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Disruption of the thyroid hormone system and patterns of altered thyroid hormone serum concentrations after chemical exposures in adult rodents – a systematic review

2026-01-01T00:00:00Z

Title: Disruption of the thyroid hormone system and patterns of altered thyroid hormone serum concentrations after chemical exposures in adult rodents – a systematic review Authors: Baig, Asma H; Forner-Piquer, Isabel; Ermler, Sibylle; Kortenkamp, Andreas Abstract: Identification of thyroid hormone system-disrupting chemicals (THSDC) requires a solid understanding of the mechanisms by which exposure leads to adverse outcomes in the thyroid hormone system (THS). In this systematic review we present the results from our extensive evidence mapping of thyroid hormone (TH) and thyroid stimulating hormone (TSH) patterns in serum or plasma, after exposure to various THSDCs in adult rodents. Our review of 234 peer-reviewed studies revealed that only a small group of compounds induced changes in T4 and TSH consistent with the canonical view of the hypothalamic-pituitary-thyroid (HPT) negative feedback loop, whilst the most frequent pattern was a decrease in T4 without TSH changes. The lack of a TSH response may have been due to T4 decreases not being sufficient to change HPT feedback. However, risk-of-bias analysis also identified deficits in TH/TSH analytical methodology, including the timepoints of TH measurements, possibly explaining discrepancies between studies. We further compared T4/TSH patterns to mechanism-of-action information and other THS-related outcomes and found that THSDC frequently affected TH synthesis, induced hepatic enzymes involved in TH metabolism, and exhibited other differences in pharmacokinetic properties. Given the diverse chemical nature of the various THSDCs and variety of molecular targets in the THS, there is likely no single explanation for the different patterns observed. Our compilation of T4/TSH patterns observed after different chemical exposures demonstrated that it is important to not solely rely on the canonical serum hormonal patterns to determine adversity of chemical exposures. Chemicals with different responses should be carefully considered, as current regulatory criteria may fail to identify them as being harmful to human health. Description: ...

Hydrogels Augmented With Artificial Sweeteners can Inhibit Multidrug‐Resistant Acinetobacter baumannii Growth and Biofilm Formation While Demonstrating Safety in Pre‐Clinical Pilot Human Trials

2026-08-26T00:00:00Z

Title: Hydrogels Augmented With Artificial Sweeteners can Inhibit Multidrug‐Resistant Acinetobacter baumannii Growth and Biofilm Formation While Demonstrating Safety in Pre‐Clinical Pilot Human Trials Authors: Han, Jie; Soliman, Mohamed; Zhang, Bin; Krawiel, Dominika; McCarthy, Ronan R Abstract: There is a critical need for novel therapeutic strategies to tackle multidrug‐resistant bacterial infections. Artificial sweeteners (AS) specifically acesulfame potassium, sodium saccharin, and sodium cyclamate, have recently demonstrated antimicrobial activity against multidrug‐resistant bacteria. In this study, polyvinyl alcohol (PVA)‐borate hydrogel is developed as a carrier for antimicrobial AS to combat wound infections. Through extensive optimization, we developed cytocompatible 8% AS‐loaded hydrogels with 3% PVA + 3% borax that reduced the viability of multidrug‐resistant Acinetobacter baumannii AB5075 by 99.9% colony‐forming unit enumeration following 1 h hydrogel treatment. Most currently available wound dressings have limited efficacy against bacterial biofilms, but we demonstrate that each of these sweeteners can attenuate A. baumannii and Pseudomonas aeruginosa dual‐microbial biofilms. Haemolysis and cell viability assays demonstrate excellent blood compatibility and non‐cytotoxic behavior of the sweetener‐loaded hydrogels. To further evaluate the clinical potential of these AS‐loaded hydrogels, we conducted a pilot Phase I clinical study with human volunteers focused on evaluating short‐term safety and irritancy. This study revealed that the dressings had no adverse effects on the volunteers. This research underscores the translational potential of hydrogels augmented with AS and their capacity to overcome many of the hurdles that typically lead to wound dressing failure. Description: Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Telomere length elongation by epigenetic modifier drugs: A potential mechanism by which cancer develops chemo-resistance

2025-01-01T00:00:00Z

Title: Telomere length elongation by epigenetic modifier drugs: A potential mechanism by which cancer develops chemo-resistance Authors: Al-dulaimi, Sarah Abstract: Telomeres are specialised structures localized at the ends of eukaryotic linear chromosomes. Telomeres play an important role in protecting chromosome ends by preventing the activation of DNA damage response (DDR). In normal cells, telomeres become shorter with each cell division, which eventually leads to cellular senescence. Cancer cells, avoid telomere shortening by activating mechanisms that maintain telomere lengths. Most normal cells reach replicative senescence after 90 population doublings and then enter telomere crisis. This suggest that many premalignant cells lose their ability to keep dividing before they can accumulate additional mutations. Two mechanisms are known: telomerase reactivation and alternative lengthening of telomere (ALT). 80% -85% of cancer cells activates telomerase. The telomerase enzyme consists of two subunits, telomerase reverse transcriptase (TERT) and telomerase RNA (TR). ALT is active in around 15-20 % of cancer cells and maintains telomere lengths via alternative lengthening of telomere via homologous recombination. A common feature of ALT-positive human cells is the presence of C-circles and promyelocytic leukemia (PML) nuclear bodies (ALT-associated PML (APBs)). POLD3, a subunit of DNA polymerase has also been shown to be essential for ALT activity. The hypomethylating drug 5-aza-2′-deoxycytidine (5-aza) is widely used in the treatment of haematological malignancies. Moreover, cancer cells rapidly become resistant to the drug, leading to relapse. The study presented in this thesis investigated the short term (72 h) and long term (over one month) effects of 5-aza on telomere biology in breast cancer cells, with a focus on ALT activity and POLD3 expression. Telomere maintenance mechanisms were investigated using qPCR, c-circle and TRAP assays. The TIF (Telomere dysfunction induced foci) was used to detect DNA damage at telomeres and immunofluorescence for the detection of ALTassociated PML. POLD3 gene expression was quantified using qPCR and western blotting. Short-term 5-aza treatment modestly altered telomerase activity while significantly promoting ALT activation, which was accompanied by increased expression of POLD3. Silencing of POLD3 using siRNA in 5-aza treated cells resulted in telomere shortening. Long-term exposure to 5-aza led to the development of drug resistance, with cells acquiring the ability to proliferate at higher concentrations of 5-aza, and reduced sensitivity to doxorubicin, alongside increased migratory capacity. However, resistant cells exhibited enhanced sensitivity to radiotherapy. Collectively, our findings demonstrate that low-dose (10 uM) and prolonged exposure to 5- aza promotes ALT- dependent telomere maintenance through POLD3 upregulation, contributing to cancer cell survival and therapeutic resistance. These findings identify a novel mechanism by which cancer cells develop resistance to epigenetic therapy and also highlight telomere maintenance pathways as promising targets to improve treatment outcomes. Resistance to 5-aza significantly compromises the efficacy of combination therapies, including those involving chemotherapy and radiotherapy Description: This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London

Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting

2026-06-22T00:00:00Z

Title: Dysregulation of sphingolipid-metabolizing enzymes in Friedreich’s ataxia: In vitro and in vivo insights into therapeutic targeting Authors: Ramchunder, Z; Kalef-Ezra, E; Suleman, S; Edzeamey, FJ; Szunyogh, S; Gittins, O; Mena, NC; Wade-Martins, R; Valle, A; Pourzand, C; Anjomani Virmouni, S Abstract: Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder caused by a GAA repeat expansion within the FXN gene, leading to reduced frataxin levels. This deficiency results in mitochondrial dysregulation, oxidative stress, and progressive cell death. Currently, only one approved treatment exists for FRDA in the United States, Canada, and the European Union, which improves neurological outcomes but has not been fully evaluated for broader disease symptoms. Therefore, identifying new therapeutic targets remains essential. Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA. Description: Data and code availability: • All data reported in this paper will be shared by the lead contact upon request. • This paper does not report original code. • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.