Nanographene-Fused Expanded Carbaporphyrin Tweezers.

A nanographene-fused expanded carbaporphyrin (5) and its BF2 complex (6) were synthesized. Single-crystal X-ray structures revealed that 5 and 6 are connected by two hexa-peri-hexabenzocoronene (HBC) units and two dipyrromethene or BODIPY units, respectively. As prepared, 5 and 6 both show nonaromatic character with figure-of-eight carbaoctaphyrin (1.1.1.0.1.1.1.0) cores and adopt tweezers-like conformations characterized by a partially confined space between the two constituent HBC units. The distance between the HBC centers is >10 Å, while the dihedral angles between the two HBC planes are 30.5 and 35.2° for 5 and 6, respectively. The interactions between 5 and 6 and fullerene C60 were studied both in organic media and in the solid state. Proton NMR spectral titrations of 5 and 6 with C60 revealed a 1:1 binding mode for both macrocycles. In toluene-d8, the corresponding binding constants were determined to be 1141 ± 17 and 994 ± 10 M-1 for 5 and 6, respectively. Single-crystal X-ray diffraction structural analyses confirmed the formation of 1:1 fullerene inclusion complexes in the solid state. The C60 guests in both complexes are found within triangular pockets composed of two HBC units from the tweezers-like receptor most closely associated with the bound fullerene, as well as an HBC unit from an adjacent host. Femtosecond transient absorption measurements revealed subpicosecond ultrafast charge separation between 5 (and 6) and C60 in the complexes. To the best of our knowledge, the present report provides the first example wherein a nanographene building block is incorporated into the core of a porphyrinic framework.

Murine Coronavirus Disease 2019 Lethality Is Characterized by Lymphoid Depletion Associated with Suppressed Antigen-Presenting Cell Functionality.

The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.

Development and validation of a self-management self-efficacy scale for premature birth prevention (SMSE-PBP) for women of childbearing age.

BACKGROUND: This study aimed to develop and evaluate the validity and reliability of a self-management self-efficacy for premature birth prevention (SMSE-PBP) in women of childbearing age (WCA). METHODS: Instrument development and validation were undertaken in three phases: conceptualization, item generation and evaluation of content validity, and evaluation of construct and concurrent validity and reliability. Data were analyzed using exploratory and second-order confirmatory factor analyses, and concurrent validity was examined using Pearson's correlation coefficients. The reliability was analyzed using omega hierarchical and Cronbach's ⍺. RESULTS: Content validity was assessed by experts and cognitive interviews of WCA. The SMSE-PBP consists of a second-order 3-dimension and 10-factor scale with 60 items; therefore, the construct and concurrent validity of the SMSE-PBP were supported. The omega values were 0.93 for pre-pregnancy SMSE-PBP, 0.92 for pregnancy SMSE-PBP, and 0.94 for hospital SMSE-PBP. Cronbach's ⍺ was 0.88 for pre-pregnancy SMSE-PBP, 0.96 for pregnancy SMSE-PBP, and 0.96 for hospital SMSE-PBP. CONCLUSIONS: The SMSE-PBP scale is valid and reliable for WCA; it is helpful for WCA and health professionals to assess women's SMSE-PBP and pre-pregnancy, pregnancy, or hospital SMSE-PBP. The next steps should include assessing the relationship with pregnancy health behaviors.

Evaluation of the anti-androgenic and cytotoxic effects of benzophenone-3 in male Sprague-Dawley rats.

Benzophenone-3 (BP-3, 2-hydroxy-4-methoxybenzophenone, oxybenzone) is one of the most widely used types of benzophenone organic sunscreen. However, this compound is a potentially harmful toxicant. The aim of this study was 2-fold to: (1) utilize a Hershberger bioassay in vivo in castrated male Sprague-Dawley rats to investigate the anti-androgenic activities of BP-3, and (2) use in vitro a methyl tetrazolium assay to compare the toxicity between Leydig cells (TM3 cells) and mouse fibroblast (NIH-3T3) cell lines. In the Hershberger assay, rats were divided into 6 groups (each of n = 7): a vehicle control, negative control, positive control, PB-3 low (40 mg/kg), BP-3 intermediate (200 mg/kg), and BP-3 high (1000 mg/kg)-dose. The weight of the ventral prostate was significantly decreased at BP-3 doses of 200 or 1,000 mg/kg/day. In addition, the levator anibulbocavernosus muscle weights were also significantly reduced at BP-3 doses of 40, 200, or 1,000 mg/kg/day. In the MTT assay, the viability of NIH-3T3 mouse fibroblast cells was within the normal range. However, the TM3 mouse testis Leydig cell viability was significantly lowered in a concentration-dependent manner. Therefore, data indicate that BP-3 might exert in vivo anti-androgenic and in vitro cytotoxic effects in cells associated with the male reproductive system compared to normal non-reproductive cells.Abbreviation: BP-3: benzophenone-3; CG: Cowper's gland; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GP: glans penis; LABC: levator anibulbocavernosus muscle; MTT: methyl tetrazolium; NC: negative control; PC: positive control; SV: seminal vesicle; TP: testosterone propionate; VC: vehicle control; VP: ventral prostate.

Activated Leukocyte Cell Adhesion Molecule Regulates the Expression of Interleukin-33 in RSV Induced Airway Inflammation by Regulating MAPK Signaling Pathways.

PURPOSE: The respiratory syncytial virus (RSV) is a common respiratory virus that causes acute lower respiratory tract infectious diseases, particularly in young children and older individuals. Activated leukocyte cell adhesion molecule (ALCAM) is a membrane glycoprotein expressed in various cell types, including epithelial cells, and is associated with inflammatory responses and various cancers. However, the precise role of ALCAM in RSV-induced airway inflammation remains unclear, and our study aimed to explore this gap in the literature. METHODS: C57BL/6 wild-type, ALCAM knockout mice and airway epithelial cells were infected with RSV and the expression of ALCAM and inflammatory cytokines were measured. We also conducted further experiments using Anti-ALCAM antibody and recombinant ALCAM in airway epithelial cells. RESULTS: The expression levels of ALCAM and inflammatory cytokines increased in both RSV-infected mice and airway epithelial cells. Interestingly, IL-33 expression was significantly reduced in ALCAM-knockdown cells compared to control cells following RSV infection. Anti-ALCAM antibody treatment also reduced IL-33 expression following RSV infection. Furthermore, the phosphorylation of ERK1/2, p38, and JNK was diminished in ALCAM-knockdown cells compared to control cells following RSV infection. Notably, in the control cells, inhibition of these pathways significantly decreased the expression of IL-33. In vivo study also confirmed a reduction in inflammation induced by RSV infection in ALCAM deficient mice compared to wild-type mice. CONCLUSION: These findings demonstrate that ALCAM contributes to RSV-induced airway inflammation at least partly by influencing IL-33 expression through mitogen-activated protein kinase signaling pathways. These results suggest that targeting ALCAM could be a potential therapeutic strategy for alleviating IL-33-associated lung diseases.

The utility of ChatGPT as a generative medical translator.

PURPOSE: Large language models continue to dramatically change the medical landscape. We aimed to explore the utility of ChatGPT in providing accurate, actionable, and understandable generative medical translations in English, Spanish, and Mandarin pertaining to Otolaryngology. METHODS: Responses of GPT-4 to commonly asked patient questions listed on official otolaryngology clinical practice guidelines (CPG) were evaluated with the Patient Education materials Assessment Tool-printable (PEMAT-P.) Additional critical elements were identified a priori to evaluate ChatGPT's accuracy and thoroughness in its responses. Multiple fluent speakers of English, Mandarin, and Spanish evaluated each response generated by ChatGPT. RESULTS: Total PEMAT-P scores differed between English, Mandarin, and Spanish GPT-4 generated responses depicting a moderate effect size of language, Eta-Square 0.07 with scores ranging from 73 to 77 (P-value = 0.03). Overall understandability scores did not differ between English, Mandarin, and Spanish depicting a small effect size of language, Eta-Square 0.02 scores ranging from 76 to 79 (P-value = 0.17), nor did overall actionability scores Eta-Square 0 score ranging 66-73 (P-value = 0.44). Overall a priori procedure-specific responses similarly did not differ between English, Spanish, and Mandarin Eta-Square 0.02 scores ranging 61-78 (P-value = 0.22). CONCLUSION: GPT-4 produces accurate, understandable, and actionable outputs in English, Spanish, and Mandarin. Responses generated by GPT-4 in Spanish and Mandarin are comparable to English counterparts indicating a novel use for these models within Otolaryngology, and implications for bridging healthcare access and literacy gaps. LEVEL OF EVIDENCE: IV.

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency.

BACKGROUND: Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. METHODS: We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. RESULTS: We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. CONCLUSION: Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.

π-Extended Hexapyrrolylbenzenes: Exploring Charge-Transfer Phenomena in Donor-Acceptor Propellers.

A family of propeller-shaped donor-acceptor hexapyrrolylbenzenes (HPBs) were designed and synthesized by sequential nucleophilic substitution of hexafluorobenzene with π-extended pyrroles. In particular, four hybrids were obtained, containing various combinations of electron-rich and electron-poor acenaphthylene-fused pyrroles. Additionally, to probe the efficiency of ortho transfer interactions, a system was designed containing unique donor and acceptor subunits spatially separated with four unfunctionalized pyrroles. DFT calculations showed propeller-shaped geometries of all HPB molecules and separation of frontier molecular orbitals between donor and acceptor subunits. Steady-state and time-resolved photophysical measurements revealed charge-transfer (CT) character of the emission with strong positive dependence on solvent polarity. The principal CT pathway involves ortho-positioned pairs of donors and acceptors and requires bending of the acceptor in the excited state.

Establishment of multicenter COVID-19 therapeutics preclinical test system in Republic of Korea.

Throughout the recent COVID-19 pandemic, South Korea led national efforts to develop vaccines and therapeutics for SARS-CoV-2. The project proceeded as follows: 1) evaluation system setup (including Animal Biosafety Level 3 (ABSL3) facility alliance, standardized nonclinical evaluation protocol, and laboratory information management system), 2) application (including committee review and selection), and 3) evaluation (including expert judgment and reporting). After receiving 101 applications, the selection committee reviewed pharmacokinetics, toxicity, and efficacy data and selected 32 final candidates. In the nonclinical efficacy test, we used golden Syrian hamsters and human angiotensin-converting enzyme 2 transgenic mice under a cytokeratin 18 promoter to evaluate mortality, clinical signs, body weight, viral titer, neutralizing antibody presence, and histopathology. These data indicated eight new drugs and one repositioned drug having significant efficacy for COVID-19. Three vaccine and four antiviral drugs exerted significant protective activities against SARS-CoV-2 pathogenesis. Additionally, two anti-inflammatory drugs showed therapeutic effects on lung lesions and weight loss through their mechanism of action but did not affect viral replication. Along with systematic verification of COVID-19 animal models through large-scale studies, our findings suggest that ABSL3 multicenter alliance and nonclinical evaluation protocol standardization can promote reliable efficacy testing against COVID-19, thus expediting medical product development.

Association between social networks and symptoms of post-traumatic stress during the pandemic: Cohort study in South Korea.

BACKGROUND: This study estimated the association between pre-pandemic social network properties and symptoms of posttraumatic stress during the coronavirus disease 2019 (COVID-19) pandemic in South Korea. METHODS: We conducted four online mental health surveys during COVID-19 (from March 14, 2020, to December 11, 2021) among individuals enrolled in a community-based cohort study (previously recruited from 2013 to 2018). Among 4060 people interviewed at the pre-pandemic baseline, 2652 individuals (men = 951, women = 1701) who responded to at least one of the four surveys conducted were included. At baseline, each individual's social network, including size and average closeness, was measured in an egocentric way. Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5) was measured at each survey point. A generalized linear model and a generalized linear mixed model were used after stratified by sex. RESULTS: Among men, network size was negatively associated with total PCL-5 score (b = -0.42, SE = 0.16, p = 0.002). The magnitude of the association increased over time and was maximal by the 4th survey (b = -0.65, SE = 0.31, p = 0.037). Among women, average closeness was negatively associated with the total PCL-5 score (b = -1.16, SE = 0.37, p = 0.002). In analyses disaggregated by symptom clusters, social networks were associated explicitly with symptoms of intrusion and mood but not with avoidance and arousal symptoms. CONCLUSION: In this cohort of adults followed for more than a year during the outbreak of COVID-19 in South Korea, social networks established before the onset of the COVID-19 pandemic had a protective association against developing symptoms of PTSD during the first two years of the pandemic.

Clinical and Economic Impact of Pharmacists' Intervention on Care of Pediatric Hematology and Oncology Patients.

INTRODUCTION: Children with cancer may be one of the most vulnerable groups to drug-related adverse events because they possess characteristics of patients with cancer as well as pediatric patients. To evaluate the clinical and economic impact of pharmacists' intervention on the care of pediatric hematology and oncology patients in the inpatient and outpatient settings of a children's hospital. METHODS: The pharmacist-intervention records from 2017 were retrospectively reviewed. Intervention rate, type of drug-related problems, acceptance rate, and frequently involved drugs in pharmacist interventions were analyzed. One physician and one pharmacist evaluated the clinical significance of each intervention. A cost-benefit analysis was conducted from hospital and patient perspective. The benefit from cost savings by reducing the number of prescribed drugs that are disposed was estimated as the benefit from hospital perspective. The benefit from cost avoidance based on the potential to avoid an adverse drug event (ADE) was estimated as the benefit from patient perspective. The cost of reviewing prescriptions was estimated based on the pharmacists' salary and the time involved. RESULTS: In 2017, 2361 interventions were performed in 381 pediatric patients with cancer. The acceptance rate was 97.2%. More than half of the interventions were regarded as clinically "significant" (58.8%) and "very significant" (14.6%). The cost-benefit of US$28,705 was determined from hospital perspective, with a cost-benefit ratio of 1.45:1. The cost-benefit of US$35,611 was calculated from patient perspective, with a cost-benefit ratio of 1.55:1. CONCLUSIONS: Pharmacists' intervention in the care of hematology and oncology pediatric patients was effective in preventing clinically significant ADEs and had a positive economic impact on the health-care budget from both hospital and patient perspective.

Circadian rest-activity rhythm and longitudinal brain changes underlying late-life cognitive decline.

AIM: The neurobiological substrates underlying the relationship of circadian rest-activity rhythm (RAR) alteration with accelerated late-life cognitive decline are not clearly understood. In the present study, the longitudinal relationship of objectively measured circadian RAR with in vivo Alzheimer disease (AD) pathologies and cerebrovascular injury was investigated in older adults without dementia. METHODS: The present study included 129 participants without dementia who participated in the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease) cohort. All participants underwent actigraphy at baseline and two consecutive [11 C] Pittsburgh compound-B positron emission tomography (PET), [18 F] fluorodeoxyglucose-PET, magnetic resonance imaging, and Mini-Mental State Examination (MMSE) at baseline and at a 2-year follow-up assessment. The associations of circadian RAR with annualized change in neuroimaging measures including global amyloid-beta retention, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensity volume were examined. RESULTS: Delayed acrophase at baseline was significantly associated with greater annualized decline of AD-CM over a 2-year period, but not with that of other neuroimaging measures. In contrast, other circadian RAR parameters at baseline had no association with annualized change of any neuroimaging measures. Annualized decline of AD-CM was also significantly positively associated with the annual change in MMSE scores. Furthermore, a mediation analysis showed that greater reduction in AD-CM mediated the effect of delayed acrophase at baseline on faster decline of MMSE score. CONCLUSION: The findings indicate that delayed acrophase in late life may cause or predict hypometabolism at AD-signature brain regions, which underlies cognitive decline in the near future.

Prevalence and causative drugs of drug-induced Parkinsonism in pediatric patients.

Although several studies provided evidence on the epidemiology of drug-induced Parkinsonism (DIP) and its causative drugs, it is still limited in pediatrics. This study aimed to investigate the prevalence and risk of DIP in pediatrics. We used the Health Insurance Review and Assessment Service-Pediatric Patients Sample in Korea between 2010 and 2017 to estimate the annual prevalence of DIP and causative drug use using a cross-sectional design. The risk of DIP associated with causative drugs was evaluated using a case-crossover design. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated using a conditional logistic regression. A total of 2925 pediatric patients had diagnosed with DIP from 2010 to 2017. Most patients were aged between 12 and19 years old, and 99.8% had any diagnosis of mental health disorder (MHD). During the study period, the prevalence of DIP increased by 10.0-fold from 2010 to 2017. All causative drugs showed a corresponding increase in their use, with atypical antipsychotics being the most prominent (increase ratio, 2.07). For both in the prevalence of DIP and atypical antipsychotic use, the increment was much bigger in patients with non-psychotic MHD than that in patients with psychotic MHD. In the case-crossover study, antipsychotics showed the largest aOR with DIP. Risperidone among antipsychotics showed the highest risk for DIP (aOR = 7.09, 95% CI = 3.83-13.09), followed by aripiprazole (aOR = 5.03, 95% CI = 2.88-8.80). This study suggests that the increase in DIP prevalence in pediatric patients might be because of the increased use of atypical antipsychotics.

Interactions between Malassezia and New Therapeutic Agents in Atopic Dermatitis Affecting Skin Barrier and Inflammation in Recombinant Human Epidermis Model.

Several studies have reported the pathogenic role of Malassezia in atopic dermatitis (AD); the significance of Malassezia's influence on AD needs to be further investigated. Dupilumab, a monoclonal antibody to anti-Interleukin (IL) 4Rα, and ruxolitinib, a Janus kinase (JAK)1/2 inhibitor, are the first approved biologics and inhibitors widely used for AD treatment. In this study, we aimed to investigate how Malassezia Restricta (M. restricta) affects the skin barrier and inflammation in AD and interacts with the AD therapeutic agents ruxolitinib and anti-IL4Rα. To induce an in vitro AD model, a reconstructed human epidermis (RHE) was treated with IL-4 and IL-13. M. restricta was inoculated on the surface of RHE, and anti-IL4Rα or ruxolitinib was supplemented to model treated AD lesions. Histological and molecular analyses were performed. Skin barrier and ceramide-related molecules were downregulated by M. restricta and reverted by anti-IL4Rα and ruxolitinib. Antimicrobial peptides, VEGF, Th2-related, and JAK/STAT pathway molecules were upregulated by M. restricta and suppressed by anti-IL4Rα and ruxolitinib. These findings show that M. restricta aggravated skin barrier function and Th2 inflammation and decreased the efficacy of anti-IL4Rα and ruxolitinib.

Life stress, sleep disturbance and depressive symptoms: The moderating role of prefrontal activation during emotion regulation.

OBJECTIVES: Evidence suggests that emotion regulation difficulty may play an important role in the association between life stress, sleep disturbance and depressive symptoms. We proposed two models depicting the possible moderating roles of prefrontal cortex activation during emotion regulation in the associations among these variables and tested them. We hypothesized that (1) the association between stress and sleep disturbance would differ across prefrontal cortex activation during emotion regulation (moderation model) and (2) the indirect effects of stress on depressive symptoms through sleep disturbance would depend on prefrontal cortex activation during emotion regulation (moderated mediation model). METHODS: Forty-eight healthy adults without sleep disorders based on nocturnal polysomnography participated in this study. They received functional magnetic resonance imaging scans while performing an emotion regulation task. They also completed questionnaires assessing life stress, sleep disturbance and depressive symptoms. The proposed models were tested using the PROCESS macro for SPSS. RESULTS: As hypothesized, there was a significant moderating effect of prefrontal cortex activation during emotion regulation on the association between life stress and sleep disturbance. Furthermore, right lateral prefrontal cortex activation had a moderating role in the indirect effect of life stress on depressive symptoms through sleep disturbance. CONCLUSION: These findings highlight the important role of prefrontal cortex function during emotion regulation in the associations between stress, sleep disturbance and depressive symptoms. Increasing lateral prefrontal cortex recruitment when regulating the emotional response to negative life events may be critical for the prevention and intervention of depression as well as sleep problems.

Ex Vivo Treatment with Allogenic Mesenchymal Stem Cells of a Healthy Donor on Peripheral Blood Mononuclear Cells of Patients with Severe Alopecia Areata: Targeting Dysregulated T Cells and the Acquisition of Immunotolerance.

Alopecia areata (AA) is an autoimmune condition related to the collapse of the immune privilege of hair follicles. Certain AA populations present severe clinical manifestations, such as total scalp hair or body hair loss and a treatment refractory property. The aim of this study was to assess the effects of allogenic human mesenchymal stem cells (hMSCs) from healthy donors on the peripheral blood mononuclear cells (PBMCs) of severe AA patients, with a focus on the change in the cell fraction of Th1, Th17, and Treg cells and immunomodulatory functions. PBMCs of 10 AA patients and eight healthy controls were collected. Levels of Th17, Th1, and Treg subsets were determined via flow cytometry at baseline, activation status, and after co-culturing with hMSCs. All participants were severe AA patients with SALT > 50 and with a long disease duration. While the baseline Th1 and Treg levels of AA patients were comparable to those of healthy controls, their Th17 levels were significantly lower than those of the controls. When stimulated, the levels of CD4+IFN-γ+ T cells of the AA patients rose sharply compared to the baseline, which was not the case in those of healthy controls. The cell fraction of CD4+Foxp3+ regulatory T cells also abruptly increased in AA patients only. Co-culturing with allogenic hMSCs in activated AA PBMCs slightly suppressed the activation levels of CD4+INF-γ+ T cells, whereas it significantly induced the differentiation of CD4+Foxp3+ regulatory T cells. However, these changes were not prominent in the PBMCs of health controls. To examine the pathomechanisms, PBMCs of healthy donors were treated with IFN-γ to induce AA-like environment and then treated with allogenic grants and compared with ruxolitinib as a positive treatment control. hMSC treatment was shown to significantly inhibit the mRNA levels of proinflammatory cytokines, such as IFN-γ, TNF-α, IL-1α, IL-2R, IL-15, and IL-18, and chemokines, such as CCR7 and CCR10, in IFN-treated PBMCs. Interestingly, hMSCs suppressed the activation of JAK/STAT signaling by IFN in PBMCs with an effect that was comparable to that of ruxolitinib. Furthermore, the hMSC treatment showed stronger efficacy in inducing Foxp3, IL-10, and TGF-ß mRNA transcription than ruxolitinib in IFN-treated PBMCs. This study suggests that allogenic hMSC treatments have therapeutic potential to induce immune tolerance and anti-inflammatory effects in severe AA patients.

The Low-Fluence Q-Switched Nd:YAG Laser Treatment for Melasma: A Systematic Review.

Melasma is a common pigmentary disorder with a complex pathogenesis, of which the treatment is challenging. Conventional treatment often leads to inconsistent results with unexpected pigmentary side effects and high recurrence rates. Recently, the low-fluence Q-switched Nd:YAG laser (LFQSNY) has been widely used for treating melasma, especially in Asia. We reviewed literatures on the LFQSNY treatment of melasma published between 2009 and May 2022 to evaluate the efficacy and adverse events, including its combination therapy. A systematic PubMed search was conducted and a total of 42 articles were included in this study. It was hard to summarize the heterogenous studies, but LFQSNY appeared to be a generally effective and safe treatment for melasma considering the results of previous conventional therapies. However, mottled hypopigmentation has been occasionally reported to develop and persist as an adverse event of LFQSNY, which may be associated with the high accumulated laser energy. When used aggressively, even LFQSNY can induce hyperpigmentation via unwanted inflammation, especially in darker skin. Although few studies have reported considerable recurrence rates three months after treatment, unfortunately, there is a lack of the long-term follow-up results of LFQSNY in melasma. To enhance the effectiveness and reduce the adverse events, LFQSNY has been used in combination with other treatment modalities in melasma, including topical bleaching agents, oral tranexamic acid, chemical peeling, or diverse energy-based devices, which generally reduced side effects with or without significant superior efficacy compared to LFQSNY alone.

Phospholipase Cγ1 represses colorectal cancer growth by inhibiting the Wnt/ß-catenin signaling axis.

As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extracellular ligands and mediate intracellular signal transduction. PLCγ1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLCγ1 and cancer behavior remains undefined. To investigate the role of PLCγ1 in colorectal carcinogenesis, we generated an intestinal tissue-specific Plcg1 knock out (KO) in adenomatous polyposis coli (Apc) Min/+ mice. Plcg1 deficiency in ApcMin/+ mice showed earlier death, with a higher colorectal tumor incidence in both number and size than in wild-type mice. Mechanistically, inhibition of PLCγ1 increased the levels of its substrate phosphoinositol 4,5-bisphosphate (PIP2) at the plasma membrane and promoted the activation of Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3ß (GSK3ß) to enhance ß-catenin signaling. Enhanced cell proliferation and Wnt/ß-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLCγ1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLCγ1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/ß-catenin-dependent intestinal tumor formation.

Maclurin exerts anti-cancer effects in human osteosarcoma cells via prooxidative activity and modulations of PARP, p38, and ERK signaling.

Maclurin [(3,4-dihydroxyphenyl)-(2,4,6-trihydroxyphenyl) methanone] is a natural compound that can be extracted from white mulberry(Morus alba) and purple mangosteen(Garcinia mangostana). Maclurin is known for its dual-sided effect on reactive oxygen species (ROS). Osteosarcoma is a primary malignant tumor of the bone and is one of the most aggressive cancers. It is common especially in children and young adults and can progress into highly metastatic cancer. In this study, we investigated the anti-cancer effects of maclurin on U2OS human osteosarcoma cells. The results indicated that maclurin exerts prooxidative effects and induces apoptosis via capase-3-independent PARP regulation in U2OS human osteosarcoma cells. Maclurin also inhibits the migration of U2OS human osteosarcoma cells. Maclurin modulates two of the three major mitogen-activated protein kinases that are closely linked with cancer metastasis; that is, it activates p38 and inactivates Extracellular signal-regulated kinase. The apoptosis-inducing effects of maclurin on U2OS osteosarcoma cells were diminished by additional treatment with antioxidant N-acetyl cysteine (NAC), but the migration-inhibiting effect was not affected by NAC treatment. This further suggested the only apoptosis-inducing effect of maclurin may be strongly related to its prooxidative activity. Taken together, these results suggested that maclurin may be a strong candidate molecule as an anti-osteosarcoma agent.

A Light-Harvesting/Charge-Separation Model with Energy Gradient Made of Assemblies of meta-Pyridyl Zinc Porphyrins.

Self-assembly of porphyrins is a fascinating topic, not only for mimicking chlorophyll assemblies in photosynthetic organisms, but also for the potential of creating molecular-level devices. Herein, zinc porphyrin derivatives bearing a meta-pyridyl group at the meso position were prepared and their assemblies studied in chloroform. Among the porphyrins studied, one with a carbamoylpyridyl moiety gave a distinct 1 H NMR spectrum in CDCl3 , which allowed the supramolecular structure in solution to be probed in detail. Ring-current-induced chemical-shift changes in the 1 H NMR spectrum, together with vapor-pressure osmometry and diffusion-ordered NMR spectroscopy, among other evidence, suggested that the porphyrin molecules form a trimer with a triangular cone structure. Incorporation of a directly linked porphyrin-ferrocene dyad with the same assembling properties in the assemblies led to a rare example of a light-harvesting/charge-separation system in which an energy gradient is incorporated and reductive quenching occurs.