Local Epidermal Endocrine Estrogen Protects Human Melanocytes against Oxidative Stress,a Novel Insight into Vitiligo Pathology

As the outermost barrier of the body, skin is a major target of oxidative stress. In the brain, estrogen has been reported synthesized locally and protects neurons from oxidative stress. Here, we explored whether estrogen is also locally synthesized in the skin to protect from oxidative stress and whether aberrant local estrogen synthesis is involved in skin disorders. Enzymes and estrogen receptor expression in skin cells were examined first by quantitative real-time PCR and Western blot analyses. Interestingly, the estrogen synthesis enzyme was mainly localized in epidermal keratinocytes and estrogen receptors were mainly expressed in melanocytes among 13 kinds of cultured human skin cells. The most abundant estrogen synthesis enzyme expressed in the epidermis was 17β-hydroxysteroid dehydrogenase 1 (HSD17β1) localized in keratinocytes, and the most dominant estrogen receptor expressed in the epidermis was G protein-coupled estrogen receptor 1 (GPER1) in melanocytes. To investigate whether keratinocyte-derived estradiol could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with H₂O₂ in the presence or absence of 17β estradiol or co-cultured with HSD17β1 siRNA-transfected keratinocytes. Keratinocyte-derived estradiol exhibited protective effects against H₂O₂-induced cell death. Further, reduced expression of HSD17β1 in the epidermis of skin from vitiligo patients was observed compared to the skin from healthy donors or in the normal portions of the skin in vitiligo patients. Our results suggest a possible new target for interventions that may be used in combination with current therapies for patients with vitiligo.     

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.     

Na+ and/or Cl− Toxicities Determine Salt Sensitivity in Soybean (Glycine max (L.) Merr.), Mungbean (Vigna radiata (L.) R. Wilczek), Cowpea (Vigna unguiculata (L.) Walp.), and Common Bean (Phaseolus vulgaris L.)

Grain legumes are important crops, but they are salt sensitive. This research dissected the responses of four (sub)tropical grain legumes to ionic components (Na⁺ and/or Cl⁻) of salt stress. Soybean, mungbean, cowpea, and common bean were subjected to NaCl, Na⁺ salts (without Cl⁻), Cl⁻ salts (without Na⁺), and a “high cation” negative control for 57 days. Growth, leaf gas exchange, and tissue ion concentrations were assessed at different growing stages. For soybean, NaCl and Na⁺ salts impaired seed dry mass (30% of control), more so than Cl⁻ salts (60% of control). All treatments impaired mungbean growth, with NaCl and Cl⁻ salt treatments affecting seed dry mass the most (2% of control). For cowpea, NaCl had the greatest adverse impact on seed dry mass (20% of control), while Na⁺ salts and Cl⁻ salts had similar intermediate effects (~45% of control). For common bean, NaCl had the greatest adverse effect on seed dry mass (4% of control), while Na⁺ salts and Cl⁻ salts impaired seed dry mass to a lesser extent (~45% of control). NaCl and Na⁺ salts (without Cl⁻) affected the photosynthesis (P_n) of soybean more than Cl⁻ salts (without Na⁺) (50% of control), while the reverse was true for mungbean. Na⁺ salts (without Cl⁻), Cl⁻ salts (without Na⁺), and NaCl had similar adverse effects on P_n of cowpea and common bean (~70% of control). In conclusion, salt sensitivity is predominantly determined by Na⁺ toxicity in soybean, Cl⁻ toxicity in mungbean, and both Na⁺ and Cl⁻ toxicity in cowpea and common bean.     

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.     

Oxytocin Signaling as a Target to Block Social Defeat-Induced Increases in Drug Abuse Reward

There is huge scientific interest in the neuropeptide oxytocin (OXT) due to its putative capacity to modulate a wide spectrum of physiological and cognitive processes including motivation, learning, emotion, and the stress response. The present review seeks to increase the understanding of the role of OXT in an individual’s vulnerability or resilience with regard to developing a substance use disorder. It places specific attention on the role of social stress as a risk factor of addiction, and explores the hypothesis that OXT constitutes a homeostatic response to stress that buffers against its negative impact. For this purpose, the review summarizes preclinical and clinical literature regarding the effects of OXT in different stages of the addiction cycle. The current literature affirms that a well-functioning oxytocinergic system has protective effects such as the modulation of the initial response to drugs of abuse, the attenuation of the development of dependence, the blunting of drug reinstatement and a general anti-stress effect. However, this system is dysregulated if there is continuous drug use or chronic exposure to stress. In this context, OXT is emerging as a promising pharmacotherapy to restore its natural beneficial effects in the organism and to help rebalance the functions of the addicted brain.     

Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca²⁺ supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca²⁺ concentration ([Ca²⁺]) under elevated pH and/or high [Ca²⁺] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca²⁺] measurements reveal that such alkalization not only upsurges Ca²⁺ influx into PT cells, but the mode of Ca²⁺ entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca²⁺ signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.