Apigenin Suppresses Innate Immune Responses and Ameliorates Lipopolysaccharide-Induced Inflammation via Inhibition of STING/IRF3 Pathway.

The stimulator of interferon genes (STING) signaling pathway is crucial for the pathogenesis of autoimmune and inflammatory disorders, including acute lung injury (ALI). Apigenin (4[Formula: see text],5,7-trihydroxyflavone) is a natural flavonoid widely found in fruits, vegetables, and Chinese medicinal herbs that exhibits a range of pharmacological effects, such as antibacterial and anti-inflammatory activities. However, the efficacy of apigenin in STING pathway-mediated diseases remains unclear. Accordingly, this study screened Chinese medicines to identify potent agents that reduced the synthesis of type I interferons (IFNs). The results revealed apigenin as a potent compound with low cytotoxicity that markedly reduced the synthesis of type I IFNs in response to STING pathway agonists. Besides, apigenin markedly suppressed innate immune responses triggered by the STING agonist SR-717. Mechanistically, apigenin downregulated IFN beta 1 (IFNB1) expression mediated by the STING pathway via dose-dependent inhibition of STING expression, reduction of dimerization, nuclear translocation of phosphorylated IRF3, and disruption of the association between STING and IRF3. Moreover, apigenin effectively mitigated pathological pulmonary inflammation and lung edema in lipopolysaccharide (LPS)-induced ALI in mice. Apigenin further strongly attenuated the hallmarks of immoderate inflammation (interleukin (IL)-6, IL-1[Formula: see text], and tumor necrosis factor [Formula: see text]) and innate immune responses (IFNB1, C-X-C motif chemokine ligand 10, and IFN-stimulated gene 15) by preventing the activation of the STING/IRF3 pathway both in vitro and in vivo. Importantly, SR-717 significantly reversed the inhibitory effects of apigenin in LPS-induced THP1-BlueTM ISG macrophages. Collectively, apigenin effectively alleviated innate immune responses and mitigated inflammation in LPS-induced ALI via inhibition of the STING/IRF3 pathway. These findings suggest the potential of apigenin as a prophylactic and therapeutic candidate for managing STING-mediated diseases.

BRD4-binding enhancer promotes CRC progression by interacting with YY1 to activate the Wnt pathway through upregulation of TCF7L2.

Colorectal carcinoma (CRC), one of the most life-threatening cancer types, is associated with aberrant expression of epigenetic modifiers and activation of the Wnt pathway. However, the role of epigenetic regulators in driving cancer cell proliferation and their potential as therapeutic targets affecting the Wnt pathway remain unclear. In this study, BRD4 was found to promote the progression of CRC both in vitro and in vivo. The expression of BRD4 correlated with shortened CRC patient survival. In addition, BRD4 function was strongly correlated with the Wnt pathway, but rather through regulation of TCF7L2 at transcriptional levels. BRD4 and H3K27ac have overlapping occupancies in the cis-regulatory elements of TCF7L2, suggesting enhancer-based epigenetic regulation. Numerous YY1 binding sites were found in the abovementioned region. YY1 recruited BRD4 to bind to cis-regulatory elements of TCF7L2, thereby regulating the expression of TCF7L2. Altogether, this study validates that BRD4 performs a canonical epigenetic regulatory function in CRC and can be used in the treatment of Wnt pathway-dependent CRC or other malignancies with clinically available bromodomain inhibitors.

Difficult Blood Typing Caused by Rouleaux Agglutination in Patient with Acute Brain Trauma: a Case Report.

BACKGROUND: Rouleaux agglutination is a common cause of difficult blood typing, but it is rarely reported in patients with acute brain trauma. METHODS: This article describes a 69-year-old male with head injury who was admitted to the hospital. Blood typing showed type O, Rh(D) positive, but the Rh(D) control was also positive. After ruling out the possibility of the patient having abnormal autoantibodies, it was suspected that rouleaux agglutination might be the cause. Microscopic examination of the specimen revealed rouleaux agglutination, which was believed to be the cause of the false-positive Rh(D) control result. The patient's red blood cells were treated with physiological saline and retested by microcolumn gel card testing. RESULTS: The retest showed negative Rh(D) control results, indicating normal results. The patient subsequently received normal blood transfusion. CONCLUSIONS: Laboratory personnel should be aware of the possibility of difficult blood typing caused by rouleaux agglutination in various diseases, especially in relatively rare traumatic diseases.

Impaired Humoral Immunity Identified in Inactivated SARS-CoV-2 Vaccine Recipients without Anti-Spike RBD Antibodies.

Inactivated SARS-CoV-2 vaccines have been deployed in a significant portion of the world population, who have widely varied responses to vaccination. Understanding this differential response would help the development of new vaccines for non-responders. Here, we conducted surveillance of anti-Spike receptor-binding domain (RBD) antibody levels in a large cohort of 534 healthy Chinese subjects vaccinated with two doses of inactivated SARS-CoV-2 vaccines. We show that the positive rate of antibodies among vaccinated subjects rapidly wanes as the interval between antibody testing and vaccination increases (14 to 119 days: 81.03%, 363 of 448 subjects; 120 to 149 days: 46.43%, 13 of 28 subjects; more than 150 days: 20%, 1 of 5 subjects). However, the antibodies were maintained at high levels in 16 convalescent COVID-19 patients at more than 150 days after recovery. We also found that increased age and body mass index are associated with decreased antibody levels. Vaccinated subjects who fail to produce antibodies display impaired B-cell activating humoral immunity, which was confirmed in COVID-19 patients without antibodies detected at 4 to 18 days after diagnosis. IMPORTANCE Our study illustrates the immune responses engaged by encountering antigen, highlighting the critical roles of B-cell activating humoral immunity in the body's antibody production.

Schisandrin B regulates macrophage polarization and alleviates liver fibrosis via activation of PPARγ.

BACKGROUND: Schisandrin B (Sch B), the main ingredient of Schisandra chinensis, displays many bioactivities. This study aimed to identify the drug target of Sch B against liver fibrosis and describe the related molecular mechanisms. METHODS: The effects of Sch B on liver fibrosis and macrophage polarization was investigated in vivo and in vitro. Furthermore, we analyzed the regulatory effect of Sch B on peroxisome proliferator-activated receptor gamma (PPARγ). RESULTS: Our data showed that Sch B dramatically alleviated liver inflammation and fibrosis and inhibited macrophage activation via PPARγ. Sch B binds with PPARγ by molecular docking. Immunofluorescence double staining showed that PPARγ was mainly expressed in macrophages rather than hepatic stellate cells (HSCs) in liver fibrosis. Importantly, Sch B strongly inhibited macrophage polarization in fibrotic livers compared with the model group. Further, the results revealed that Sch B efficiently inhibited macrophage polarization and also decreased the levels of inflammatory cytokines in vitro. Knockdown of PPARγ by small interfering RNA (siRNA) inhibited the effect of Sch B on macrophage polarization. Mechanistically, Sch B regulated macrophage polarization through inhibition of the nuclear factor (NF)-κB signaling pathway via PPARγ both in vivo and in vitro. CONCLUSIONS: These results suggested that Sch B alleviated carbon tetrachloride (CCl4)-induced liver inflammation and fibrosis by inhibiting macrophage polarization via targeting PPARγ.

The Diagnostic Value of Multi-Index Combined Detection in Patients with COVID-19.

BACKGROUND: To investigate the clinical value of multi-index combined detection in the diagnosis of new coronavirus disease 2019 (COVID-19). METHODS: A total of 63 laboratory confirmed patients treated in our hospital were selected as the COVID-19 group, including 28 severe patients and 35 non-severe patients. Another 50 healthy subjects undergoing physical examination simultaneously were selected as the healthy group. Here we performed a study on the laboratory characteristics and explored their efficacy for diagnosis of the disease. RESULTS: Compared with healthy people, the abnormal indicators of patients with COVID-19 are low levels of lymphocytes (LYM), red blood cells (RBC), hemoglobin (HGB), platelets (PLT), total protein (TP), and albumin (ALB), and high levels of monocytes (MON), aspartate aminotransferase (AST), gamma glutamyl transpeptidase (GGT), and C-reactive protein (CRP). The level of MON and CRP in severe patients were significantly increased compared with non-severe pneumonia patients, and indicators such as LYM and ALB were significantly reduced (p < 0.05). The sensitivity and specificity of the combined detection of LYM, MON, RBC, HGB, PLT, TP, ALB, AST, GGT, and CRP was 97.7% and 91.7%, which was higher than the single item (p < 0.05). The sensitivity and specificity of combined detection of LYM, MON, ALB, and CRP to predict the severity of COVID-19 were 96.4% and 73.0%, which were higher than those of separate detections (p < 0.05). CONCLUSIONS: The index of LYM, MON, RBC, HGB, PLT, TP, ALB, AST, GGT, and CRP can be used for the diagnosis of new COVID-19, and the indicators of LYM, MON, ALB, and CRP may be predictors of severe pneumonia. The combined detection of the laboratory indexes can diagnose COVID-19 and predict the severity more effectively and accurately.

Rare dimeric guaianes from Xylopia vielana and their multidrug resistance reversal activity.

Thirteen undescribed dimeric guaianes were isolated from the leaves of Xylopia vielana Pierre. Their structures were elucidated by NMR spectroscopy and mass spectrometry, and the absolute configurations of vielanins G-Q were determined by a combination of the circular dichroism (CD) exciton chirality method, chemical conversion, and electronic CD (ECD) spectroscopy analysis. Vielaninors A and B are the first examples of trinor-guaiane-dimers. Multidrug resistance reversal activity assay of the isolates was evaluated in doxorubicin-resistant human breast cancer cells. Vielanins H, K-M, P, and Q were noncytotoxic and enhanced the cytotoxicity of doxorubicin by 2.1-41.6-fold at 10 µM.

Bioactive seco-abietane rearranged diterpenoids from the aerial parts of Salvia prionitis.

Five previously undescribed 4,5-seco-abietane rearrange diterpenoids (1-5, Prionidipene A-E) were isolated from the aerial parts of Salvia prionitis, along with thirteen known seco-abietane diterpenoids (6-18). The structures of 1-5 were elucidated mainly based on analysis of NMR and MS data. The absolute configurations of 1-3 were determined by evaluation of experimental and calculated electronic circular dichroism (ECD) spectra. Putative biosynthetic pathways toward the formation of 1 and 2 are proposed. The nitric oxide (NO) production inhibitory effects of all isolates in lipopolysaccharide (LPS)-induced in RAW 264.7 cells were evaluated. Interestingly, compounds 4 and 9 with a furan-ring showed potent inhibitory activity with IC50 values of 14.56 and 15.11 µM, respectively.

Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P-glycoprotein via inhibition of p38 MAPK signaling.

In this study, we investigated the mechanism by which tomentodione M (TTM), a novel natural syncarpic acid-conjugated monoterpene, reversed multi-drug resistance (MDR) in cancer cells. TTM increased the cytotoxicity of chemotherapeutic drugs such as docetaxel and doxorubicin in MCF-7/MDR and K562/MDR cells in a dose- and time-dependent manner. TTM reduced colony formation and enhanced apoptosis in docetaxel-treated MCF-7/MDR and K562/MDR cells, and it enhanced intracellular accumulation of doxorubicin and rhodamine 123 in MDR cancer cells by reducing drug efflux mediated by P-gp. TTM decreased expression of both P-gp mRNA and protein by inhibiting p38 MAPK signaling. Similarly, the p38 MAPK inhibitor SB203580 reversed MDR in cancer cells by decreasing P-gp expression. Conversely, p38 MAPK-overexpressing MCF-7 and K562 cells showed higher P-gp expression than controls. These observations indicate that TTM reverses MDR in cancer cells by decreasing P-gp expression via p38 MAPK inhibition.

Xylopiana A, a Dimeric Guaiane with a Case-Shaped Core from Xylopia vielana: Structural Elucidation and Biomimetic Conversion.

Xylopiana A (1), a dimeric guaiane with an unprecedented pentacyclo[5.2.1.01,2.04,5'.05,4']decane-3,2'-dione core, and three biosynthetically related intermediates, compounds 2-4, were isolated from the leaves of Xylopia vielana. Their structures and absolute configurations were determined by a combination of spectroscopic data, X-ray crystallography, electronic circular dichroism calculations, and chemical conversion. The structure of known vielanin A was revised to be compound 3. Compound 4 exerted a 3.7-fold potentiation effect on doxorubicin susceptibility at the tested concentration of 10 µM.

Isolation, Structure Elucidation, and Absolute Configuration of Syncarpic Acid-Conjugated Terpenoids from Rhodomyrtus tomentosa.

Three new syncarpic acid-conjugated sesquiterpenoids, tomentodiones E-G (1-3), and six new syncarpic acid-conjugated monoterpenoids, tomentodiones H-M (4-9), were isolated from the leaves of Rhodomyrtus tomentosa. Compounds 1-3 represent the first examples of ß-calacorene-based meroterpenoids. Their structures and absolute configurations were determined by a combination of NMR and ECD spectroscopy and X-ray diffraction analysis. On the basis of ECD data analysis for isolated and synthesized compounds, an empirical rule was proposed to determine the absolute configuration at C-7' of syncarpic acid-conjugated terpenoids. Additionally, a study of the reversal effect of multidrug resistance in doxorubicin-resistant human breast cancer cells showed that the noncytotoxic (+)-4 exerted the strongest potentiation effect of doxorubicin susceptibility, with an enhancement of 16.5-fold at a concentration of 30 µM.

Bats as the main prey of wintering long-eared owl (Asio otus) in Beijing: Integrating biodiversity protection and urban management.

The loss of biodiversity from urbanized areas is a major environmental problem challenging policy-makers throughout the world. Solutions to this problem are urgently required in China. We carried out a case study of wintering long-eared owls (Asio otus) and their main prey to illustrate the negative effects of urbanization combined with ineffective conservation of biodiversity in Beijing. Field monitoring of owl numbers at two roosting sites from 2004 to 2012 showed that the owl population had fallen rapidly in metropolitan Beijing. Analysis of pellet contents identified only seven individuals of two species of shrew. The majority of mammalian prey comprised four bat and seven rodent species, making up 29.3% and 29.5% of the prey items, respectively. Prey composition varied significantly among years at the two sample sites. At the urban site the consumption of bats and rodents declined gradually over time, while predation on birds increased. In contrast, at the suburban site the prey composition showed an overall decrease in the number of bats, a sharp increase and a subsequent decrease in bird prey, and the number of rodent prey fell to a low point. Rapid development of real estate and inadequate greenfield management in city parks resulted in negative effects on the bird and small mammal habitat of urban areas in Beijing. We suggest that measures to conserve biodiversity should be integrated into future urban planning to maintain China's rich biodiversity while also achieving sustainable economic development.