Dopamine release and negative valence gated by inhibitory neurons in the laterodorsal tegmental nucleus.

GABAergic neurons in the laterodorsal tegmental nucleus (LDTGABA) encode aversion by directly inhibiting mesolimbic dopamine (DA). Yet, the detailed cellular and circuit mechanisms by which these cells relay unpleasant stimuli to DA neurons and regulate behavioral output remain largely unclear. Here, we show that LDTGABA neurons bidirectionally respond to rewarding and aversive stimuli in mice. Activation of LDTGABA neurons promotes aversion and reduces DA release in the lateral nucleus accumbens. Furthermore, we identified two molecularly distinct LDTGABA cell populations. Somatostatin-expressing (Sst+) LDTGABA neurons indirectly regulate the mesolimbic DA system by disinhibiting excitatory hypothalamic neurons. In contrast, Reelin-expressing LDTGABA neurons directly inhibit downstream DA neurons. The identification of separate GABAergic subpopulations in a single brainstem nucleus that relay unpleasant stimuli to the mesolimbic DA system through direct and indirect projections is critical for establishing a circuit-level understanding of how negative valence is encoded in the mammalian brain.

Protein expression pattern of calcium-responsive transactivator in early postnatal and adult testes.

Calcium-responsive transactivator (CREST), a nuclear protein highly expressed in postmitotic neurons, is involved in the regulation of cell cycle, differentiation and dendritic development of neuronal cells. Its mRNA has been detected in the testis of adult rat, whilst its protein expression and distribution pattern in the testis remain to be elucidated. In this study, we examined the distribution of CREST in the adult testes of both rats and human as well as the expression pattern of CREST in the testes of postnatal developing rats. In the adult testes of both human and rats, immunohistochemical analysis revealed that CREST was selectively distributed in the mature Sertoli cells but not in the spermatogenic cells. In the testes of postnatal developmental rats, CREST was expressed not only in Sertoli cells but also in the gonocytes and spermatogenic cells at the initial stage of spermatogenic cell differentiation. CREST immunoreactivity continued to increase in Sertoli cells during differentiation, reaching its peak in adulthood. However, CREST immunostaining intensity dramatically decreased as the spermatogenic cells differentiate, disappearing in the post-differentiation stage. Furthermore, Brg1 and p300, two CREST-interacting proteins ubiquitously expressed in the body, are found to be colocalized with CREST in the spermatogenic epithelial cells including Sertoli cells. The unique expression pattern of CREST in developing testis suggests that CREST might play regulatory roles in the differentiation of spermatogenic epithelial cells. The Sertoli cell-specific expression of CREST in the adulthood hints that CREST might be a novel biomarker for the mature Sertoli cells.

Effect of a Tranexamic Acid, Kojic Acid, and Niacinamide Containing Serum on Facial Dyschromia: A Clinical Evaluation

Background: Stubborn dyschromia such as melasma and post-inflammatory hyperpigmentation (PIH) are leading causes for cosmetic consultation. Topical treatment is challenging, using a range of modalities, to stop, hinder, and/or prevent steps in the pigment production process. Tranexamic acid (TXA), a potent plasmin inhibitor, is proposed to control pigmentation by inhibiting the release of inflammatory mediators involved in triggering melanogenesis. TXA has been recently introduced as a topical therapy aimed at reducing pigmentation in melasma. Methods: In a 12-week clinical study, a novel, topical facial serum containing 3% TXA, 1% kojic acid, and 5% niacinamide was evaluated for its effectiveness in treating melasma, PIH, and hyperpigmentation in Brazilian female subjects with Fitzpatrick skin types I-IV. Efficacy evaluations were performed at pre-treatment baseline, weeks 2, 4, 8, and 12, and included expert clinical grading, bio-instrumental measurements, and self-assessment questionnaires. Cutaneous tolerability was also evaluated by assessing subjective and objective irritation of the treatment area. Results: A significant improvement in the appearance of PIH, hyperpigmentation, melasma, skin texture, and skin tone homogeneity was observed beginning at week 2 and continued through week 12. Melanin index, as measured by Mexameter®, demonstrated a significant decrease by week 12 as compared to both pre-treatment baseline and control. Conclusions: The findings suggest that the test product is an effective and well-tolerated treatment option for addressing hyperpigmentary conditions, including melasma. Additional in vitro data suggests that TXA may act by mediating the inhibition of PGE2-stimulated human epidermal melanocytes. J Drugs Dermatol. 2019;18(5):454-459.

Herp Promotes Degradation of Mutant Huntingtin: Involvement of the Proteasome and Molecular Chaperones.

In neurodegenerative diseases, pathogenic proteins tend to misfold and form aggregates that are difficult to remove and able to induce excessive endoplasmic reticulum (ER) stress, leading to neuronal injury and apoptosis. Homocysteine-induced endoplasmic reticulum protein (Herp), an E3 ubiquitin ligase, is an important early marker of ER stress and is involved in the ubiquitination and degradation of many neurodegenerative proteins. However, in Huntington's disease (HD), a typical polyglutamine disease, whether Herp is also involved in the metabolism and degradation of the pathogenic protein, mutant huntingtin, has not been reported. Therefore, we studied the relationship between Herp and N-terminal fragments of huntingtin (HttN-20Q and HttN-160Q). We found that Herp was able to bind to the overexpressed Htt N-terminal, and this interaction was enhanced by expansion of the polyQ fragment. Confocal microscopy demonstrated that Herp was co-localized with the HttN-160Q aggregates in the cytoplasm and tightly surrounded the aggregates. Overexpression of Herp significantly decreased the amount of soluble and insoluble HttN-160Q, promoted its ubiquitination, and inhibited its cytotoxicity. In contrast, knockdown of Herp resulted in more HttN-160Q protein, less ubiquitination, and stronger cytotoxicity. Inhibition of the autophagy-lysosomal pathway (ALP) had no effect on the function of Herp. However, blocking the ubiquitin-proteasome pathway (UPP) inhibited the reduction in soluble HttN-160Q caused by Herp. Interestingly, blocking the UPP did not weaken the ability of Herp to reduce HttN-160Q aggregates. Deletions of the N-terminal of Herp weakened its ability to inhibit HttN-160Q aggregation but did not result in a significant increase in its soluble form. However, loss of the C-terminal led to a significant increase in soluble HttN-160Q, but Herp still maintained the ability to inhibit aggregate formation. We further found that the expression level of Herp was significantly increased in HD animal and cell models. Our findings suggest that Herp is a newly identified huntingtin-interacting protein that is able to reduce the cytotoxicity of mutant huntingtin by inhibiting its aggregation and promoting its degradation. The N-terminal of Herp serves as the molecular chaperone to inhibit protein aggregation, while its C-terminal functions as an E3 ubiquitin ligase to promote the degradation of misfolded proteins through the UPP. Increased expression of Herp in HD models may be a pro-survival mechanism under stress.

Enhanced efficacy of a topical antioxidants regimen in conjunction with a home-use non-ablative fractional diode laser in photodamaged facial skin.

BACKGROUND: Photodamaged facial skin is characterized by fine lines and wrinkles, mottled pigmentation, and other changes. OBJECTIVE: To evaluate and compare the efficacy and tolerance of a home-use laser device when used alone or in combination with an antioxidant facial treatment for moderate photodamage. METHODS: This was a 49-subject, evaluator-blinded, split-face, randomized, single-center, 24-week, phase-2, study. In phase 1, all subjects were treated on one facial side with test products and a home-use laser device and the other side was treated with laser alone for 12 weeks, followed by a 2-week regression period during which they used only support materials. For phase 2, all subjects were divided into 2 independent treatment groups. For the next 10 weeks, subjects of first group treated the assigned facial side with test products and support materials and the other facial side with only support materials. Subjects in the second group treated their entire face with only support materials. Efficacy and tolerance were assessed by clinical grading, VISIA-CR imaging, and self-assessment questionnaires. RESULTS: The combination of laser and test products improved all photodamage parameters evaluated. CONCLUSION: The test products enhanced and prolonged clinical benefits obtained with the laser alone.