Change in Cutibacterium acnes phylotype abundance and improvement of clinical parameters using a new dermocosmetic product containing Myrtus communis and Celastrol enriched plant cell culture extracts in patients with acne vulgaris.

BACKGROUND: Acne is a multifactorial chronic inflammatory disease of the pilosebaceous unit, where Cutibacterium acnes plays a main role. Recent papers demonstrated that specific C. acnes phylotypes were correlated with the severity of inflammatory acne and reported a specific loss of C. acnes phylotype diversity in this context. OBJECTIVES: The aim of this exploratory study was to evaluate the efficacy of a new dermocosmetic product containing Myrtus communis and Celastrol-enriched plant cell culture extracts on C. acnes phylotype abundance and clinical parameters in subjects with mild to moderate acne vulgaris. METHODS: Cutibacterium acnes phylotype diversity was evaluated by single-locus sequence typing sequencing on the nonlesional areas of the forehead, that is, areas excluding inflammatory lesions (papules and pustules) on day 1 (D1) and after 56 days (D57) of twice daily application of the dermocosmetic product on the whole face. Clinical efficacy on acne was also assessed by acne lesion counting and Global Evaluation Acne (GEA) score on D1 and D57. RESULTS: Our study confirmed the link between the presence of some C. acnes phylotypes and acne severity. The dermocosmetic cream was linked to a positive impact on C. acnes phylotypes: a significant decrease in pro-pathogen phylotype IC and increase in nonpathogen phylotype IB were observed in the nonlesional areas of acne on D57 compared to D1. In parallel, the clinical results showed a significant decrease in inflammatory and comedonal acne lesions and a significant improvement in the acne severity according to the GEA score. CONCLUSIONS: This study showed that the application of a new dermocosmetic product containing M. communis and Celastrol-enriched plant cell culture extracts was linked to a change in the C. acnes phylotype abundance and an improvement in acne severity.

24-Month-olds and over remember novel object names after a single learning event.

In the context of word learning, it is commonly assumed that repetition is required for young children to form and maintain in memory an association between a novel word and its corresponding object. For instance, at 2 years of age, children are able to disambiguate word-related situations in one shot but are not able to further retain this newly acquired knowledge. It has been proposed that multiple fast-mapping experiences would be required to promote word retention or that the inferential reasoning needs to be accompanied by explicit labeling of the target. We hypothesized that when 2-year-olds simply encounter an unambiguous learning context, word learning may be fast and maintained in time. We also assumed that, under this condition, even a single exposure to an object would be sufficient to form a memory trace of its name that would survive a delay. To test these hypotheses, 2- and 4-year-olds were ostensively taught three arbitrary word-object pairs using a 15-s video sequence during which each object was manually displayed and labeled three times in a row. Retention was measured after a 30-min distractive period using a forced-choice procedure. Our results provide evidence that declarative memory does not need repetition to be formed and maintained, for at least a 30-min period, by children as young as 2 years. This finding suggests that the mechanisms required for extremely rapid and robust word acquisition not only are present in preschoolers with developed language and cognitive skills but also are already operative at a younger age.

Neonatal leptin exposure specifies innervation of presympathetic hypothalamic neurons and improves the metabolic status of leptin-deficient mice.

The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive synaptic inputs from neurons of the arcuate nucleus of the hypothalamus (ARH) that contains orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neuropeptides. The axon outgrowth from the ARH to PVH occurs during a critical postnatal period and is influenced by the adipocyte-derived hormone leptin, which promotes its development. However, little is known about leptin's role in specifying patterns of cellular connectivity in the different compartments of the PVH. To address this question, we used retrograde and immunohistochemical labeling to evaluate neuronal inputs onto sympathetic preautonomic and neuroendocrine neurons in PVH of leptin-deficient mice (Lep(ob)/Lep(ob)) exposed to a postnatal leptin treatment. In adult Lep(ob)/Lep(ob) mice, densities of AgRP- and α-melanocortin stimulating hormone (αMSH)-immunoreactive fibers were significantly reduced in neuroendocrine compartments of the PVH, but only AgRP were reduced in all regions containing preautonomic neurons. Moreover, postnatal leptin treatment significantly increased the density of AgRP-containing fibers and peptidergic inputs onto identified preautonomic, but not onto neuroendocrine cells. Neonatal leptin treatment neither rescued αMSH inputs onto neuroendocrine neurons, nor altered cellular ratios of inhibitory and excitatory inputs. These effects were associated with attenuated body weight gain, food intake and improved physiological response to sympathetic stimuli. Together, these results provide evidence that leptin directs cell type-specific patterns of ARH peptidergic inputs onto preautonomic neurons in the PVH, which contribute to normal energy balance regulation.

Nuclear and Urinary Measurements Show the Efficacy of Sun-Protection Factor 50+ Sunscreen against DNA Photoproducts upon Real-Life Recreational Exposure.

Sunscreens have been shown to protect against UVR-induced DNA damage in human skin under laboratory conditions. We presently extended these observations to real-life conditions in volunteers after their ordinary exposure habits during summer holidays. Volunteers were randomly assigned to a control group and an educated group supplied with a SPF ≥50 sunscreen and receiving instructions for use. A questionnaire was used to determine the extent of exposure. No difference in average solar UVR exposure was found between the two groups. DNA photoprotection was first assessed by, to our knowledge, a previously unreported noninvasive assay on the basis of the quantification of pyrimidine dimers released by DNA repair in urine. Damage was also quantified in the nuclear DNA extracted from the roof of suction blisters collected after recreational exposure. The urinary concentration of photoproducts was significantly higher in the control than in the educated group. The same trend was observed for the level of photoproducts in the DNA from suction blisters. The unambiguous observation of an efficient photoprotection against DNA damage afforded by sunscreen under real-life conditions provides strong support for the efficiency of the sunscreens. In addition, the results validate the use of urinary DNA photoproducts as a noninvasive assay applicable to photoprotection.

A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.

In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lepob/ob ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lepob/ob mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lepob/ob mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lepob/ob females, but only to the DMHv in Lepob/ob males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.

Multiple co-localizations in arcuate GHRH-eGFP neurons in the mouse hypothalamus.

In the present work, we took advantage of a recently described model of GHRH-enhanced green fluorescent protein (eGFP) transgenic mice to evaluate the extent of co-localization of GHRH neurons with galanin (GAL), neurotensin (NT) and tyrosine hydroxylase (TH) in 3- and 8-month-old male and female mice. The total number of GHRH-eGFP neurons along the rostro-caudal axis of the arcuate nucleus did not differ according to gender or age. GAL-immunoreactivity was present in 40-44% of 3-month-old GHRH-eGFP neurons in male and female arcuate nucleus, respectively, but only 25-22% in 8-month-old mice. TH immunoreactivity occurred in 36-35% of GHRH-eGFP neurons in male and female arcuate nucleus from 3-month-old mice and these proportions increased to 40 and 45% in 8-month-old mice. NT immunoreactivity was present in 14 and 24% of GHRH-eGFP neurons in male and female arcuate nucleus from 3-month-old mice up to 28 and 26% in 8-month-old mice. Thus, co-localization of peptides and enzyme in GHRH-eGFP neurons displays a sexual dimorphism at 3-month of age for NT, and at 8-month for TH, while the total number of GHRH-eGFP neurons does not exhibit gender difference at either age. In summary, it appears that changes in co-localized (and presumably co-released) peptides, rather than GHRH per se, may contribute to the changes in sexually dimorphic GH secretion with aging in the mouse.

Sexually dimorphic distribution of sst2A somatostatin receptors on growth hormone-releasing hormone neurons in mice.

The pulsatile pattern of GH secretion exhibits sexual dimorphism that is likely to depend on somatostatin (SRIH) effects on somatoliberin (GHRH) neurons in the hypothalamus. Using transgenic GHRH-enhanced green fluorescent protein (eGFP) mice, no difference in the total number of GHRH-eGFP neurons or change in somatostatin receptor sst2 and SRIH mRNA levels in ventromedial hypothalamic nucleus-arcuate nucleus and periventricular nucleus regions and GHRH mRNA levels in the ventromedial hypothalamic-arcuate region were observed between male and female mice. However, the percentage of GHRH-eGFP neurons bearing sst2A receptors reached 78% in female vs. 26% in male GHRH-eGFP mice (P < 0.02). This sex difference in sst2A distribution on GHRH neurons may play an important role in the sexually differentiated pattern of GH secretion.

Brain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleus.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development, and the Bdnf gene produces two populations of transcripts with either a short or long 3' untranslated region (3' UTR). Deficiencies in BDNF signaling have been shown to cause severe obesity in humans; however, it remains unknown how BDNF signaling impacts the organization of neuronal circuits that control energy balance. METHODS: We examined the role of BDNF on survival, axonal projections, and synaptic inputs of neurons in the arcuate nucleus (ARH), a structure critical for the control of energy balance, using Bdnf (klox/klox) mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity. RESULTS: We found that a small fraction of neurons that express the receptor for BDNF, TrkB, also expressed proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related protein (AgRP) in the ARH. Bdnf(klox/klox) mice had normal numbers of POMC, NPY, and TrkB neurons in the ARH; however, retrograde labeling revealed a drastic reduction in the number of ARH axons that project to the paraventricular hypothalamus (PVH) in these mice. In addition, fewer POMC and AgRP axons were found in the dorsomedial hypothalamic nucleus (DMH) and the lateral part of PVH, respectively, in Bdnf (klox/klox) mice. Using immunohistochemistry, we examined the impact of BDNF deficiency on inputs to ARH neurons. We found that excitatory inputs onto POMC and NPY neurons were increased and decreased, respectively, in Bdnf (klox/klox) mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice. CONCLUSION: This study shows that the majority of TrkB neurons in the ARH are distinct from known neuronal populations and that BDNF plays a critical role in directing projections from these neurons to the DMH and PVH. We propose that hyperphagic obesity due to BDNF deficiency is in part attributable to impaired axonal growth of TrkB-expressing ARH neurons.

Changes in lipoprotein kinetics associated with type 2 diabetes affect the distribution of lipopolysaccharides among lipoproteins.

CONTEXT: Lipopolysaccharides (LPSs) are inflammatory components of the outer membrane of Gram-negative bacteria and, in plasma, are mostly associated with lipoproteins. This association is thought to promote their catabolism while reducing their proinflammatory effects. OBJECTIVES: Our aim was to determine the impact of lipoprotein kinetics on plasma LPS distribution and how it may affect patients with type 2 diabetes mellitus (T2DM). DESIGN: We performed a kinetic study in 30 individuals (16 T2DM patients, 14 controls) and analyzed the impact of changes in lipoprotein kinetics on LPS distribution among lipoproteins. RESULTS: Plasma LPS levels in T2DM patients were not different from those in controls, but LPS distribution in the two groups was different. Patients with T2DM had higher LPS-very low-density lipoprotein (VLDL; 31% ± 7% vs 22% ± 11%, P = .002), LPS-high-density lipoprotein (HDL; 29% ± 9% vs 19% ± 10%, P = .015), free (nonlipoprotein bound) LPS (10% ± 4% vs 7% ± 4%, P = .043) and lower LPS-low-density lipoprotein (LDL; 30% ± 13% vs 52% ± 16%, P = .001). In multivariable analysis, VLDL-LPS was associated with HDL-LPS (P < .0001); LDL-LPS was associated with VLDL-LPS (P = .004), and VLDL apolipoprotein (apo) B100 catabolism (P = .002); HDL-LPS was associated with free LPS (P < .0001) and VLDL-LPS (P = .033); free LPS was associated with HDL-LPS (P < .0001). In a patient featuring a dramatic decrease in VLDL catabolism due to apoA-V mutation, LDL-LPS was severely decreased (0.044 EU/mL vs 0.788 EU/mL in controls). The difference between T2DM patients and controls for LDL-LPS fraction was no longer significant after controlling for VLDL apoB100 total fractional catabolic rate. CONCLUSIONS: Our data suggest that in humans, free LPS transfers first to HDL and then to VLDL, whereas the LPS-bound LDL fraction is mainly derived from VLDL catabolism; the latter may hence represent a LPS catabolic pathway. T2DM patients show lower LDL-LPS secondary to reduced VLDL catabolism, which may represent an impaired catabolic pathway.

Postnatal dietary fatty acid composition permanently affects the structure of hypothalamic pathways controlling energy balance in mice.

BACKGROUND: We previously reported that dietary lipid quality during early life can have long-lasting effects on metabolic health and adiposity. Exposure to a postnatal diet with low dietary omega-6 (n-6) or high omega-3 (n-3) fatty acid (FA) content resulted in reduced body fat accumulation when challenged with a moderate Western-style diet (WSD) beginning in adolescence. OBJECTIVE: We determined whether this programming effect is accompanied by changes in hypothalamic neural projections or modifications in the postnatal leptin surge, which would indicate the altered development of hypothalamic circuits that control energy balance. DESIGN: Neonatal mice were subjected to a control diet (CTR) or experimental diet with altered relative n-6 and n-3 FA contents [ie, a diet with a relative reduction in n-6 fatty acid (LOW n-6) or a diet with a relative increase in n-3 fatty acid (HIGH n-3) compared with the CTR from postnatal day (PN) 2 to 42]. RESULTS: Compared with CTR mice, mice fed a LOW n-6 or HIGH n-3 during postnatal life showed significant reductions in the density of both orexigenic and anorexigenic neural projections to the paraventricular nucleus of the hypothalamus at PN 28. These impairments persisted into adulthood and were still apparent after the WSD challenge between PNs 42 and 98. However, the neuroanatomical changes were not associated with changes in the postnatal leptin surge. CONCLUSION: Although the exact mechanism remains to be elucidated, our data indicate that the quality of dietary FA during postnatal life affects the development of the central regulatory circuits that control energy balance and may do so through a leptin-independent mechanism.

Characterization of MCH-gene-overprinted-polypeptide-immunoreactive material in hypothalamus reveals an inhibitory role of pro-somatostatin1-64 on somatostatin secretion.

The melanin-concentrating hormone (MCH) gene encodes two proteins, pro-MCH and MCH-gene-overprinted polypeptide (MGOP), produced through alternative splicing of the primary transcript. Our initial purpose was to characterize the MGOP-immunoreactive material. First, MGOP mRNA was clearly found in rat and mouse hypothalami but Western blot analysis failed to unambiguously identify MGOP in protein extracts. Immunohistochemical experiments with wild-type and MCH gene-null mice demonstrated genuine expression of MGOP confined to the MCH-containing neurons in the lateral hypothalamus area and the presence of an 'MGOP-like' antigen in periventricular nucleus and arcuate nucleus neurons and their area of projection. This suggested a colocalization in somatostatin (SRIF) hypophysiotropic neurons. Further characterization, using SRIF gene-null mice and Western blot analysis with recombinant proteins, revealed that the MGOP-like product was pro-SRIF1-64. The role of pro-SRIF1-64 on fetal hypothalamic neurons was evaluated and a strong tonic inhibitory effect on SRIF secretion was found. These results (i) indicate that MGOP expression is restricted to the MCH neurons in the lateral hypothalamus and that MGOP-like immunoreactivity outside this system corresponds to pro-SRIF1-64, and (ii) provide the first evidence for a negative feedback regulation by pro-SRIF1-64 on SRIF secretion, suggesting new mechanisms by which the pro-region of a neuropeptide precursor may control the regulated secretion of a neuropeptide derived from the same precursor.