanding activity of HOXB4 on hematopoietic progenitors in day 4-6 embryoid bodies was blunted in the presence of basic FGF (FGF2), indicating a dominant negative effect of FGF signaling on the earliest hematopoietic cells. In summary, our results strongly suggest that HOXB4 modulates the response of HSCs to multiple extrinsic signals in a concerted manner, thereby shifting the balance toward stem cell self-renewal.

Background The heterogeneity of endothelial cell types underlies their remarkable ability to sub-specialize and provide specific requirements for a given vascular bed. Here, we compared rat microvascular endothelial cells (MECs) derived from the brain and spinal cord in both basal and inflammatory conditions. Methods We used whole rat genome microarrays to compare, at different time points, basal and TNF-α-induced gene expression of rat MECs from in vitro models of the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). Validation at both messenger RNA (mRNA) and protein levels was performed on freshly extracted microvessels (MVs) from the brain and spinal cord (BMVs and SCMVs, respectively), as these were considered the closest in vivo tissues to cultured MECs. Results Most of the genes encoding adhesion/tight junction molecules and known endothelial markers were similarly expressed in brain and spinal cord MECs (BMECs and SCMECs, respectively). However, one striking finding was the higher expression of several Hox genes, which encode transcription factors involved in positional identity. The differential expression of Hoxa9 and Hoxb7 at the mRNA levels as well as protein levels was confirmed in BMVs and SCMVs. Although the TNF-α response was in general higher in BMECs than in SCMECs at 12 h, the opposite was observed at 48 h. Furthermore, we found that expression of Tnfrsf1a and Tnfrsf1b encoding the TNF receptor super-family member 1a/TNFR1 and 1b/TNFR2, respectively, were constitutively higher in BMVs compared to SCMVs. However, only Tnfrsf1b was induced in SCMECs in response to TNF-α at 24 and 48 h. Conclusions Our results support a role for HOX members in defining the positional identities of MECs in vivo. Our data also suggest that the delayed transcriptional activation upon TNF-α treatment in SCMECs results from the requirement of the TNF-induced expression of Tnfrsf1b . In contrast, its high basal expression in BMECs might be sufficient to confer an immediate and efficient TNF-α response.

The estrogen receptor alpha (ERalpha) is a ligand-regulated transcription factor. However, a wide variety of other extracellular signals can activate ERalpha in the absence of estrogen. The impact of these alternate modes of activation on gene expression profiles has not been characterized. We show that estrogen, growth factors and cAMP elicit surprisingly distinct ERalpha-dependent transcriptional responses in human MCF7 breast cancer cells. In response to growth factors and cAMP, ERalpha primarily activates and represses genes, respectively. The combined treatments with the anti-estrogen tamoxifen and cAMP or growth factors regulate yet other sets of genes. In many cases, tamoxifen is perverted to an agonist, potentially mimicking what is happening in certain tamoxifen-resistant breast tumors and emphasizing the importance of the cellular signaling environment. Using a computational analysis, we predicted that a Hox protein might be involved in mediating such combinatorial effects, and then confirmed it experimentally. Although both tamoxifen and cAMP block the proliferation of MCF7 cells, their combined application stimulates it, and this can be blocked with a dominant-negative Hox mutant. The activating signal dictates both target gene selection and regulation by ERalpha, and this has consequences on global gene expression patterns that may be relevant to understanding the progression of ERalpha-dependent carcinomas.

Neonatal diethylstilbestrol (DES) exposure elicits a wide range of abnormalities in the female mouse genital tract. This animal model system is suitable for investigating the mechanism of DES syndrome in humans. Accumulated evidence has shown that critical periods in development are present for distinct and permanent alterations in the female genital tract of mice exposed to DES neonatally (DES-mice). These effects of DES and other estrogens are mainly mediated by estrogen receptor α (ERα) through multiple pathways. Induction of ERα by DES exposure in neonatal stromal and epithelial cells, and successive premature activation of estrogen-regulated genes are thought to be essential to induce the abnormalities. Induction of malformation, permanent changes in estrogen-regulated genes, such as protooncogenes and growth factors, and carcinogenesis are assumed to be interdependent. This review focuses the following topics to discuss the molecular basis of DES-induced abnormalities mainly based on the results by histochemical techniques in the uterus: spatiotemporal expression of ERa and coactivators, proteins relating morphogenesis, and estrogen-regulated protooncogenes and growth factors.

We previously reported that favorable and poor prognostic chromosomal rearrangements in acute myeloid leukemia (AML) were associated with distinct levels of HOX expression. We have now analyzed HOX expression in 50 independent adult AML patients (median age=62 years), together with FLT3 and FLT3-ligand mRNA levels, and FLT3 mutation determination. By cluster analysis, we could divide AMLs into cases with low, intermediate and high HOX expression. Cases with high expression were uniquely restricted to a subset of AMLs with intermediate cytogenetics (P=0.0174). This subset has significantly higher levels of FLT3 expression and appears to have an increase of FLT3 mutations (44%), while CEBPalpha mutations were infrequent (6%). FLT3 mRNA levels were correlated with the expression of multiple HOX genes, whereas FLT3 mutations were correlated with HOXB3. In some cases, FLT3 was expressed at levels equivalent to GAPDH in the absence of genomic amplification. We propose that high HOX expression may be characteristically associated with a distinct biologic subset of AML. The apparent global upregulation of HOX expression could be due to growth-factor signaling or, alternatively, these patterns may reflect a particular stage of differentiation of the leukemic cells.

Runx gene family transcription factors play important regulatory roles in metazoan development. The Drosophila genome contains four Runx genes, two of which are well studied (runt and lozenge) and two of which have not been explored in depth yet (CG42267 and CG34145). In the absence of paralog-specific orthologs in vertebrates, we investigated the evolutionary conservation of the Drosophila Runx genes in the genomes of mosquito, red flour beetle, honeybee, and distantly related Bilateria. All four Drosophila Runx genes are conserved in other endopterygote insects. Strikingly, their genetic linkage and genomic arrangement is also highly conserved despite past recombination events in the same genomic region. The preservation of Runx gene cluster organization for at least 300 million years resembles that of insect Hox and selected Wnt genes. We propose a model for the conserved cluster organization of developmental gene family paralogs based on differential coduplication of regulatory elements that act over long distances.

The PLZF gene is translocated in a subset of all- trans -retinoic acid resistant acute promyelocytic leukaemia (APL) cases, encodes a DNA binding transcription factor and is expressed highly in haematopoietic progenitor cells as well-developing central nervous system (CNS). The spatially restricted and temporally dynamic pattern of PLZF expression in the developing CNS suggested that it might play a role in the circuitry regulating hindbrain segmentation. We have now identified a PLZF binding site (PLZF-RE) in an enhancer region of Hoxb2 that itself is required for directing high-level expression in rhombomers 3 and 5 of the developing hindbrain. The wild-type r3/r5 enhancer linked to a heterologous promoter was responsive to regulation by PLZF, and this activity was lost in variants containing a mutated PLZF-RE. Compared with the wild-type protein, the binding of the APL-associated reciprocal RAR α –PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding. Consistent with this, the N-terminal POZ domain was required for cooperative binding of PLZF to a multimerized PLZF-RE. In the context of the r3/r5 enhancer, the PLZF-RE cooperated for PLZF binding with an additional A/T-rich motif positioned downstream of the PLZF-RE. This A/T motif was previously shown to be essential for the regulation of Hoxb2 expression in r3 and r5 in cooperation with another Krüppel-like zinc finger protein Krox 20. The presence of both the PLZF-RE and the A/T-rich motif was required for a maximal effect of PLZF on a heterologous promoter and was essential in vivo to direct the expression of a lacZ reporter in the chick neural tube. Hence, both PLZF and Krox20 cooperate with a common A/T motif in mediating in vivo activity of the Hoxb2 enhancer. Our findings indicate that Hoxb2 is a direct target for regulation by PLZF in the developing CNS and suggest that deregulation of Hox gene expression may contribute to APL pathogenesis.