ß-endorphin suppresses ultraviolet B irradiation-induced epidermal barrier damage by regulating inflammation-dependent mTORC1 signaling.

Solar ultraviolet B (UVB) radiation triggers excessive inflammation, disrupting the epidermal barrier, and can eventually cause skin cancer. A previous study reported that under UVB irradiation, epidermal keratinocytes synthesize the proopiomelanocortin-derived peptide ß-endorphin, which is known for its analgesic effect. However, little is known about the role of ß-endorphin in UVB-exposed skin. Therefore, in this study, we aimed to explore the protective role of ß-endorphin against UVB irradiation-induced damage to the skin barrier in normal human keratinocytes (NHKs) and on a human skin equivalent model. Treatment with ß-endorphin reduced inflammatory responses in UVB-irradiated NHKs by inactivating the NF-κB signaling pathway. Additionally, we found that ß-endorphin treatment reversed UVB-induced abnormal epidermal proliferation and differentiation in NHKs and, thus, repaired the skin barrier in UVB-treated skin equivalents. The observed effects of ß-endorphin on UVB-irradiated NHKs were mediated via blockade of the Akt/mTOR signaling pathway. These results reveal that ß-endorphin might be useful against UVB-induced skin injury, including the disruption of the skin barrier function.

Acute effects of (-)-gallocatechin gallate-rich green tea extract on the cerebral hemodynamic response of the prefrontal cortex in healthy humans.

Objective: The benefits of long-term consumption of green tea on the brain are well known. However, among many ingredients of green tea, the acute effects of (-)-gallocatechin gallate-rich green tea extract (GCG-GTE), have received comparatively less attention. Herein, we investigated the acute effects of oral ingestion of green tea with GCG-GTE, which contains close replicas of the ingredients of hot green tea, on task-dependent hemodynamics in the prefrontal cortex of healthy adult human brains. Methods: In this randomized, double-blind, placebo-controlled, parallel group trial, 35 healthy adults completed computerized cognitive tasks that demand activation of the prefrontal cortex at baseline and 1 h after consumption of placebo and 900 mg of GCG-GTE extract supplement. During cognitive testing, hemodynamic responses (change in HbO2 concentration) in the prefrontal cortex were assessed using functional near-infrared spectroscopy (fNIRS). Results: In fNIRS data, significant group x session interactions were found in the left (p = 0.035) and right (p = 0.036) dorsolateral prefrontal cortex (DLPFC). In behavioral data, despite the numerical increase in the GCG-GTE group and the numerical decrease in the Placebo group, no significant differences were observed in the cognitive performance measure between the groups. Conclusion: The result suggests a single dose of orally administered GCG-GTE can reduce DLPFC activation in healthy humans even with increased task demand. GCG-GTE is a promising functional material that can affect neural efficiency to lower mental workload during cognitively demanding tasks. However, further studies are needed to verify this.

Kaempferol tetrasaccharides restore skin atrophy via PDK1 inhibition in human skin cells and tissues: Bench and clinical studies.

Skin aging is a major risk factor for the dermal diseases, and interventions to attenuate cellular senescence are expected to reduce the risk for age-related diseases involving skin atrophy. However, blocking cell death or extending proliferation causally results in side effects and an increased cancer risk. For identification of a safer approach, we focused on PDK1 inhibition, which could revert cellular senescence and reduce senescence factors in skin in vitro, in a human skin equivalent model and in an exploratory, placebo-controlled, interventional trial. Natural phytochemical kaempferol tetrasaccharides resulted in a significant reduction in cellular senescence, and an increase in collagen fiber was observed in the skin cell and human skin equivalent. Clinical enhancement in skin appearance was noted in multiple participants, and an immunohistochemical study revealed improvement in the histological appearance of skin tissue and extracellular matrix. This change was associated with relative improvement in histological markers of senescence and clinical appearance of the aged skin and an increase in collagen fiber, an essential factor for preventing skin atrophy and consistency of the basement membrane. These results indicate that PDK1 inhibition is a potentially effective antiaging intervention, suggesting a diagnostic role and preventive actions of PDK1 in senescence-associated skin atrophy.

Platelet-to-White Blood Cell Ratio Is Associated with Adverse Outcomes in Cirrhotic Patients with Acute Deterioration.

Background: The platelet-to-white blood cell ratio (PWR) is a hematologic marker of the systemic inflammatory response. Recently, the PWR was revealed to have a role as an independent prognostic factor for mortality in patients with hepatitis B virus (HBV)-related acute-on-chronic failure (ACLF) and HBV-related liver cirrhosis (LC) with acute decompensation (AD). However, the prognostic role of the PWR still needs to be investigated in LC patients with AD. In this study, we analyzed whether the PWR could stratify the risk of adverse outcomes (death or liver transplantation (LT)) in these patients. Methods: A prospective cohort of 1670 patients with AD of liver cirrhosis ((age: 55.2 ± 7.8, male = 1226 (73.4%)) was enrolled and evaluated for 28-day and overall adverse outcomes. Results: During a median follow-up of 8.0 months (range, 1.9−15.5 months), 424 (25.4%) patients had adverse outcomes (death = 377, LT = 47). The most common etiology of LC was alcohol use (69.7%). The adverse outcome rate was higher for patients with a PWR ≤ 12.1 than for those with a PWR > 12.1. A lower PWR level was a prognostic factor for 28-day adverse outcomes (PWR: hazard ratio 1.707, p = 0.034) when adjusted for the etiology of cirrhosis, infection, ACLF, and the MELD score. In the subgroup analysis, the PWR level stratified the risk of 28-day adverse outcomes regardless of the presence of ACLF or the main form of AD but not for those with bacterial infection. Conclusions: A lower PWR level was associated with 28-day adverse outcomes, indicating that the PWR level can be a useful and simple tool for stratifying the risk of 28-day adverse outcomes in LC patients with AD.

The Role of Gut Dysbiosis in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic inflammation. Recently, the role of the gut microbiome has increasingly emerged in human health and disease. Additionally, the gut microbiome might have a major role in the development of liver disease. In this review, we examine evidence to support the role of gut dysbiosis in cirrhosis and ACLF. Additionally, we explore the mechanism by which the gut microbiome contributes to the development of ACLF, with a focus on alcohol-induced liver disease.

Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

A quantitative, objective method for evaluating the surgical outcomes of baggy eyelid correction using orbital gray scale analysis.

BACKGROUND: Baggy lower eyelids (BLEs) are a common cosmetic problem that is treated using various methods. However, validated objective methods for evaluating the treatment are limited. AIMS: A novel BLE correction procedure, transconjunctival fat resection, and subsequent fat grafting, was assessed using the orbital gray scale (OGS), a previously suggested objective measure for BLEs. METHODS: All patients were evaluated using both the tear trough rating scale (TTRS), a surgeon-derived evaluation method, and OGS, an objective computer-derived assessment. Changes throughout the surgery and their relationship to clinical characteristics, as well as the association between the two measurements, were statistically analyzed. RESULTS: A total of 50 patients who underwent surgery were analyzed. No major complications other than wrinkles were observed. All patients showed improvement in both the TTRS scores and OGS values (P < 0.05). Lateral OGS was improved to a greater extent in older patients (P < 0.05). Medial OGS change was associated with improvement of tear trough depression (P < 0.05). Lateral OGS change was related to decreased infraorbital fat herniation (P < 0.05). Total OGS change was related to improvement of both tear trough depression and fat prolapse (P < 0.05). CONCLUSION: The total OGS change was significantly associated with improvements in tear trough depression and fat bulging. Therefore, it could be a convenient objective evaluation measure for eyelid correction procedures.

Effectiveness of Transconjunctival Fat Removal and Resected Fat Grafting for Lower Eye Bag and Tear Trough Deformity.

IMPORTANCE: The main treatment of lower eye bags is changing from fat removal techniques to fat repositioning techniques. However, fat repositioning techniques have potential complications because of disruption of the middle lamellae, leading to contracture and shortening. OBJECTIVE: To determine whether transconjunctival fat removal followed by resected fat grafting is an effective alternative method of eye bag treatment. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study of 229 consecutive patients who underwent transconjunctival fat removal followed by resected fat grafting from November 1, 2011, to October 31, 2017, was conducted by review of medical records from the Seoul H Dermatology Clinic in Seoul, Korea. MAIN OUTCOMES AND MEASURES: Comparison of patient satisfaction and modified Goldberg scores before and after surgery. RESULTS: A total of 229 patients (mean [SD] age, 41.24 [11.11] years; range, 20-69 years; 164 [71.6%] female) underwent transconjunctival fat removal followed by resected fat grafting. Of the 229 patients, 224 (97.8%) were satisfied with their surgical results, and major improvements were seen in the mean (SD) preoperative and postoperative scores for orbital fat prolapse (preoperative: 1.94 [0.63]; postoperative: 0.07 [0.21]), tear trough depression (preoperative: 1.61 [0.75]; postoperative: 0.33 [0.42]), skin transparency (preoperative: 1.15 [0.97]: postoperative: 0.22 [0.37]), and triangular malar mound (preoperative: 0.37 [0.61]; postoperative: 0.34 [0.58]). Although the orbicularis prominence worsened after surgery, this outcome should be interpreted as a good result for Asian patients. Skin elasticity deteriorated postoperatively. CONCLUSIONS AND RELEVANCE: The findings suggest that transconjunctival fat removal followed by resected fat grafting is an effective and safe technique to treat lower eyelid fat herniation without increased complication rates and provides good patient and surgeon satisfaction. LEVEL OF EVIDENCE: 4.

Assessment of age- and sex-related changes in baggy lower eyelids using a novel objective image analysis method: Orbital gray scale analysis.

BACKGROUND: Baggy lower eyelids (BLEs) are a common aesthetic problem of aging. Valid and reliable assessment tools for BLEs are required to evaluate the current status and treatment outcome. AIMS: Age- and sex-related changes in BLEs were assessed with the orbital gray scale (OGS), a novel objective image analysis method. METHODS: We gathered frontal-view photographs of the faces of the patients who sought for correction of BLEs. Based on the clinical pattern, we classified the BLEs of the subjects into medial (M), medial and central (MC), and medial to lateral (MCL) types. Severity was evaluated using the OGS, a modified method of the linear gray scale analysis. RESULTS: The BLEs of 1034 subjects were classified. The most common types were MCL type in the men and MC type in the women, respectively. The M and MC types were common in the young subjects, whereas the MCL type was more common in the old subjects (P < .001). The measurements of OGS in 104 subjects showed positive correlation with age, a higher mean value in the men, and a trend toward higher values in the order of M, MC, and MCL types (P < .001 for central and lateral OGS scores). In a multiple linear regression analysis, central and lateral OGS values were significantly related with age, sex, and M-C-L classification type (P < .001). CONCLUSION: The M-C-L classification and OGS were significantly associated with both age and sex, proving that they could be potent objective assessment tools for BLEs.

BAF53b, a Neuron-Specific Nucleosome Remodeling Factor, Is Induced after Learning and Facilitates Long-Term Memory Consolidation.

Although epigenetic mechanisms of gene expression regulation have recently been implicated in memory consolidation and persistence, the role of nucleosome-remodeling is largely unexplored. Recent studies show that the functional loss of BAF53b, a postmitotic neuron-specific subunit of the BAF nucleosome-remodeling complex, results in the deficit of consolidation of hippocampus-dependent memory and cocaine-associated memory in the rodent brain. However, it is unclear whether BAF53b expression is regulated during memory formation and how BAF53b regulates fear memory in the amygdala, a key brain site for fear memory encoding and storage. To address these questions, we used viral vector approaches to either decrease or increase BAF53b function specifically in the lateral amygdala of adult mice in auditory fear conditioning paradigm. Knockdown of Baf53b before training disrupted long-term memory formation with no effect on short-term memory, basal synaptic transmission, and spine structures. We observed in our qPCR analysis that BAF53b was induced in the lateral amygdala neurons at the late consolidation phase after fear conditioning. Moreover, transient BAF53b overexpression led to persistently enhanced memory formation, which was accompanied by increase in thin-type spine density. Together, our results provide the evidence that BAF53b is induced after learning, and show that such increase of BAF53b level facilitates memory consolidation likely by regulating learning-related spine structural plasticity.SIGNIFICANCE STATEMENT Recent works in the rodent brain begin to link nucleosome remodeling-dependent epigenetic mechanism to memory consolidation. Here we show that BAF53b, an epigenetic factor involved in nucleosome remodeling, is induced in the lateral amygdala neurons at the late phase of consolidation after fear conditioning. Using specific gene knockdown or overexpression approaches, we identify the critical role of BAF53b in the lateral amygdala neurons for memory consolidation during long-term memory formation. Our results thus provide an idea about how nucleosome remodeling can be regulated during long-term memory formation and contributes to the permanent storage of associative fear memory in the lateral amygdala, which is relevant to fear and anxiety-related mental disorders.

Donor-Site Morbidity after Partial Second Toe Pulp Free Flap for Fingertip Reconstruction.

BACKGROUND: In this study, we characterize the morbidity at the donor-site of partial second toe pulp free flaps in terms of wound management as well as long-term outcomes. METHODS: A single-institutional retrospective review was performed for patients who had undergone partial second toe pulp free flap transfer to the fingertip. Patient charts were reviewed for infection, skin necrosis, wound dehiscence, and hematoma for the donor site. Additionally, a questionnaire survey was given to patients who had a follow-up of longer than 1 year to characterize long-term postoperative pain and appearance. RESULTS: The review identified a total of 246 cases. Early wound complications were significant for wound dehiscence (n=8) and hematoma (n=5) for a wound complication rate of 5.3%. The questionnaire was distributed to 109 patients, and 54 patients completed the survey. Out of these 54 patients, 15 patients continued to have donor-site pain (28%) at a mean follow-up period of 32.4 months. However, the pain intensity was relatively low in the range between 2 to 5, on a 0-10 scale. None of these patients felt this donor-site pain interfered significantly with daily activity, nor did any patient require pain medications of any type. Donor-site appearance was satisfactory to most patients. CONCLUSIONS: The partial second toe pulp flap was associated with low rates of wound complications and favorable long-term outcomes. Given the functional and aesthetic gain in the recipient finger, donor-site morbidities appear acceptable in this patient population. This study can be helpful in counseling patients regarding donor-site morbidity during the informed consent process.

Selective Control of Fear Expression by Optogenetic Manipulation of Infralimbic Cortex after Extinction.

Evidence from rodent and human studies has identified the ventromedial prefrontal cortex, specifically the infralimbic cortex (IL), as a critical brain structure in the extinction of conditioned fear. However, how IL activity controls fear expression at the time of extinction memory retrieval is unclear and controversial. To address this issue, we used optogenetics to precisely manipulate the activity of genetically targeted cells and to examine the real-time contribution of IL activity to expression of auditory-conditioned fear extinction in mice. We found that inactivation of IL, but not prelimbic cortex, impaired extinction retrieval. Conversely, photostimulation of IL excitatory neurons robustly enhanced the inhibition of fear expression after extinction, but not before extinction. Moreover, this effect was specific to the conditioned stimulus (CS): IL activity had no effect on expression of fear in response to the conditioned context after auditory fear extinction. Thus, in contrast to the expectation from a generally held view, artificial activation of IL produced no significant effect on expression of non-extinguished conditioned fear. Therefore, our data provide compelling evidence that IL activity is critical for expression of fear extinction and establish a causal role for IL activity in controlling fear expression in a CS-specific manner after extinction.

Optogenetic activation of presynaptic inputs in lateral amygdala forms associative fear memory.

In Pavlovian fear conditioning, the lateral amygdala (LA) has been highlighted as a key brain site for association between sensory cues and aversive stimuli. However, learning-related changes are also found in upstream sensory regions such as thalamus and cortex. To isolate the essential neural circuit components for fear memory association, we tested whether direct activation of presynaptic sensory inputs in LA, without the participation of upstream activity, is sufficient to form fear memory in mice. Photostimulation of axonal projections from the two main auditory brain regions, the medial geniculate nucleus of the thalamus and the secondary auditory cortex, was paired with aversive footshock. Twenty-four hours later the same photostimulation induced robust conditioned freezing and this fear memory formation was disrupted when glutamatergic synaptic transmission was locally blocked in the LA. Therefore, our results prove for the first time that synapses between sensory input areas and the LA, previously implicated as a crucial brain site for fear memory formation, actually are sufficient to serve as a conditioned stimulus. Our results strongly support the idea that the LA may be sufficient to encode and store associations between neutral cue and aversive stimuli during natural fear conditioning as a critical part of a broad fear memory engram.

Memory recall and modifications by activating neurons with elevated CREB.

Memory is supported by a specific ensemble of neurons distributed in the brain that form a unique memory trace. We previously showed that neurons in the lateral amygdala expressing elevated levels of cAMP response-element binding protein are preferentially recruited into fear memory traces and are necessary for the expression of those memories. However, it is unknown whether artificially activating just these selected neurons in the absence of behavioral cues is sufficient to recall that fear memory. Using an ectopic rat vanilloid receptor TRPV1 and capsaicin system, we found that activating this specific ensemble of neurons was sufficient to recall established fear memory. Furthermore, this neuronal activation induced a reconsolidation-like reorganization process, or strengthening of the fear memory. Thus, our findings establish a direct link between the activation of specific ensemble of neurons in the lateral amygdala and the recall of fear memory and its subsequent modifications.

Serum gastrin levels in different stages of distal gastric carcinogenesis: is there a role for serum gastrin in tumor growth?

BACKGROUND/AIMS: Elevated levels of serum gastrin (SG) have been associated with tumorigenic effects in a number of gastrointestinal cancers. We decided to investigate the relationship between SG and gastric epithelial lesions. MATERIALS AND METHODS: A total of 90 patients with gastric epithelial lesions (hyperplastic polyp, 12; adenoma, 41; early gastric cancer, 29; advanced gastric cancer, 8) were enrolled as the case group and 79 patients without epithelial lesions were enrolled as the control group. RESULTS: Serum gastrin levels were significantly different between the case and control groups (p<0.001). A high SG level (>80 pg/mL), intestinal metaplasia, and a pepsinogen I/II ratio <3 were independently associated with an increased risk of epithelial lesions (odds ratio: 14.6, 9.4, and 4.1, respectively, p<0.05). SG levels in case subjects showed a unimodal distribution pattern as the disease progressed. The mean SG level was highest in those with hyperplastic polyps and then decreased significantly to the control level in the gastric cancer group. Higher SG levels in each disease category were not associated with increased tumor size, synchronicity, invasiveness, presence of lymph node metastasis, or a higher cellular proliferation index (p>0.05). CONCLUSION: An increased SG level was an independent and potent risk factor for gastric epithelial lesions. However, it does not seem to relate with distal gastric tumor growth. Serial decreases in SG levels should be considered a warning sign in index hypergastrinemic patients with no prior Helicobacter pylori eradication.

CREB and neuronal selection for memory trace.

Despite considerable progress over the past several decades, our understanding of the mechanisms underlying memory encoding, storage, and expression in a complex neural network are far from complete. In particular, how some neurons rather than others are selectively engaged to encode memory remains largely unknown. Using virus-mediated gene delivery into a small subset of neurons in a given network, molecular imaging of neuronal activity, pharmacological perturbation of specific neurons' activity and animal behavior assays, recent studies have begun to provide insight into molecular and cellular mechanisms responsible for the selection of neurons for inclusion into a memory trace. Here, we focus on a review of recent findings supporting the hypothesis that the level of the transcription factor CREB (cAMP/Ca(2+)-response element binding protein) is a key factor governing which neurons are recruited to a given memory trace. These recent findings open a new perspective on memory trace at the neural circuit level and also raise many important questions. Future studies employing more advanced neurobiological techniques for targeting defined populations of neurons and manipulating their activity in time and space in a complex neural network will give answers to these newly emerging questions and extend our understanding of the neurobiological basis of the memory trace.

Brain region-specific activity patterns after recent or remote memory retrieval of auditory conditioned fear.

Memory is thought to be sparsely encoded throughout multiple brain regions forming unique memory trace. Although evidence has established that the amygdala is a key brain site for memory storage and retrieval of auditory conditioned fear memory, it remains elusive whether the auditory brain regions may be involved in fear memory storage or retrieval. To investigate this possibility, we systematically imaged the brain activity patterns in the lateral amygdala, MGm/PIN, and AuV/TeA using activity-dependent induction of immediate early gene zif268 after recent and remote memory retrieval of auditory conditioned fear. Consistent with the critical role of the amygdala in fear memory, the zif268 activity in the lateral amygdala was significantly increased after both recent and remote memory retrieval. Interesting, however, the density of zif268 (+) neurons in both MGm/PIN and AuV/TeA, particularly in layers IV and VI, was increased only after remote but not recent fear memory retrieval compared to control groups. Further analysis of zif268 signals in AuV/TeA revealed that conditioned tone induced stronger zif268 induction compared to familiar tone in each individual zif268 (+) neuron after recent memory retrieval. Taken together, our results support that the lateral amygdala is a key brain site for permanent fear memory storage and suggest that MGm/PIN and AuV/TeA might play a role for remote memory storage or retrieval of auditory conditioned fear, or, alternatively, that these auditory brain regions might have a different way of processing for familiar or conditioned tone information at recent and remote time phases.