Alleviating depressive-like behavior in DSS-induced colitis mice: Exploring naringin and poncirin from Poncirus trifoliata extracts.

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), often have concomitant mental disorders such as depression and anxiety. Therefore, a bidirectional approach involving the gut and brain axes is necessary for the prevention and treatment thereof. In this study, we explored the potential of Poncirus trifoliata extract (PT), traditionally known for its neuroprotective effects against gastrointestinal diseases, as a natural treatment agent for IBD in a dextran sulfate sodium (DSS)-induced colitis model. Oral administration of PT ameliorated weight loss and inflammatory responses in mice with DSS-induced colitis. Furthermore, PT treatment effectively restored the colon length and ameliorated enterocyte death by inhibiting DSS-induced reactive oxygen species (ROS)-mediated necroptosis. The main bioactive components of PT, poncirin and naringin, confirmed using ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-qTOF), can be utilized to regulate necroptosis. The antidepressant-like effects of PT were confirmed using open field test (OFT) and tail suspension test (TST). PT treatment also restored vascular endothelial cell integrity in the hippocampus. In the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) regions of the hippocampus, PT controlled the neuroinflammatory responses of proliferated microglia. In conclusion, PT, which contains high levels of poncirin and naringin, has potential as a bidirectional therapeutic agent that can simultaneously improve IBD-associated intestinal and mental disorders.

Kinetic modeling of the plasma pharmacokinetic profiles of ADAMTS13 fragment and its Fc-fusion counterpart in mice.

Introduction: Fusion of the fragment crystallizable (Fc) to protein therapeutics is commonly used to extend the circulation time by enhancing neonatal Fc-receptor (FcRn)-mediated endosomal recycling and slowing renal clearance. This study applied kinetic modeling to gain insights into the cellular processing contributing to the observed pharmacokinetic (PK) differences between the novel recombinant ADAMTS13 fragment (MDTCS) and its Fc-fusion protein (MDTCS-Fc). Methods: For MDTCS and MDTCS-Fc, their plasma PK profiles were obtained at two dose levels following intravenous administration of the respective proteins to mice. The plasma PK profiles of MDTCS were fitted to a kinetic model with three unknown protein-dependent parameters representing the fraction recycled (FR) and the rate constants for endocytosis (kup, for the uptake into the endosomes) and for the transfer from the plasma to the interstitial fluid (kpi). For MDTCS-Fc, the model was modified to include an additional parameter for binding to FcRn. Parameter optimization was done using the Cluster Gauss-Newton Method (CGNM), an algorithm that identifies multiple sets of approximate solutions ("accepted" parameter sets) to nonlinear least-squares problems. Results: As expected, the kinetic modeling results yielded the FR of MDTCS-Fc to be 2.8-fold greater than that of MDTCS (0.8497 and 0.3061, respectively). In addition, MDTCS-Fc was predicted to undergo endocytosis (the uptake into the endosomes) at a slower rate than MDTCS. Sensitivity analyses identified the association rate constant (kon) between MDTCS-Fc and FcRn as a potentially important factor influencing the plasma half-life in vivo. Discussion: Our analyses suggested that Fc fusion to MDTCS leads to changes in not only the FR but also the uptake into the endosomes, impacting the systemic plasma PK profiles. These findings may be used to develop recombinant protein therapeutics with extended circulation time.

Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin-converting enzyme 2.

The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.

Efficacy and Safety of Fibroblast Growth Factor-21 Analogs for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis: A Systematic Review and Meta-Analysis.

Fibroblast growth factor (FGF)-21 analogs are potential therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). This systematic review and meta-analysis aimed to assess the efficacy and safety of the FGF-21 analogs, efruxifermin, pegbelfermin, and pegozafermin for MASH treatment. A comprehensive systematic review and meta-analysis of randomized controlled trials from five major databases was conducted. Primary efficacy outcomes focused on liver histological improvement, while secondary efficacy outcomes encompassed reductions in liver fat content and improvements in biochemical parameters. Safety outcomes examined included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Eight eligible studies involving 963 patients were included in this review. Compared with the placebo group, the FGF-21 analog-treated group exhibited significantly improved primary efficacy outcomes, specifically ≥1 stage improvement in fibrosis with no worsening of MASH (risk ratio [RR] = 1.83; 95% confidence interval [CI] = 1.27-2.62) and at least two-point improvement in the non-alcoholic fatty liver disease activity score with no worsening of fibrosis (RR = 2.85; 95% CI = 2.06-3.95). Despite an increased risk of TEAEs (RR = 1.17; 95% CI = 1.08-1.27) and treatment-related adverse events (RR = 1.75; 95% CI = 1.40-2.19), FGF-21 analogs exhibited an acceptable safety profile. FGF-21 analogs were significantly better in achieving liver histological improvements and beneficial biochemical outcomes compared with placebo, with a tolerable safety pattern. These findings shed light on the efficacy and safety of FGF-21 analogs and provide valuable evidence for their application as MASH therapeutics.

Significant CO2 emission in the shallow inshore waters of the southeastern Yellow Sea in 2020.

This study investigated the carbonate system and air-sea CO2 exchange in the inshore waters along South Korea's western coastline in 2020. Overlooking these waters might introduce significant errors in estimating air-sea CO2 fluxes of the southeastern Yellow Sea, given their interaction with land, offshore regions, and sediments. During periods other than summer, seasonal variations in seawater CO2 partial pressure (pCO2) could be generally explained by thermal effects. Tidal mixing and shallow depths resulted in weaker stratification-induced carbon export compared to offshore regions. However, during summer, inshore waters exhibited high spatial variability in pCO2, ranging from approximately 185 to 1000 µatm. In contrast to offshore waters that modestly absorbed CO2, inshore waters shallower than 20 m emitted ∼100 Gg C yr-1 to the atmosphere. However, considering the high heterogeneity of the study area, additional observations with high spatial and temporal resolution are required to refine estimates of air-sea CO2 exchange.

Clinical and radiological results of high tibial of osteotomy over the age of 65 are comparable to that of under 55 at minimum 2-year follow-up: a propensity score matched analysis.

PURPOSE: The results of medial open-wedge high tibial osteotomy (MOWHTO) according to age is inconclusive. This study aimed to compare the clinical outcomes and failure of MOWHTO in patients < 55 years and > 65 years. METHODS: Consecutive patients who underwent MOWHTO from July 2009 to August 2020 were retrospectively analyzed. 205 patients were considered for analysis. A 1-to-1 propensity score matched analysis to assess clinical outcomes scores including International Knee Documentation Committee (IKDC) subjective score and Lysholm score, radiologic outcomes, complication, and Total Knee Arthroplasty (TKA) conversion between patients > 65 years and patients < 55 years was performed. Radiologic outcomes included Hip-Knee-Ankle (HKA) angle, Weight Bearing Line ratio (WBLR), posterior tibial slope (PTS), and Insall-Salvati (IS) ratio before and after surgery. RESULTS: The follow-up period was 50.4 months in patients > 65 years and 55.3 months in patients < 55 years. There was no significant difference in the preoperative and postoperative HKA angle, WBLR, PTS, IS ratio, IKDC score and Lysholm score between the two groups. The arthroscopic evaluation of cartilage did not show any statistically significant differences between the two groups. Regarding Minimal clinically important differences (MCID), in the 26% of the older group exceeded MCID of IKDC score; 45% of the older group exceeded MCID of Lysholm score. In the younger group, 24% exceeded MCID of IKDC score and 35% exceeded MCID of Lysholm score. In older group, there were 7 (11.3%) cases of TKA conversion while no TKA conversion was recorded in the younger group. (P = 0.007) The average time to TKA conversion was 67 months. (42 months to 90 months) Kaplan-Meier analysis revealed that the survival rate was 95.2% at 4 years in the older group. CONCLUSION: Similar clinical results were obtained in patients over 65 years of age that were eligible for MOWHTO at minimum 2-year follow-up as in patients under 55 years of age. MOWHTO may be a viable option in older patients if proper indications are met. However, the risk of TKA conversion must be considered preoperatively and discussed with patients. STUDY DESIGN: Cohort study; Level of evidence, 3.

Bile salt hydrolase catalyses formation of amine-conjugated bile acids.

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.

Knowledge and the behavioral patterns of photoprotection among Koreans with skin disease.

BACKGROUND: Photoprotection is crucial in preventing the development and progression of various skin diseases. However, patients with skin disease have limited awareness of photoprotection. We evaluated the knowledge and behavioral patterns of photoprotection among Koreans with skin diseases. METHODS: A cross-sectional study was conducted in 11 general hospitals across South Korea. The study population consisted of patients aged 19 years or older who visited dermatologic clinics for their skin diseases. A self-administered questionnaire was used to collect patient demographics, knowledge of photoprotection, and photoprotective habits. RESULTS: In this study, 1173 patients with skin cancer, hyperpigmentary disorders, hypopigmentary disorders, or other skin diseases participated. Females scored significantly higher in knowledge of photoprotection compared to males (mean score 8.4 vs. 7.8; p < .001), and younger patients (<50 years) scored higher than older patients (mean score 8.7 vs. 7.5; p < .001). Males also reported longer sun exposure times and lower usage of photoprotective measures (both p < .001). Patients with skin cancer had the lowest mean knowledge score (7.1 ± 2.6) and were less likely to use photoprotective measures compared to other groups (p < .001). In contrast, patients with hyperpigmentation actively avoided sun exposure compared with other groups (p < 0.001). CONCLUSIONS: Knowledge of photoprotection among Korean patients with skin diseases varied depending on the gender, age, and type of skin disease. Their photoprotective behaviors were inadequate, especially among males and those with skin cancer. These findings emphasize the importance of educating and tailoring photoprotection strategies for patients with skin diseases.

Association between Perceived Activity Restriction Due to People's Perception of Aging and Unmet Medical Needs among Middle-Aged and Elderly People: A Population-Based Study.

Background and Objectives: The older members of a population might experience unmet medical needs, despite desiring medical care due to activity limitations driven by their perception of aging. This study conducted a cross-sectional analysis of the association between perceived activity restriction (PAR) due to people's own perception of aging and unmet medical needs (UMN) in late middle-aged and older Koreans based on the Korean National Health and Nutrition Examination Survey (KNHANES). Materials and Methods: The 2016-2020 KNHANES was used to analyze a total of 2008 participants among groups aged 45 years or older by applying individual weights imposed from the raw data. The independent variable of PAR was assessed using self-reported questionnaires based on the global activity limitation indicator. Also, the dependent variable of UMN, referring to the state in which a patient's medical care or service was insufficient, inadequate, or lacking, was assessed using a single question. After excluding missing values, the data on 2008 individuals were analyzed using a chi-square test, weighted logistic regression, and a stratified analysis of gender, age, and the presence of chronic illnesses. Results: The group that experienced PAR had an OR 2.13 higher (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.27-3.56) to present UMN than the group that did not experience PAR. Furthermore, the results of the stratified analysis indicated that, in the group of female participants with chronic illness and in the group of elderly people, experiencing PAR was associated with a higher experience of UMN. Conclusions: There was a close association between PAR and UMN. In particular, when PAR occurred in the group of female participants with chronic illness and in the group of elderly people, the incidence rate of UMN was also found to be high. This finding highlights the need for policies and institutional measures to reduce UMN within vulnerable groups with an increased risk of medical inaccessibility due to activity restriction.

Hydrovoltaic Electricity Generator with Hygroscopic Materials: A Review and New Perspective.

The global energy crisis caused by the overconsumption of nonrenewable fuels has prompted researchers to develop alternative strategies for producing electrical energy. In this review, a fascinating strategy that simply utilizes water, an abundant natural substance throughout the globe and even in air as moisture, as a power source is introduced. The concept of the hydrovoltaic electricity generator (HEG) proposed herein involves generating an electrical potential gradient by exposing the two ends of the HEG device to dissimilar physicochemical environments, which leads to the production of an electrical current through the active material. HEGs, with a large variety of viable active materials, have much potential for expansion toward diverse applications including permanent and/or emergency power sources. In this review, representative HEGs that generate electricity by the mechanisms of diffusion, streaming, and capacitance as case studies for building a fundamental understanding of the electricity generation process are discussed. In particular, by comparing the use and absence of hygroscopic materials, HEG mechanism studies to establish active material design principles are meticulously elucidated. The review with future perspectives on electrode design using conducting nanomaterials, considerations for high performance device construction, and potential impacts of the HEG technology in improving the livelihoods are reviewed.

Temporal variations in the surface aragonite saturation state of the Yellow Sea: Observations at the Socheongcho Ocean Research Station during 2017-2022.

Accurately constraining the natural variability of the carbonate system is essential for evaluating long-term changes in coastal areas, which result from the absorption of anthropogenic CO2. This is particularly important given the significant variation in physical and biological processes in these regions. In this regard, the analysis of surface carbonate chemistry in the Yellow Sea was conducted using discrete seawater samples obtained from the Socheongcho Ocean Research Station (37.423°N, 124.738°E) between 2017 and 2022. Our bottle data and sensor pH measurements revealed considerable seasonal variations of aragonite saturation state (ΩAR), typically ranging from 1.6 to 3.9. These variations are particularly pronounced during the summer and early winter. Our dataset serves as a baseline for understanding the long-term changes in ocean acidification in the Yellow Sea, the complex biogeochemical processes in coastal areas, and their impact on ocean acidification.

Preparation of Hot-Melt-Extruded Solid Dispersion Based on Pre-Formulation Strategies and Its Enhanced Therapeutic Efficacy.

In this study, an amorphous solid dispersion containing the poorly water-soluble drug, bisacodyl, was prepared by hot-melt extrusion to enhance its therapeutic efficacy. First, the miscibility and interaction between the drug and polymer were investigated as pre-formulation strategies using various analytical approaches to obtain information for selecting a suitable polymer. Based on the calculation of the Hansen solubility parameter and the identification of the single glass transition temperature (Tg), the miscibility between bisacodyl and all the investigated polymers was confirmed. Additionally, the drug-polymer molecular interaction was identified based on the comprehensive results of dynamic vapor sorption (DVS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, and a comparison of the predicted and experimental values of Tg. In particular, the hydroxypropyl methylcellulose (HPMC)-based solid dispersions, which exhibited large deviation between the calculated and experimental values of Tg and superior physical stability after DVS experiments, were selected as the most appropriate solubilized bisacodyl formulations due to the excellent inhibitory effects on precipitation based on the results of the non-sink dissolution test. Furthermore, it was shown that the enteric-coated tablets containing HPMC-bisacodyl at a 1:4 ratio (w/w) had significantly improved in vivo therapeutic laxative efficacy compared to preparations containing un-solubilized raw bisacodyl in constipation-induced rabbits. Therefore, it was concluded that the pre-formulation strategy, using several analyses and approaches, was successfully applied in this study to investigate the miscibility and interaction of drug-polymer systems, hence resulting in the manufacture of favorable solid dispersions with favorable in vitro and in vivo performances using hot-melt extrusion processes.

Clinical factors for choosing active surveillance: an analysis of papillary thyroid microcarcinoma patients with recurrence.

Objective: Active surveillance (AS) has been suggested as a management option for low-risk papillary thyroid microcarcinoma (PTMC). However, the currently proposed selection criteria for AS application do not consider various clinical factors. The purpose of this study was to analyze clinical factors related to recurrence that could be confirmed preoperatively in patients who underwent surgery for PTMC and to identify factors worth considering when deciding whether to apply AS. Materials and methods: Data were collected from patients with PTMC who underwent surgical treatment at Chungnam National University Hospital. A retrospective cohort was established according to the presence or absence of recurrence during the follow-up period. In total, 2717 patients were enrolled, of whom 60 experienced recurrence. Various clinical factors that could be identified before surgery were analyzed. Results: The relationship between various clinical factors that could be confirmed preoperatively and recurrence was confirmed through Cox regression analysis and Kaplan-Meier curve analysis. BRAF mutation and the tall cell variant were significantly more common in patients with recurrence. In patients aged 55 years or older, the risk of recurrence was lower than in younger patients, while the recurrence-free survival (RFS) rate was higher. Conclusion: When choosing between surgical treatment or AS in PTMC patients, additional consideration of the patient's clinical factors, such as age and BRAF mutation status, may be required in addition to the existing criteria.

Preparation and characterization of zwitterion-substituted lignin/Nafion composite membranes.

In this study, a novel zwitterion-substituted lignin (ZL) containing amino and sulfonic acid groups was synthesized, and ZL/Nafion composite membranes were fabricated as proton exchange membranes. Kraft lignin was modified using an aminosilane and 1,3-propanesultone via a continuous grafting reaction to provide zwitterionic moieties. Chemical structural analyses confirmed the successful introduction of the zwitterion moiety into lignin. In particular, the surface charge of ZL is positive in an acidic medium and negative in a basic medium, suggesting that ZL is a zwitterionic material. ZL was incorporated into a Nafion membrane to enhance its ion exchange capacity, thermal stability, and hydrophilicity. The proton conductivity of ZL/Nafion 0.5 %, 151.0 mS/cm, was 55.3 % higher than that of unmodified ML (methanol-soluble lignin)/Nafion 0.5 % (97.2 mS/cm), indicating that the zwitterion moiety of ZL enhances the proton transport ability. In addition, oxidative stability evaluation confirmed that ZL/Nafion 2 % was chemically more durable than pure Nafion. This confirmed that using lignin as a membrane additive yielded positive results in terms of chemical durability and oxidation stability in Nafion. Therefore, ZL is expected to be utilized as a multifunctional additive and exhibits the potential for fuel cell applications.

Cutaneous Cytomegalovirus Infection Presenting As Recalcitrant Bullous Pemphigoid Lesion.

Cytomegalovirus (CMV) infection is common among immunocompromised hosts; however, its cutaneous manifestation is considered rare in comparison to internal organ involvement. Clinical manifestations of cutaneous CMV infection generally include perioral or perianal ulcerations. On the other hand, autoimmune bullous dermatosis can have bullae and ulcerations similar to those caused by cutaneous CMV infection. Autoimmune bullous dermatosis requires treatment with immunosuppressive agents for relatively long periods, which may cause reduction of immunocompetence. Because of this iatrogenic immunosuppression, patients with autoimmune bullous dermatosis subsequently acquire increased risk for opportunistic infections. However, cases of bullous pemphigoid (BP) complicated by cutaneous CMV infection are rarely reported. Herein, we report the case of an 88-year-old male who had BP and subsequently recalcitrant perianal skin lesions, which were eventually diagnosed as cutaneous CMV infections.

Corrigendum: Motility increase of Adherent Invasive Escherichia coli (AIEC) induced by a sub-inhibitory concentration of recombinant endolysin LysPA90.

[This corrects the article DOI: 10.3389/fmicb.2022.1093670.].

Three-dimensional evaluation of the association between tongue position and upper airway morphology in adults: A cross-sectional study.

Objective: This study aimed to evaluate the association between low tongue position (LTP) and the volume and dimensions of the nasopharyngeal, retropalatal, retroglossal, and hypopharyngeal segments of the upper airway. Methods: A total of 194 subjects, including 91 males and 103 females were divided into a resting tongue position (RTP) group and a LTP group according to their tongue position. Subjects in the LTP group were divided into four subgroups (Q1, Q2, Q3, and Q4) according to the intraoral space volume. The 3D slicer software was used to measure the volume and minimum and average cross-sectional areas of each group. Airway differences between the RTP and LTP groups were analyzed to explore the association between tongue position and the upper airway. Results: No significant differences were found in the airway dimensions between the RTP and LTP groups. For both retropalatal and retroglossal segments, the volume and average cross-sectional area were significantly greater in the patients with extremely low tongue position. Regression analysis showed that the retroglossal airway dimensions were positively correlated with the intraoral space volume and negatively correlated with A point-nasion-B point and palatal plane to mandibular plane. Males generally had larger retroglossal and hypopharyngeal airways than females. Conclusions: Tongue position did not significantly influence upper airway volume or dimensions, except in the extremely LTP subgroup.

TrkB inhibition of DJ-1 degradation promotes the growth and maintenance of cancer stem cell characteristics in hepatocellular carcinoma.

Although TrkB may be associated with the pathogenesis of various cancer by upregulation, how upregulation of TrkB led to tumor progression in hepatocellular carcinoma (HCC) and the signaling mechanisms by which TrkB induces motility, invasion, metastasis, drug resistance, and acquisition of self-renewal traits has remained unclear. Here, we demonstrated that TrkB was significantly upregulated in highly metastatic HCC cells and HCC patients. Also, the increased TrkB levels were significantly correlated with tumor stages and poor survival of HCC patients. Furthermore, the upregulated TrkB expression enhances the metastatic ability of HCC cells through reduced anoikis sensitivity, induced migration, and colony formation. Most strikingly, TrkB markedly enhances the activation of STAT3 by preventing DJ-1 degradation through the formation of the TrkB/DJ-1 complex. This signaling mechanism is responsible for triggering cellular traits of highly aggressive HCC. The activation of the EMT program of HCC via increasing DJ-1 stability by TrkB induces the gain of cancer stem cell states and chemoresistance via the upregulation of stem cells cell markers and ABC transporters. Also, TrkB-mediated inhibition of DJ-1 degradation promotes tumor formation and metastasizes to other organs in vivo. Our observations illustrate that TrkB is a prognostic and therapeutic targeting in promoting aggressiveness and metastasis of HCC.

Corrigendum: Combination effect of engineered endolysin EC340 with antibiotics.

[This corrects the article DOI: 10.3389/fmicb.2022.821936.].