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Publications

A complete up-to-date list of publications of Robert can be found on Google Scholar and full-texts might be available from the Warwick Research Active Portal (WRAP).

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Organometallic Anticancer Complexes with Activated Ligands

New study from Ed Lant's PhD project, entitled "Tuning Ligand Substituents for Enhanced Catalytic Activity and Antiproliferative Effects in Rh(III) Azopyridine Complexes".

chemical sturcture lant paper We report the synthesis and characterisation of ten novel half-sandwich Rh(III) azopyridine complexes as potential anticancer agents, with the general formula [Rh(η5-Cpx)(4-R2-phenylazopy-5-R1)Cl]PF6, where Cpx = Cp*, CpxPh or CpxPhPh, R1 = H, Br, or CF3, and R2 = H, OH or NMe2. X-ray crystallographic data for complex 2 (R1 = Br, R2 = OH, Cpx = CpxPh) and complex 3 (R1 = CF3, R2 = OH, Cpx = CpxPh) confirm their typical half-sandwich “piano-stool” geometry. The substituents have a major effect on the cytotoxicity of these complexes towards human ovarian (A2780 and cisplatin-resistant A2780cis), lung (A549), prostate (PC-3) and breast (MCF-7) cancer cells, and non-cancerous human lung fibroblasts (MRC5). Potencies range from sub-micromolar to inactive within the concentration range investigated (<100 µM). Selectivity for cancer cells over non-cancerous cell is strongly dependent on the nature of the bidentate ligand. The nano-molar active, highly lipophilic complex 2 was strongly accumulated by cells, and catalyzed the oxidation of NADH to NAD+, and GSH to GSSG. Notably, complex 2 is almost an order of magnitude less toxic in vivo than cisplatin. These complexes appear to have an unusual mechanism of anticancer activity, associated not only with Rh(III) but also the azo bond and activated cyclopentadienyl methyl groups.
Mon 12 May 2025, 09:45 | Tags: Original Article 2025

A clock in mammalian cells modulates bacterial cellular entry

Title:

The cellular mammalian clock regulates Staphylococcus aureus invasion in epithelial cells
Authors: Pooja Agarwal, Giridhar Chandrasekharan, Jaspreet Grewal, Robert Dallmann, and Meera Unnikrishnan
s.aureus timing

An endogenous biological clock, the circadian clock, coordinates life with the 24-hour day/night cycle of the environment. The unit of this circadian clock is the cell but in multicellular organisms, such as mammals, a circadian timing system (CTS) with a central pacemaker orchestrates peripheral clocks and the overall finely tuned temporal order. For example, the CTS changes immune responses to infections depending on time-of-day, however, its role in controlling bacterial infections at a cellular level is not understood.

In this study, we investigated the role of the host cellular clock during infection by Staphylococcus aureus, a highly drug-resistant, facultatively intracellular human pathogen. Our findings revealed that S. aureus invasion into epithelial cells is dependent on the cellular circadian phase. Interestingly, in BMAL1, an essential clock protein, deficient cells bacterial uptake was significantly higher compared to parental A549 cells. RNA sequencing of BMAL1 knockdown (KD) cells showed a significant upregulation of GP340, coding for the receptor of SraP, an S. aureus adhesin. An S. aureus mutant lacking SraP did not exhibit a circadian rhythm of uptake into A549 cells nor an increased uptake into BMAL1 KD compared to the parental A549 cells. Of note, bacterial mutants for other adhesins continued to show a rhythmic and higher uptake in BMAL1 KD cells.

Hence, we report that S. aureus invasion of epithelial cells is clock-modulated and mediated through S. aureus SraP, suggesting potential for host clock-directed therapy against this pathogen.

Tue 06 May 2025, 22:10 | Tags: Preprint 2025

Cationic antimicrobial copolymers reveal immunomodulatory properties in LPS stimulated macrophages in vitro

Great collaboration with Seb Perrier's group characterising the anti-inflammatory properties of anti-microbial polymers led by Sophie Laroque.

Graphical abstract Antimicrobial polymers, which have emerged as a promising alternative to antibiotics in the fight against antimicrobial resistance, are based on the design of cationic host defence peptides (CHDPs). Being a part of the mammalian innate immune system, CHDPs possess both antimicrobial and immunoregulatory effects to manage bacterial infections. However, the immunomodulatory effects of antimicrobial polymers remain largely unexplored. Within this work, a library of 15 copolymers were synthesised by reversible addition-fragmentation chain transfer (RAFT) polymerisation and their abilities to modulate pro-inflammatory pathways in LPS-activated murine and human macrophages were investigated. We found that two diblock copolymers with cationic units copolymerised with either apolar or hydrophilic comonomers appeared to have anti-inflammatory activity through suppression of the activation of the NF-κB signalling pathway, scavenging of reactive oxygen species and reduced production of the pro-inflammatory cytokine IL-6. Furthermore, the cationic-apolar copolymer exhibits
significant antimicrobial activity against P. aeruginosa. Thus, this promising copolymer holds potential as a dual-action therapeutic, effectively combating bacterial infections while curbing prolonged inflammation and thereby preventing sepsis at the site of infection.
Wed 09 Apr 2025, 19:41 | Tags: Preprint 2025

Chronopharmacokinetics of the antidepressant paroxetine: an in vitro and in vivo approach

Led by the fantastic Soraia Silva as part of her PhD work in Ana Fortuna's lab at Coimbra University, this collaboration was published in Neuropharmacology now.

brain plasma ration

Soraia shows how time of day significantly influences how much of the antidepressant SSRI paroxetine gets into the brain after intranasal application.

The circadian rhythm influences homeostatic functions such as sleep, physical activity and food intake as well as pharmacotherapy, namely pharmacokinetics. To investigate the impact of the circadian rhythm on the pharmacokinetics of paroxetine, in vitro synchronized permeability studies were carried out in a tri-culture blood-brain barrier model. Paroxetine demonstrated lower apparent permeability when the cells were incubated at 24 h post-synchronization than at 36 h. Additionally, in vivo chronopharmacokinetic studies were performed in CD-1 female mice administered with paroxetine (5 mg/kg) by intranasal route in the early morning or evening. Paroxetine exposure in the brain was higher when it was administered at the beginning of the active phase (ZT13) compared with the rest phase (ZT1) (p<0.001), probably owing to the lower levels of P-glycoprotein expressed in the brain at the active phase (p<0.05). Since melatonin production depends on serotonin, its plasma concentrations were also assessed in vivo. The results demonstrated that melatonin concentrations increased 12 h after paroxetine nasal instillation at ZT13 (p<0.05), but remained unchanged at ZT1, suggesting that the drug effect is influenced by administration time.

In conclusion, the circadian rhythm impacted the pharmacokinetics of paroxetine, especially its distribution into the brain, the target organ. This emphasizes the importance of the time of administration in antidepressant dosing, highlighting its relevance for future studies.

Wed 02 Apr 2025, 00:00 | Tags: Original Article 2025


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