TGFß signalling: a nexus between inflammation, placental health and preeclampsia throughout pregnancy.

BACKGROUND: The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFß) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFß signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFß signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFß signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFß is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE: This comprehensive review aims to explore and elucidate the roles of the major members of the TGFß superfamily, including TGFßs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS: A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfß', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfß signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfß signalling', 'placental macrophages tgfß', 'endothelial cells tgfß', 'endothelium tgfß signalling', 'trophoblast invasion tgfß signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfß', 'tgfß preeclampsia', 'tgfß placental development', 'TGFß placental function', 'endothelial dysfunction preeclampsia tgfß signalling', 'vascular remodelling placenta TGFß', 'inflammation pregnancy tgfß', 'immune response pregnancy tgfß', 'immune tolerance pregnancy tgfß', 'TGFß pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfß pregnancy tregs', 'TGFß placenta NK cells', 'TGFß placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES: A comprehensive understanding of TGFß signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFß ligands contribute to the proper functioning of a healthy maternal-foetal interface. However, dysregulation of TGFß signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFß signalling. WIDER IMPLICATIONS: The dysregulation of TGFß signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFß signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE.

Combination of biological screening in a cellular model of viral latency and virtual screening identifies novel compounds that reactivate HIV-1.

Although highly active antiretroviral therapy (HAART) has converted HIV into a chronic disease, a reservoir of HIV latently infected resting T cells prevents the eradication of the virus from patients. To achieve eradication, HAART must be combined with drugs that reactivate the dormant viruses. We examined this problem in an established model of HIV postintegration latency by screening a library of small molecules. Initially, we identified eight molecules that reactivated latent HIV. Using them as templates, additional hits were identified by means of similarity-based virtual screening. One of those hits, 8-methoxy-6-methylquinolin-4-ol (MMQO), proved to be useful to reactivate HIV-1 in different cellular models, especially in combination with other known reactivating agents, without causing T-cell activation and with lower toxicity than that of the initial hits. Interestingly, we have established that MMQO produces Jun N-terminal protein kinase (JNK) activation and enhances the T-cell receptor (TCR)/CD3 stimulation of HIV-1 reactivation from latency but inhibits CD3-induced interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α) gene transcription. Moreover, MMQO prevents TCR-induced cell cycle progression and proliferation in primary T cells. The present study documents that the combination of biological screening in a cellular model of viral latency with virtual screening is useful for the identification of novel agents able to reactivate HIV-1. Moreover, we set the bases for a hypothetical therapy to reactivate latent HIV by combining MMQO with physiological or pharmacological TCR/CD3 stimulation.

Effects of diterpenes from latex of Euphorbia lactea and Euphorbia laurifolia on human immunodeficiency virus type 1 reactivation.

The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy, referred to as HAART. HIV-1 reservoirs are long-lived resting CD4+ memory cells containing the virus latently integrated. Since the HIV-1 reservoirs are not targeted by HAART, reactivation therapy has been suggested to purge viral latency. Bioassay-guided study of an ethyl acetate extract of Euphorbia laurifolia afforded two isomeric diterpenes that showed differential activity over HIV-1 reactivation. A previously reported compound was isolated too from Euphorbia lactea. This compound showed a potent HIV-1 reactivating effect. Bioassays results showed that HIV-1 reactivation activity is influenced by distinct structural characteristics.

Denbinobin, a naturally occurring 1,4-phenanthrenequinone, inhibits HIV-1 replication through an NF-kappaB-dependent pathway.

Anthraquinones and structurally related compounds have been recently shown to exert antiviral activities and thus exhibit a therapeutic potential. In this study we report the isolation of the 1,4-phenanthrenequinone, denbinobin, from a variety of Cannabis sativa. Denbinobin does not affect the reverse transcription and integration steps of the viral cycle but prevents HIV-1 reactivation in Jurkat T cells activated by TNFalpha, mAbs anti-CD3/CD28 or PMA. In addition, denbinobin inhibits HIV-1-LTR activity at the level of transcription elongation and also TNFalpha-induced HIV-1-LTR transcriptional activity. We found that denbinobin prevents the binding of NF-kappaB to DNA and the phosphorylation and degradation of NF-kappaB inhibitory protein, IkappaBalpha, and inhibits the phosphorylation of the NF-kappaB p65 subunit in TNFalpha-stimulated cells. These results highlight the potential of the NF-kappaB transcription factor as a target for natural anti-HIV-1 compounds such as 1,4-phenanthrenequinones, which could serve as lead compounds for the development of an alternative therapeutic approach against AIDS.

Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation.

The persistence of latent reservoirs of HIV-1 represents a major barrier to virus eradication in patients treated with antiretrovirals. Prostratin is a non-tumor promoting 12-deoxyphorbol monoester capable of up-regulating viral expression from latent provirus and therefore is potentially useful for HIV adjuvant therapy and similar properties might be elicited by related non-tumor promoting phorboids. We have therefore investigated a series of phorbol 13-monoesters for their capacity to reactivate HIV latency. Using a Jurkat T cell line containing latent HIV proviruses, we found that prostratin and phorbol-13-stearate effectively activate HIV-1 gene expression in these latently infected cells, with phorbol-13-stearate being at least 10-fold more potent than prostratin, and its activity rapidly decreasing with a shortening of the acyl side chain. We further demonstrated that phorbol-13-stearate and prostratin stimulate IKK-dependent phosphorylation and degradation of IkappaBalpha, leading to activation of NF-kappaB. Moreover, prostratin, phorbol-13-hexanoate and phorbol-13-stearate also activate the JNK and ERK pathways. Studies with isoform-specific PKC inhibitors suggest that the classical PKCs play a prominent role in the responses elicited by phorbol-13-stearate. Nevertheless, this compound induces a translocation pattern of the PKC isotypes alpha and delta to cellular compartments distinctly different from that elicited by prostratin and PMA.

A meroterpenoid NF-kappaB inhibitor and drimane sesquiterpenoids from Asafetida.

Investigation of an acetone extract from Asafetida afforded two drimane sesquiterpene dienones (fetidones A and B, 1a,b) and several known sesquiterpene coumarin ethers, one of which (8-acetoxy-5-hydroxyumbelliprenin, 2a) showed potent and specific NF-kappaB-inhibiting properties. This, coupled to a negligible cytotoxicity, qualifies 2a as a new anti-inflammatory chemotype, and its occurrence in asafetida might rationalize the use of this gum resin to alleviate and prevent colon inflammatory disturbances.