The discovery of potentially active diterpenoids to inhibit the pyroptosis from Callicarpa arborea.

Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1ß secretion in J771A.1 cells, revealed 28 compounds with an IC50 below 10.5 µM. Compound 1 was the most potent with an IC50 of 0.68 µM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine.

Synthesis and anti-inflammatory evaluation of new chalcone derivatives bearing bispiperazine linker as IL-1ß inhibitors.

In this work, a series of novel chalcone derivatives bearing bispiperazine linker have been synthesized and in vitro anti-inflammatory, cytotoxic activity and anti-inflammatory mechanism have been screened. The results indicated that most bispiperazinochalcone derivatives displayed good inhibition of NO (IC50 < 20 µM) and low cytotoxicity (CC50 > 40 µM), and selectively inhibited the production of IL-1ß via inhibiting NLRP3 inflammasome activation, as promising candidate compounds for the treatment of NLRP3 inflammasome-driven diseases.

Dioscin, a Steroidal Saponin Isolated from Dioscorea nipponica, Attenuates Collagen-Induced Arthritis by Inhibiting Th17 Cell Response.

Dioscin, a steroidal saponin isolated from Dioscorea nipponica Makino, has previously been shown to possess antiarthritic effects. However, the underlying mechanism is still elusive. Herein, we investigated the therapeutic effects of dioscin on collagen-induced arthritis (CIA) in DBA/1 mice and related mechanism. Cytokine production in CII-specific immune responses were measured by enzyme-linked immunosorbent assay (ELISA); Th17 cell-related gene expression, including IL-17A, ROR γτ and IL-23p19, were detected by qPCR analysis; Surface marker, T regulatory (Treg) cells and intracellular cytokines (IL-17A and IFN- γ ) were evaluated by flow cytometry. We performed Th17 cell differentiation assay in vitro. Results showed that, in vivo, dioscin treatment significantly reduced the severity of CIA, which was accompanied by decreased Th17 response, but not Th1 and Treg response; dioscin-treated mice also showed lower percentage of CD11b + Gr-1 + neutrophils; In vitro, dioscin treatment suppressed the differentiation of naive CD4 + T cells into Th17 cell and decreased IL-17A production. Collectively, our results indicate that dioscin exerts antiarthritic effects by inhibiting Th17 cell immune response.

Gene polymorphisms of DISC1 is associated with schizophrenia: Evidence from a meta-analysis.

BACKGROUND: Previous studies suggest an association between Disrupted in schizophrenia 1 (DISC1) polymorphisms and schizophrenia (SCZ). However, the available data are often inconsistent, regarding the difference in sample size, ethnicity, genotyping method, etc. Thus, we carried out a meta-analysis to determine whether DISC1 polymorphisms contributed susceptibility to SCZ. METHODS: A methodical literature review was operated using the English and Chinese core electronic databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were applied to determine the correlation between DISC1 gene polymorphisms and SCZ susceptibility. Subgroup analyses were carried out by stratification of ethnicity. P values were Bonferroni adjusted to account for multiple testing. Publication bias was evaluated by funnel plots, Egger's test and the trim and fill method. RESULTS: Meta-analyses results suggested that DISC1 polymorphisms (rs821616 and rs821597) increased SCZ risk in overall populations. In subgroups of ethnicity, DISC1 polymorphisms (rs821616 and rs821597) was associated with susceptibility to SCZ among the Chinese population (for rs821616: TT+AT vs. AA: OR=1.338, 95% CI=1.124-1.592, P=0.001; T vs. A: OR=1.300, 95% CI=1.124-1.504, P<0.000; for rs821597: AA+AG vs. GG: OR=1.508, 95% CI=1.268-1.794, P<0.001; A vs. G: OR=1.345, 95% CI=1.184-1.527, P<0.001). A positive correlation was also observed between the single marker rs821616 and SCZ among the Japanese population in the recessive model (TT vs. AT+AA: OR=1.524, 95% CI=1.185-1.959, P=0.001). There was no significant relationship between other DISC1 polymorphisms (rs3738401, rs2273890, rs3738398, rs3738402, rs2492367, rs843979, rs3737597, rs4658971, rs1538979, rs1000731 and rs3738399) and SCZ. CONCLUSIONS: DISC1 polymorphisms increased a risk of SCZ, especially in the Chinese population. In order to further corroborate our findings, large well-designed epidemiological studies are needed.

Highly oxygenated lanostane-type triterpenoids and their bioactivity from the fruiting body of Ganoderma gibbosum.

Eight new highly oxygenated lanostane triterpenes, gibbosic acids A-H (1-8), along with three known ones (9-11), were isolated from the fruiting body of Ganoderma gibbosum. The structures of new isolates were assigned by NMR and HRESIMS experiments. The absolute configurations of 1 were further confirmed by single crystal X-ray diffraction data and computational ECD methods. Immunoregulatory effect and anti-inflammatory activities of these compounds were screened in murine lymphocyte proliferation assay and in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, respectively. Compound 2 exhibited immunostimulatory effect both in lymphocyte proliferation assay without any induction and ConA-induced mitogenic activity of T-lymphocyte, and the proportion of lymphocyte proliferation at the concentration of 0.1µM are 20.01% and 21.40%, respectively.

[Antimicrobial resistance characteristics of and disinfectant-resistant gene distribution in Staphylococcus aureus isolates from male urogenital tract infection].

OBJECTIVE: To study the antibiotic- and disinfectant-resistance features of and disinfectant-resistant gene distribution in Staphylococcus aureus (Sa) isolated from the urogenital tract of male patients with urogenital tract infection (UTI). total of 152 Sa isolates were collected from the urethral discharge specimens from male UTI patients. The minimum inhibition concentration (MIC) of antimicrobial agents and disinfectants commonly used against Sa were tested by standard ager dilution; the methicillin-resistant Sa (MRSA) isolates detected by cefoxitin disk diffusion and mecA gene amplification; Staphylococcal cassette chromosome mec (SCCmec) genotyping performed by multiplex PCR; the disinfectants gene qac (quaternary ammonium compound) amplified by PCR; and the clonal relatedness of qacA/B-positive MRSA isolates investigated by pulsed-field gel electrophoresis (PFGE). RESULTS: Out of the 152 Sa isolates, 91 (59.9%) were found to be MRSA. SCCmec genotyping showed SCCmec V to be the main type, accounting for 63.7% (58/91), with 8 (8.8%) isolates of SCCmec I, 2 (2.2%) isolates of SCCmec II, 19 (20.9%) isolates of SCCmec III, and 4 (4. 4%) isolates of SCCmec IV. The Sa isolates exhibited high rates of non-susceptibility to penicillin (95.4%) , erythromycin (72.4% ) , ciprofloxacin (42. 8%), and levofloxacin (44.7%), and a fairly high sensitivity to nitrofurantoin, teicoplanin, linezolid, and vancomycin. The MIC in the Sa isolates was 0. 25 -16 microg/ml for chlorhexidine; MIC50 and MIC90 were 2.0 and 4.0 microg/ml respectively for MRSA strains and both 1.0 microg/ml for MSSA strains. Out of the 152 Sa isolates, 72 (47.4%) harbored the qacA/B gene, 6 (3.9%) the smar (qacC + qacD) gene, 9 (5.9%) the qacE delta 1 gene, and 2 (1.3%) the qacH gene, but no qacG and qacJ genes were detected. PFGE analysis showed that the qacA/B-positive MRSA isolates were distributed CONCLUSION: Clinical Sa isolates exhibited varied degrees of resistance to commonly used antibiotics, and in a polyclonal manner. some showed a robust tolerance to chlorhexidine. The main disinfectant-resistant gene is qacA/B. Antimicrobial agents and disinfectants should be used rationally according to clinicians.

Impairments of social cues recognition and social functioning in Chinese people with schizophrenia.

Previous studies have suggested that social cognition deficits, and impaired social functioning, were associated with schizophrenia. However, specificity of the relationships between social cues recognition and social functioning remain largely undefined. The authors speculated that the two were related, and further that recognition of verbal and non-verbal social cues were impaired in people with schizophrenia. A total of 71 people (40 schizophrenia patients and 31 matched normal controls) voluntarily participated in this study. Social cues recognition abilities were measured by the eye gaze discrimination task and the faux pas recognition task. Social functioning was assessed using the Social Functioning Scale. Correlation analysis revealed a significant association between faux pas and, in particular, the social functioning subscales of the Social Functioning Scale (independence and employment) in patients with schizophrenia. Furthermore, the authors also observed that clinical participants performed significantly worse in both the eye gaze discrimination and faux pas recognition tasks than their healthy counterparts. These findings suggested that impaired social cues recognition in people with schizophrenia may be a possible explanation for their impaired social functioning.

Impaired recognition of fear in a Chinese man with bilateral cingulate and unilateral amygdala damage.

LJM, a 41-year-old schizophrenic Chinese man with bilateral anterior cingulate gyrus (Brodmann's area 24) lesions and also a small lesion in right amygdala after an operation, was compared with normal as well as brain-damaged and schizophrenic controls in identification of morphed facial expressions of six basic emotions. In repeated administrations of the test for recognition of facial emotions, over a 1- year period, LJM performed significantly worse for expressions of fear compared with the three groups of controls. Recognition of other emotions was not significantly different from that of the controls, except that his recognition of disgust during the first session (but not in two subsequent sessions) was worse than normal and brain-damaged controls but not worse than schizophrenic controls. The dissociation between recognition of fear and other emotions supported the view that the brain has separable networks for processing different emotions, and that the right amygdala as well as the anterior part of bilateral cingulate gyrus are possible substrates involved in the special network for perception of fear. The results from the various groups of Chinese subjects indicate that they perceive emotions in a categorical manner, and that the six basic emotions are likely to be cross-cultural universals.