Small Peptide Derived from SFRP5 Suppresses Melanogenesis by Inhibiting Wnt Activity.

Melanocytes, located in the epidermis' basal layer, are responsible for melanin pigment production, crucial for skin coloration and protection against UV radiation-induced damage. Melanin synthesis is intricately regulated by various factors, including the Wnt signaling pathway, particularly mediated by the microphthalmia-associated transcription factor (MITF). While MITF is recognized as a key regulator of pigmentation, its regulation by the Wnt pathway remains poorly understood. This study investigates the role of Sfrp5pepD, a peptide antagonist of the Wnt signaling pathway, in modulating melanogenesis and its potential therapeutic implications for pigmentary disorders. To tackle this issue, we investigated smaller peptides frequently utilized in cosmetics or pharmaceuticals. Nevertheless, there is a significant scarcity of reports on peptides associated with melanin-related signal modulation or inhibiting melanin production. Results indicate that Sfrp5pepD effectively inhibits Wnt signaling by disrupting the interaction between Axin-1 and ß-catenin, thus impeding downstream melanogenic processes. Additionally, Sfrp5pepD suppresses the interaction between MITF and ß-catenin, inhibiting their nuclear translocation and downregulating melanogenic enzyme expression, ultimately reducing melanin production. These inhibitory effects are validated in cell culture models suggesting potential clinical applications for hyperpigmentation disorders. Overall, this study elucidates the intricate interplay between Wnt signaling and melanogenesis, highlighting Sfrp5pepD as a promising therapeutic agent for pigmentary disorders. Sfrp5pepD, with a molecular weight of less than 500 Da, is anticipated to penetrate the skin unlike SFRPs. This suggests a strong potential for their use as cosmetics or transdermal absorption agents. Additional investigation into its mechanisms and clinical significance is necessary to enhance its effectiveness in addressing melanin-related skin conditions.

Prevalence and prognosis of acute pancreatitis in critically ill patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic issue. In addition to the well-known respiratory and fever symptoms, gastrointestinal symptoms have also been reported. This study aimed to evaluate the prevalence and prognosis of patients with COVID-19 infection complicated with acute pancreatitis in intensive care unit (ICU). METHODS: This was a retrospective observational cohort study, and patients aged 18 years or older, admitted into the ICU in a single tertiary center from January 1, 2020, to April 30, 2022 were enrolled. Patients were identified by electronic medical records and reviewed manually. The primary outcome was the prevalence of acute pancreatitis among ICU patients with COVID-19. The secondary outcomes were the length of hospital stay, need for mechanical ventilation (MV), need for continuous renal replacement therapy (CRRT), and in-hospital mortality. RESULTS: A total of 4133 patients, admitted into the ICU, were screened. Among these patients, 389 were infected by COVID-19, and 86 were diagnosed with acute pancreatitis. COVID-19 positive patients were more likely to present with acute pancreatitis than COVID-19 negative patients (odds ratio = 5.42, 95% confidence interval: 2.35-6.58, P < 0.01). However, the length of hospital stay, need for MV, need for CRRT, and in-hospital mortality were not significantly different between acute pancreatitis patients with and without COVID-19 infection. CONCLUSIONS: Severe COVID-19 infections may cause acute pancreas damage in critically ill patients. However, the prognosis may not differ between acute pancreatitis patients with and without COVID-19 infection.

Basic Strategies of Augmentation Mammoplasty in Patients with Tendencies of Pectus Excavatum and Carinatum.

BACKGROUND: In this era of growing popularity of cosmetic surgeries, more women of various chest wall shapes are likely to receive augmentation mammoplasty. Pectus excavatum (PE) and pectus carinatum (PC) are the two most common chest wall deformities, and many asymptomatic patients visit the clinic. In this study, we presented various strategies for successfully performing breast augmentation in PE and PC patients without long-term complications such as symmastia. METHODS: From January of 2019 to December of 2021, a total of 132 patients with tendencies of PE and PC received augmentation mammoplasty in our institute. We retrospectively reviewed data on demographics, surgical procedure, outcomes, and complications. RESULTS: Among the 132 cases, 71.21% were done via inframammary approach, and 28.79% via transaxillary approach. The mean implant volume was 337.25 ± 51.46 ml, and the mean follow-up period was 16.48 ± 6.74 months. The Likert scale of outcome satisfaction scored 9.13 ± 0.48. No symmastia occurred. CONCLUSION: We presented our basic strategies of breast surgery in patients with various chest wall anomalies. Augmentation mammoplasty can benefit PE and PC patients physically as well as psychologically, to carry out healthy positive lives. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Stimulatory Effects of Extracellular Vesicles Derived from Leuconostoc holzapfelii That Exists in Human Scalp on Hair Growth in Human Follicle Dermal Papilla Cells.

Human hair follicle dermal papilla cells (HFDPCs) located in hair follicles (HFs) play a pivotal role in hair follicle morphogenesis, hair cycling, and hair growth. Over the past few decades, probiotic bacteria (PB) have been reported to have beneficial effects such as improved skin health, anti-obesity, and immuno-modulation for conditions including atopic dermatitis and inflammatory bowel disease (IBD). PB can secrete 50~150 nm sized extracellular vesicles (EVs) containing microbial DNA, miRNA, proteins, lipids, and cell wall components. These EVs can regulate communication between bacteria or between bacteria and their host. Although numerous biological effects of PB-EVs have been reported, the physiological roles of Leuconostoc holzapfelii (hs-Lh), which is isolated from human scalp tissue, and the extracellular vesicles derived from them (hs-LhEVs) are largely unknown. Herein, we investigated the effects of hs-LhEVs on hair growth in HFDPCs. We show that hs-LhEVs increase cell proliferation, migration, and regulate the cell cycle. Furthermore, hs-LhEVs were found to modulate the mRNA expression of hair-growth-related genes in vitro. These data demonstrate that hs-LhEVs can reduce apoptosis by modulating the cell cycle and promote hair growth by regulation via the Wnt/ß-catenin signal transduction pathway.

Caspase-10 affects the pathogenesis of primary biliary cholangitis by regulating inflammatory cell death.

Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment.

Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases.

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut-liver axis. The gut microbiota consists of various microorganisms that play a role in maintaining the homeostasis of the host and release a wide number of metabolites, including short-chain fatty acids (SCFAs), peptides, and hormones, continually shaping the host's immunity and metabolism. The integrity of the intestinal mucosal and vascular barriers is crucial to protect liver cells from exposure to harmful metabolites and pathogen-associated molecular pattern molecules. Dysbiosis and increased intestinal permeability may allow the liver to be exposed to abundant harmful metabolites that promote liver inflammation and fibrosis. In this review, we introduce the metabolites and components derived from the gut microbiota and discuss their pathologic effect in the liver alongside recent advances in molecular-based therapeutics and novel mechanistic findings associated with the gut-liver axis in ALD and NAFLD.

A Model to Predict 1-Month Risk of Transplant or Death in Hepatitis A-Related Acute Liver Failure.

Acute liver failure (ALF) caused by hepatitis A is a rare but fatal disease. Here, we developed a model to predict outcome in patients with ALF caused by hepatitis A. The derivation set consisted of 294 patients diagnosed with hepatitis A-related ALF (ALFA) from Korea, and a validation set of 56 patients from Japan, India, and United Kingdom. Using a multivariate proportional hazard model, a risk-prediction model (ALFA score) consisting of age, international normalized ratio, bilirubin, ammonia, creatinine, and hemoglobin levels acquired on the day of ALF diagnosis was developed. The ALFA score showed the highest discrimination in the prediction of liver transplant or death at 1 month (c-statistic, 0.87; 95% confidence interval [CI], 0.84-0.92) versus King's College criteria (KCC; c-statistic, 0.56; 95% CI, 0.53-0.59), U.S. Acute Liver Failure Study Group index specific for hepatitis A virus (HAV-ALFSG; c-statistic, 0.70; 95% CI, 0.65-0.76), the new ALFSG index (c-statistic, 0.79; 95% CI, 0.74-0.84), Model for End-Stage Liver Disease (MELD; c-statistic, 0.79; 95% CI, 0.74-0.84), and MELD including sodium (MELD-Na; c-statistic, 0.78; 95% CI, 0.73-0.84) in the derivation set (all P < 0.01). In the validation set, the performance of the ALFA score (c-statistic, 0.84; 95% CI, 0.74-0.94) was significantly better than that of KCC (c-statistic, 0.65; 95% CI, 0.52-0.79), MELD (c-statistic, 0.74; 95% CI, 0.61-0.87), and MELD-Na (c-statistic, 0.72; 95% CI, 0.58-0.85) (all P < 0.05), and better, but not statistically significant, than that of the HAV-ALFSG (c-statistic, 0.76; 95% CI, 0.61-0.90; P = 0.28) and new ALFSG indices (c-statistic, 0.79; 95% CI, 0.65-0.93; P = 0.41). The model was well-calibrated in both sets. Conclusion: Our disease-specific score provides refined prediction of outcome in patients with ALF caused by hepatitis A.

Fatty acid-binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation.

Fatty acid-binding proteins (FABPs) are intracellular lipid carriers that regulate inflammation, and pharmacological inhibition of FABP5 reduces inflammation and pain. The mechanism(s) underlying the anti-inflammatory effects associated with FABP5 inhibition is poorly understood. Herein, we identify a novel mechanism through which FABP5 modulates inflammation. In mice, intraplantar injection of carrageenan induces acute inflammation that is accompanied by edema, enhanced pain sensitivity, and elevations in proinflammatory cytokines and prostaglandin E2 (PGE2). Inhibition of FABP5 reduced pain, edema, cytokine, and PGE2 levels. PGE2 is a major eicosanoid that enhances pain in the setting of inflammation, and we focused on the mechanism(s) through which FABP5 modulates PGE2 production. Cyclooxygenase 2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) are enzymes up-regulated at the site of inflammation and account for the bulk of PGE2 biosynthesis. Pharmacological or genetic FABP5 inhibition suppressed the induction of mPGES-1 but not COX-2 in carrageenan-injected paws, which occurred predominantly in macrophages. The cytokine interleukin 1ß (IL-1ß) is a major inducer of mPGES-1 during inflammation. Using A549 cells that express FABP5, IL-1ß stimulation up-regulated mPGES-1 expression, and mPGES-1 induction was attenuated in A549 cells bearing a knockdown of FABP5. IL-1ß up-regulates mPGES-1 via NF-κB, which activates the mPGES-1 promoter. Knockdown of FABP5 reduced the activation and nuclear translocation of NF-κB and attenuated mPGES-1 promoter activity. Deletion of NF-κB-binding sites within the mPGES-1 promoter abrogated the ability of FABP5 to inhibit mPGES-1 promoter activation. Collectively, these results position FABP5 as a novel regulator of mPGES-1 induction and PGE2 biosynthesis during inflammation.

The effect of medial open wedge high tibial osteotomy on the patellofemoral joint: comparative analysis according to the preexisting cartilage status.

BACKGROUND: Although it has been known that medial open wedge high tibial osteotomy (MOWHTO) would adversely affect the patellofemoral joint, no previous study examined the surgical outcome of MOWHTO according to the preexisting cartilage status of the patellofemoral joint. The aim of this study was to investigate the effect of MOWHTO on the patellofemoral joint with regard to objective and subjective aspects according to the preexisting cartilage status. METHODS: Ninety-two patients who underwent MOWHTO and a following second-look arthroscopic assessment were included in this study. The patients were divided into two groups according to the preexisting cartilage status of the patellofemoral joint: group 1 (International Cartilage Repair Society [ICRS] grade 2 or 3) and group 2 (ICRS grade 0 or 1). Comparative analysis was performed regarding clinical scores, radiographic parameters, and arthroscopic measurements between the two groups. RESULTS: Clinical outcomes showed overall improvement from baseline to the time of second-look operation, with no significant difference between the two groups at each time point. There were no significant differences in radiographic parameters between the two groups. Radiographic grade of patellofemoral osteoarthritis in both groups showed a tendency to progress, without statistical significance. In arthroscopic assessment, the size of the cartilage lesion on the patellofemoral joint increased with time in both groups (P = 0.003), but the degree of change over time between the two groups was not statistically significant. Consistently, there was no significant difference in the frequency of progression of cartilage lesion grade in the patellofemoral joint between the two groups. CONCLUSIONS: MOWHTO would contribute to osteoarthritis progression of the patellofemoral joint regardless of the preexisting cartilage status, without an association with clinical outcomes in short-term follow-up.

Effect of a Formulation Containing Low-Dose Sodium Deoxycholate on Local Fat Reduction.

BACKGROUND: Synthetic deoxycholic acid (DCA) has been approved as an injectable drug for the nonsurgical reduction of submental fat. OBJECTIVE: In this study, we evaluated the fat-reducing effects of a new formula containing a low dose of DCA and fat dissolution by topical application of DCA. METHODS: Sodium deoxycholate (99.1% pure) and the new formulation containing 10% DCA were injected or topically applied to the dorsa of obese mice (induced by a high-fat diet). The rate of change in body weight was evaluated, together with comparisons of micro-computed tomography images, body composition measurements, and histology findings. RESULTS: The results showed that the new formula containing low-dose DCA was as effective as the older high-dose formulation with respect to the rate of change in body weight and reductions in subcutaneous fat pad area, body fat weight, and the thickness of the subcutaneous fat layer. Furthermore, topical application of the high-dose, but not the low-dose, formulation yielded promising effects. CONCLUSIONS: The development of a better protocol for the high-dose preparation, including dose optimization and application methods that minimize the adverse effects of DCA, merits further study. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine Ratings, please refer to Table of Contents or online Instructions to Authors - www.springer.com/00266 .