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TRPM8 (Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybenzyl(2-aminoethyl)carbamate) which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo.

We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO 2 extract of Nerium oleander , in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0–4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0–4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer’s disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.

Severe Congenital Adrenal Hyperplasia (CAH) is most commonly caused by genetic defects in the CYP21A2 gene, which leads to a deficiency of 21-hydroxylase enzyme and disruption in the biosynthesis of Adrenal corticosteriods. Despite treatment with corticosteroids, patients remain at significant risk for adrenal crisis, experiencing a 3-fold higher mortality rate than age matched controls. They also suffer from significant infertility, bone, metabolic, and cardiovascular disease, and hyperandrogenism in women leading to genital abnormalities, hirsutism, and other complications. We are developing an AAV5- based gene therapy (BBP-631) that will provide a functional copy of the CYP21A2 gene to the adrenal glands of CAH patients. To determine the durability of this therapy we treated cynomolgus monkeys with increasing doses of BBP-631 via intravenous injection. At 4-, 12- and 24-weeks post treatment, expression of hCYP21A2 mRNA and vector genome copies (VGC) in the adrenals and other peripheral tissues was measured. VGC was present in the liver and adrenals at 4 weeks, with durable detection through 24 weeks and total vg levels were dose dependent. hCYP21A2 RNA expression in adrenal and liver tissues was also dose dependent and continued to increase from 4 weeks through 12 weeks. There were no adverse safety signals in any of the treated animals. This data combined with efficacy data of BBP-631 in a Cyp21-/- mouse model supports our continued clinical development of BBP-631 as a treatment for congenital adrenal hyperplasia.

The increased call for practical sessions at the annual meetings, and a new focus in TLT on more practical and basic lubrication engineering principles address another need of our membership.

In fact I was privileged to have been part of a delegation representing STLE that met with His Excellency, President of the Republic of Trinidad and Tobago We presented him with an STLE Honorary Lifetime Membership due to his achievements in the fields of chemical engineering and education, as well as his longstanding commitment to his country as president.

Thought leaders involved in research, consulting and technical service comprise an additional 23%. with the remainder coming from additive suppliers and a mixture of small and/or specialized segments, i.e., makers of test equipment. STLE earned higher than average marks for its reputation, speaker/ author expertise and for the opportunity to network with peers.

It's time to begin thinking about what technical sessions you'll be attending and to register for those education courses you've wanted to take. It's also not too early to start putting together the presentation you plan on making.

There is no doubt that tribologists will play a significant role in the Bionic Age of replacement parts for humans, since many devices have moving parts, and control of friction and wear remains a challenge for the future. Following a brief overview of some of the exciting medical devices being developed to improve the quality of life and extend life expectancy.