Spotlight pubs.acs.org/crt
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ORAL DIETARY SUPPLEMENT REDUCES EARLY POSTPARTUM VULNERABILITY TO DEPRESSION Postpartum blues (PPB) affects ∼75% of women 4−6 days after giving birth, with severe PPB a high-risk factor for postpartum depression. Levels of the flavoenzyme monoamine oxidase A (MAO-A) are significantly elevated (>40%) in women suffering from PPB. MAO-A critically regulates brain function by deaminating and degrading neurotransmitters such as dopamine, norepinephrine, and serotonin, and elevated MAO-A levels are associated with major depressive episodes. Jeffrey H. Meyer and his collaborators investigated whether dietary supplements in the early postpartum period could counter the effects of increased MAO-A levels, decreasing the severity of PPB and preventing subsequent induction of postpartum depression ((2017) PNAS, 114, 3509−3514). The authors conducted an open-label study composed of 41 healthy, medication-free postpartum women, with 21 mothers taking oral supplements days 3−5 postpartum. As enhanced MAO-A function is associated with increased neurotransmitter metabolism, the supplements included L-tryptophan and L-tyrosine, precursors of serotonin, norepinephrine, and dopamine. Antioxidant-containing blueberry juice and extract were also included to counter excessive oxidative stress catalyzed by MAO-A. On day 5 postpartum, when PPB typically peaks, the study subjects were given negative statements to read, which they were asked to feel and experience while listening to Prokofiev’s “Russia Under the Mongolian Yoke”. The researchers quantitatively assessed the participants before and after for their vulnerability to depression and used established indicators to identify depressed moods and determine PPB severity. Results indicated that women in the control group had significantly higher levels of depression indicators after the sad mood induction procedure than did those in the supplement group. This work suggests that dietary supplementation targeting postpartum neurobiological changes reduces the vulnerability of postpartum women to depression. Abigail Druck Shudofsky
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SPIDER-VENOM PEPTIDE PROVIDES POTENT NEUROPROTECTION AFTER STROKE
ASIC1a-overexpressing cells with Hi1a and found that the peptide induces a delay in channel activation, likely by binding and stabilizing its resting state. They then investigated the neuroprotective efficacy of Hi1a and found that it caused concentration-dependent increases in cell viability in oxidatively stressed primary neuronal cultures, with 100 nM of the peptide increased cell viability by 77%. Excitingly, one (2 ng/kg) dose administered i.c.v. to rats 2, 4, or 8 h after stroke induction markedly reduced the size of ischemic tissue and protected both the surrounding and core tissue, the latter of which was thought to be therapeutically untreatable. Hi1a-treated animals displayed improved neurological and motor function and preserved neuronal architecture without demonstrating any adverse effects. With improved behavioral outcomes observed even when the peptide was administered 8 h poststroke onset, Hi1a is a promising therapeutic lead for neuroprotection after ischemic injury. Abigail Druck Shudofsky
Courtesy of Dr. Glenn F. King.
Oxygen deprivation in ischemic strokes causes acidosis and a drop in brain tissue pH. This decrease activates the neuronal acid-sensing ion channel 1a (ASIC1a), a principal mediator of stroke-induced neuronal damage. While tissue in the “core” stroke region is irreversibly damaged, surrounding ischemic tissue can be salvaged with quick treatment. A team led by Glenn F. King and Lachlan D. Rash isolated a venom peptide that potently inhibits ASIC1a in vitro and in vivo and protects against neuronal injury when given up to 8 h poststroke onset ((2017) PNAS, 114, 3750−3755). The authors identified and characterized Hi1a, a disulfiderich peptide from the Australian spider Hadronyche infensa that selectively and incompletely inhibits ASIC1a in a noncompetitive, pH-independent manner with slow reversibility. Using nuclear magnetic resonance structural studies, they determined that Hi1a is a “double-knot” peptide composed of two homologous inhibitor cysteine knot domains covalently connected by a short linker. The researchers treated human © 2017 American Chemical Society
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NOVEL TRIAZOLE CORE ANDROGEN RECEPTOR ANTAGONISTS HAVE IMPROVED ACTIVITY AGAINST PROSTATE CANCER
Courtesy of Dr. Claudia Ferroni and Dr. Greta Varchi.
Androgen receptor (AR) activation plays an essential role in prostate cancer progression. While AR is a therapeutic target, prostate cancers frequently develop mutation-based drug resistance. Published: May 15, 2017 1111
DOI: 10.1021/acs.chemrestox.7b00097 Chem. Res. Toxicol. 2017, 30, 1111−1112
Chemical Research in Toxicology
Spotlight
PepH1 and PepH3 were 1.6- and 3.4-fold higher than those of the negative radiometal core control. The peptides were rapidly eliminated from the brain, with 50%. Most molecules were one-spacer triazoles, which downregulated PSA by >65%, though one two-spacer compound (14b) downregulated PSA by 70%. The scientists tested these derivatives along with an additional two-spacer representative (14d) for potency and cytotoxicity in androgen-sensitive cell lines. They found that 14d was most effective at strongly inhibiting cell proliferation. When they subsequently evaluated the antitumor activity of 14d in a prostate cancer cell model resistant to other nonsteroidal antiandrogens, they found that 14d treatment resulted in potent cytocidal and antiproliferative effects. The researchers tested the efficacy of the compound in an advanced prostate cancer mouse model and found that regular treatment with 14d (50 mg/kg) resulted in 60% tumor volume inhibition. With in vitro and in vivo antitumor activity, 14d is a potent lead in AR antagonist treatment for advanced prostate cancer. Abigail Druck Shudofsky
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IDENTIFICATION OF TWO NOVEL SCAFFOLDS THAT SELECTIVELY INHIBIT C. DIF FICILE
Courtesy of Dr. Jeremy Duvall and Dr. Christina A. Scherer.
The anaerobic pathogen Clostridium dif f icile colonizes the intestinal tract when commensal bacteria are eliminated by broad-spectrum antibiotics. Infection incidence and severity have increased in recent years. As standard treatment utilizes broad-spectrum antibiotics and can lead to infection recurrence, selectively targeting C. dif ficile may be more effective at preventing relapse. A team led by Christina A. Scherer screened the Broad Institute’s diversity-oriented synthesis compound collection for activity against the bacterium. Out of ∼100 000 small molecules representing over 250 unique scaffolds, they identified and characterized two novel compound series with potent in vitro inhibition of C. dif f icile ((2017) ACS Infect. Dis., DOI: 10.1021/acsinfecdis.6b00206). The authors initially identified 220 compounds that inhibited C. dif f icile growth >80% at a concentration of 16 μg/mL. From the initial hit list, appendage and stereochemical structure−activity relationships were present including at least one hit series demonstrating stereoselective activity with only one of eight possible stereoisomers for each compound inhibiting growth. After further selectivity and potency assays, the researchers selected two series for further investigation, represented by compounds BRD3098 and BRD0761. When used against 12 different C. dif f icile isolates, both compounds inhibited all strains with greater selectivity and potency than vancomycin, the current treatment. Mice treated twice daily with oral dosing of either compound exhibited significant mortality delays and reduction compared to the vehicle control. Further investigation of the compounds revealed that while BRD3098 inhibits C. dif f icile growth, it is not bactericidal and appears to have a novel mechanism of action, and that BRD0761 is bactericidal and interferes with cell wall biosynthesis by inhibiting an enzyme essential for glutamate incorporation. Further medicinal chemistry optimization of these compounds could identify new candidates for C. dif f icile treatment. Abigail Druck Shudofsky
DENGUE VIRUS-DERIVED PEPTIDES TRANSLOCATE ACROSS THE BLOOD−BRAIN BARRIER
Courtesy of Dr. Vera Neves.
To get to the central nervous system, drugs must pass through the blood−brain barrier (BBB), a highly selective semipermeable membrane composed of brain endothelial cells connected by tight junctions. As viruses can efficiently penetrate cell membranes, a team of collaborators led by R. B. Castanho studied the potential of the Dengue virus type-2 capsid protein (DEN2C) as a trans-BBB vector ((2017) ACS Chem. Biol., DOI: 10.1021/acschembio.7b00087). DEN2C can translocate across membranes in a receptor-independent fashion carrying macromolecules that retain their function inside the cell. The basic DEN2C is composed of four α-helical domains, which the authors synthesized as isolated peptides ((PepH1−4) and assessed individually. Successful cellular translocation involves efficient membrane crossing combined with low intracellular accumulation. The researchers evaluated translocation kinetics using [99mTc(CO)3]-radiolabeled peptides in an in vitro brain endothelial barrier model. They found that PepH1 and PepH3 efficiently transmigrated across the barrier with minimal membrane retention and cellular internalization, which suggested effectual delivery to the other side. The scientists further analyzed these two radiopeptides in murine in vivo biodistribution studies and found that brain penetration was quick; 5 min after intravenous administration, brain levels of 1112
DOI: 10.1021/acs.chemrestox.7b00097 Chem. Res. Toxicol. 2017, 30, 1111−1112
