Bicyclol mitigates lipopolysaccharide-induced acute lung injury through myeloid differentiation factor 88 inhibition.

Acute lung injury (ALI) remains a significant clinical challenge due to the absence of effective treatment alternatives. This study presents a new method that employs a screening platform focusing on MyD88 affinity, anti-inflammatory properties, and toxicity. This platform was used to evaluate a 300-compound library known for its anti-inflammatory potential. Among the screened compounds, Bicyclol emerged as a standout, exhibiting MyD88 binding and a significant reduction in LPS-stimulated pro-inflammatory factors production in mouse primary peritoneal macrophages. By targeting MyD88, Bicyclol disrupts the MyD88/TLR4 complex and MyD88 polymer formation, thereby mitigating the MAPKs and NF-κB signaling pathways. In vivo experiments further confirmed Bicyclol's efficacy, demonstrating alleviated ALI symptoms, decreased inflammatory cytokines level, and reduced inflammatory cells presence in lung tissues. These findings were associated with a decrease in mortality in LPS-challenged mice. Overall, Bicyclol represents a promising treatment option for ALI by specifically targeting MyD88 and limiting inflammatory responses.

Hypericin Alleviates Chronic Kidney Disease-induced Left Ventricular Hypertrophy by Regulation of FGF23-FGFR4 Signaling Pathway.

ABSTRACT: Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum , has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.

Adult Kerion Celsi Caused by Trichophyton tonsurans Secondary to Black Dot Tinea Capitis.

A 34-year-old female patient presented with hair loss due to black dot tinea capitis caused by Trichophyton tonsurans for 6 months. Hair loss progressed to painful swelling for 2 months due to kerion Celsi which may be associated with treatment like topical minoxidil, antibiotic and corticosteroid previously. The patient was treated with oral Itraconazole initially without success but cured by Terbinafine eventually. It's very interesting that the patient caught kerion celsi secondary to a four-month history of hair loss due to black dot tinea capitis.

Impaired learning and memory in mice induced by nano neodymium oxide and possible mechanisms.

A growing number of individuals are now exposed to neodymium (Nd) owing to its extensive applications. However, the biological effects of Nd on humans, especially on learning and memory, remain elusive. To investigate whether Nd exposure affects learning and memory, in this study female ICR mice were exposed to nano Nd2 O3 via intranasal instillation at doses of 50, 100, and 150 mg/kg body weight, daily for 45 days. According to Morris water maze data, learning and memory parameters were significantly reduced in the 150 mg/kg nano-Nd2 O3 group than the sham control. Furthermore, inductively coupled plasma-mass spectroscopy analysis revealed that Nd levels were significantly higher in the hippo campus of the 100 and 150 mg/kg exposed group than the sham control; however, no significant differences were observed in the hippocampal histopathology between these groups. Furthermore, reactive oxygen species were elevated in hippocampal tissues of experimental groups than the sham control, 447.3 in high dose group and 360.0 in control group; however, malondialdehyde levels were significantly increased and superoxide dismutase activities were decreased only in mice exposed to 100 and 150 mg/kg Nd2 O3 . High-performance liquid chromatography data demonstrated that levels of glutamic acid, glycine, and gamma-aminobutyric acid were higher in the hippocampus of mice exposed to 150 mg/kg Nd2 O3 than the sham control. Our findings indicated that the neuronal injury was induced by disruption of the oxidation-antioxidation homeostasis and altered amino acid neurotransmitter levels in the hippocampus, which could result in the poor cognitive performance demonstrated by exposed mice.

Correction: Effects of nano-cerium dioxide on intestinal microflora in rats by oral subchronic exposure.

[This corrects the article DOI: 10.1371/journal.pone.0298917.].

Effects of nano-cerium dioxide on intestinal microflora in rats by oral subchronic exposure.

OBJECTIVE: To investigate intestinal toxicity in rats and the effects of Nano-cerium dioxide on intestinal flora in rats after oral sub-chronic exposure. METHOD: Forty healthy male SD rats were randomly divided into four groups: a control group (deionized water) and three groups treated with different doses of Nano-ceria (e.g., 20 mg/kg, 100 mg/kg, and 500 mg/kg), with 10 rats in each group. The rats were given intragastric administrations (every other day) for 90 days. After the last intragastric administration, fresh fecal samples were collected by pressing the abdomen, and the animals were sacrificed. Jejunum, ileum and cecum tissues were retained for pathological analysis by Hematoxylin-eosin staining. The stool samples of rats were sequenced by the Illumina NovaSeq sequencing platform, and the sequencing results were further analyzed by QIIME2 software. RESULTS: The histopathology results show that compared with the control group, in the middle- and high-dose groups, epithelial tissue was shed, lamina propria glandular structures were damaged or disappeared, and large numbers of inflammatory cells were distributed in the mucosa. The intestinal flora results show that there were no significant differences in the α-/ß-diversities in each Nano-ceria-treated group compared with the control group (P>0.05). Compared with the control group, the intestinal pathogenic bacteria, Mucispirillum and Streptococcus increased significantly after Nano-cerium dioxide ingestion, while Weissella decreased. The abundances of Akkermansia in all Nano-ceria-treated groups were higher than those in the control group, but the abundances decreased with increasing dose. MetagenomesSeq analysis show that, compared with the control group, the abundances of S24-7, Lactobacillus and Clostridiales in all experimental groups significantly decreased. CONCLUSIONS: The sub-chronic toxicity of Nano-cerium dioxide to rats can affect the structure and abundance of intestinal microflora, long-term exposure to high doses (>100 mg/kg) causes enteritis, but there was no significant difference in the diversity of gut microbiota. Therefore, we infer that the enteritis in rats may be associated with the relative ratios of the pathogenic bacteria and intestinal probiotics, and increased of the intestinal pathogenic bacteria can disrupted intestinal homeostasis.

Comparative effectiveness of upadacitinib versus dupilumab for moderate-to-severe atopic dermatitis: A retrospective cohort study.

BACKGROUND: Although efficacy and safety of Upadacitinib and Dupilumab in moderate to severe atopic dermatitis (AD) have been shown in clinical trials, real world data are still limited. The aim of this retrospective study is to indirectly compare the efficacy and safety of Upadacitinib and Dupilumab in patients with moderate to severe AD in real world practice. METHODS: A single-center retrospective cohort study was conducted. The study included patients with moderate to severe AD, who were enrolled from May 2022 to March 2024, to indirectly compare the efficacy and safety of Upadacitinib and Dupilumab over 12 weeks duration. RESULTS: Eighty-seven patients were included (46 received Upadacitinib and 41 Dupilumab). Compared with week 0, there was a significant decrease in EASI score, ADCT score and NRS score in patients of both groups in weeks 4, 8, and 12. In week 4, the reduction in EASI score, ADCT score and NRS score was significantly greater in patients of Upadacitinib group compared to those in Dupilumab group. Compared to baseline, in week 12, the decrease in IL-4, IL-13, and IL-31 level in the serum of patients in Upadacitinib group was significantly greater than that of patients in Dupilumab group. The total IgE of patients in Dupilumab group decreased significantly, while there was no significant change in patients of Upadacitinib group. Although Upadacitinib group reported more adverse events than Dupilumab group, no serious adverse events were observed. CONCLUSIONS: Both Upadacitinib and Dupilumab groups showed effective trend in patients with moderate to severe AD. Upadacitinib has better efficacy and rapid onset in the treatment of patients with moderate to severe AD.

Cyy-272, an indazole derivative, effectively mitigates obese cardiomyopathy as a JNK inhibitor.

Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.

Machine Learning Predictive Modeling for the Identification of Moderate Coronavirus Disease 2019 During the Pandemic: A Retrospective Study.

BACKGROUND: Timely differentiation of moderate COVID-19 cases from mild cases is beneficial for early treatment and saves medical resources during the pandemic. We attempted to construct a model to predict the occurrence of moderate COVID-19 through a retrospective study. METHODS: In this retrospective study, clinical data from patients with COVID-19 admitted to Hainan Western Central Hospital in Danzhou, China, between August 1, 2022, and August 31, 2022, was collected, including sex, age, signs on admission, comorbidities, imaging data, post-admission treatment, length of stay, and the results of laboratory tests on admission. The patients were classified into a mild-to-moderate-type group according to WHO guidance. Factors that differed between groups were included in machine learning models such as Bernoulli Naïve Bayes (BNB), linear discriminant analysis, support vector machine (SVM), least absolute shrinkage and selection operator (LASSO), and logistic regression (LR) models. These models were compared to select the optimal model with the best predictive efficacy for moderate COVID-19. The predictive performance of the models was assessed using the area under the curve (AUC), sensitivity, specificity, and calibration plot. RESULTS: A total of 231 patients with COVID-19 were included in this retrospective analysis. Among them, 152 (68.83%) were mild types, 72 (31.17%) were moderate types, and there were no patients with severe or critical types. A logistic regression model combined with age, respiratory rate (RR), lactate dehydrogenase (LDH), D-dimer, and albumin was selected to predict the occurrence of moderate COVID-19. The receiver operating characteristic curve (ROC) showed that AUC, sensitivity, and specificity in the model were 0.719, 0.681, and 0.635, respectively, in predicting moderate COVID-19. Calibration curve analysis revealed that the predicted probability of the model was in good agreement with the true probability. Stratified analysis showed better predictive efficacy after modeling for people aged ≤66 years (AUC = 0.7656) and a better calibration curve. CONCLUSION: The LR model, combined with age, RR, D-dimer, LDH, and albumin, can predict the occurrence of moderate COVID-19 well, especially for patients aged ≤66 years.

Successful Treatment of Severe Subcorneal Pustular Dermatosis with Adalimumab.

Subcorneal pustular dermatosis (SPD) is a rare, chronic pustular dermatosis. The pathogenesis of SPD has not been fully elucidated, but some studies have found that tumor necrosis factor (TNF)-α may be associated with its pathogenesis. Some patients with multidrug-resistant SPD have improved significantly after treatment with the anti-TNF-α agent (adalimumab). We present a case of a 28-year-old female with severe SPD who responded rapidly to adalimumab (80mg/week) in combination with acitretin and methylprednisolone within a week. With adalimumab (40 mg next week and followed by 40mg every two weeks) and gradually ceasing other systemic medication, the patient's condition continued to improve without relapse or side effects. The outcome of this case suggests that adalimumab might be an effective treatment option against multidrug-resistant SPD.

Relationship Between Myocardial Injury and Expression of PGC-1α and Its Coactivators in Chronic Keshan Disease.

OBJECTIVE: Keshan disease (KD) is a mitochondrial cardiomyopathy. The present study explored the roles of peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), the key regulator of mitochondrial structure and function, and its coactivators in myocardial injury in chronic KD. Furthermore, the usefulness of these molecules in the diagnosis of chronic KD was assessed. METHODS: In the present case-control study, 43 patients with chronic KD and 30 healthy individuals living in KD endemic areas were included. The myocardial injury indicators and mRNA expression levels of PGC-1α, nuclear respiratory factor 1 (NRF1), PPARα, and estrogen-related receptor alpha (ERRα) in peripheral blood were examined. RESULTS: It was found that the levels of atrial natriuretic peptide, creatine kinase, and lactate dehydrogenase (LDH) were higher in patients with chronic KD, when compared to controls, while the level of bradykinin was lower. Furthermore, the PGC-1α, NRF1 and PPARα mRNA levels were higher in patients with KD. The area under the receiver operating characteristic curve and the optimal diagnostic threshold of LDH was 0.937 and 304.0 U/L, respectively. It is noteworthy that the area under the combined receiver operating characteristic curve was larger, when compared to that for LDH detection alone (Z=2.055, P=0.0399). The area under the curve for the "LDH+PPARα" combination was 0.984, with 96.7% sensitivity and 93.0% specificity. CONCLUSION: The combined detection of LDH and the expression of PPARα can be performed to diagnose the chronic KD.

A review of the mechanisms of keratinocytes damage caused by Staphylococcus aureus infection in patients with atopic dermatitis.

The dysregulation of skin microflora in patients with atopic dermatitis (AD) has become a research hotspot in recent years. Metagenomic studies have shown that microbial diversity is decreased, whereas the Staphylococcus aureus infection is increased in AD. Keratinocytes are the primary barrier against the invasion of external pathogenic microorganisms. Staphylococcus aureus infection can abnormally activate innate and adaptive immune responses in keratinocytes, resulting in a vicious cycle between Staphylococcus aureus infection and AD. This article reviews the mechanisms of inflammatory damage of keratinocytes induced by Staphylococcus aureus infection in patients with AD, providing a theoretical basis for the study of new targeted drugs. This review also suggests for the management of Staphylococcus aureus infection in patients with AD.