Elucidating the link between thyroid cancer and mercury exposure: a review and meta-analysis.

Mercury (Hg) is a widely distributed and bioavailable metal of public health concern, with many known human toxicities, but data regarding mercury's influence on thyroid cancer (TC) is scarce. Mercury is known to impact several molecular pathways implicated in carcinogenesis, and its proclivity for bioaccumulation in the thyroid suggests a potential modulatory effect. We conducted a literature/systematic review of studies between 1995-2022 intending to define better and establish relationships between these two entities, congregate the evidence for mercury's potential role in thyroid carcinogenesis, and identify populations of interest for further study. Insufficient evidence precludes definitive conclusions on dietary mercury as a TC risk factor; however, several common mechanisms affected by mercury are crucial for TC development, including biochemical, endocrine, and reactive oxygen species effects. Quantitative analysis revealed associations between TC risk and mercury exposure. In three mercury studies, average urine levels were higher in TC patients, with a mean difference of 1.86 µg/g creatinine (95% CI = 0.32-3.41). In two studies investigating exposure to elevated mercury levels, the exposed group exhibited a higher risk of developing TC, with a relative risk of 1.90 (95% CI = 1.76-2.06). In three thyroid tissue studies, mercury levels (ppm) were higher in TC patients, averaging 0.14 (0.06-0.22) in cancerous cases (N = 178) and 0.08 (0.04-0.11) in normal thyroids (N = 257). Our findings suggest an association between mercury exposure and TC risk, implying a possible predisposing factor. Further research is necessary to reveal the clinical relevance of dietary and environmental mercury exposures in TC pathogenesis.

An in vivo Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics.

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics.

Discovery of Selective SIRT2 Inhibitors as Therapeutic Agents in B-Cell Lymphoma and Other Malignancies.

Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD+-dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC50 56 and 59 µM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds 55 (IC50 SIRT2 0.25 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) and 56 (IC50 SIRT2 0.78 µM and <25% inhibition at 50 µM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells.

Hydrogen gas formation from the photolysis of rhenium hydrides - mechanistic and computational studies.

The photolysis of 4,4'-disubstituted, 2,2'-bipyridine fac-Re(bpy)(CO)3H derivatives produces stoichiometric H2 gas. The rate of production varies greatly depending on the electronic nature of the disubstituted bipyridine (bpy) with halogenated substituents increasing the rate. Isotope labeling studies along with B3LYP geometry optimization DFT modeling studies indicate a mechanism involving a Re-H-Re bridging complex that leads to a dimeric Re-Re(η2-H2) state prior to dissociating H2 gas.

An N-heterocyclic carbene phenanthroline ligand: synthesis, multi-metal coordination and spectroscopic studies.

Dimetal complexes of a new N-heterocyclic carbene/phenanthroline ligand have been synthesized. Coordination of both ruthenium and rhenium to the phenanthroline moiety in combination with platinum at the carbene moiety are reported. Steady-state and time-resolved optical absorption and photoluminescence spectra were obtained for the complexes. These results illustrate significant changes occur with the incorporation of the second metal, and that the specific metal bound to the phenanthroline moiety is important to the photophysical characteristics of this system.