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New therapeutic approaches are required to improve the outcomes of lung cancer (LC), a leading cause of cancer-related deaths worldwide. Chinese herbal medicine formulae widely used in China provide a unique opportunity for improving LC treatment, and the Shuang-Huang-Sheng-Bai (SHSB) formula is a typical example. However, the underlying mechanisms of action remains unclear. This study aimed to confirm the efficacy of SHSB against lung adenocarcinoma (LUAD), which is a major histological type of LC, unveil the downstream targets of this formula, and assess the clinical relevance and biological roles of the newly identified target. An experimental metastasis mouse model and a subcutaneous xenograft mouse model were used to evaluate the anti-cancer activity of SHSB. Multi-omics profiling of subcutaneous tumors and metabolomic profiling of sera were performed to identify downstream targets, especially the metabolic targets of SHSB. A clinical trial was conducted to verify the newly identified metabolic targets in patients. Next, the metabolites and enzymes engaged in the metabolic pathway targeted by SHSB were measured in clinical samples. Finally, routine molecular experiments were performed to decipher the biological functions of the metabolic pathways targeted by SHSB. Oral SHSB administration showed overt anti-LUAD efficacy as revealed by the extended overall survival of the metastasis model and impaired growth of implanted tumors in the subcutaneous xenograft model. Mechanistically, SHSB administration altered protein expression in the post-transcriptional layer and modified the metabolome of LUAD xenografts. Integrative analysis demonstrated that SHSB markedly inhibited acetyl-CoA synthesis in tumors by post-transcriptionally downregulating ATP–citrate lyase (ACLY). Consistently, our clinical trial showed that oral SHSB administration declined serum acetyl-CoA levels of patients with LC. Moreover, acetyl-CoA synthesis and ACLY expression were both augmented in clinical LUAD tissues of patients, and high intratumoral ACLY expression predicted a detrimental prognosis. Finally, we showed that ACLY-mediated acetyl-CoA synthesis is essential for LUAD cell growth by promoting G1/S transition and DNA replication. Limited downstream targets of SHSB for LC treatment have been reported in previous hypothesis-driven studies. In this study, we conducted a comprehensive multi-omics investigation and demonstrated that SHSB exerted its anti-LUAD efficacy by actively and post-transcriptionally modulating protein expression and particularly restraining ACLY-mediated acetyl-CoA synthesis. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in several regions of China, and the prognosis of patients with ESCC is unfavorable. Evodiamine (Evo), a small molecule derived from the traditional Chinese herb Evodia rutaecarpa, has shown anti-cancer efficacy in numerous human malignancies but not in ESCC.Purpose: To determine whether Evo induces cell-cycle arrest and apoptosis in ESCC in vitro and in vivo and elucidate the underlying mechanisms.Methods: ATPlite and colony formation assay were used to validate the inhibiting effect of Evo on three ESCC cells in vitro; Two subcutaneous tumor models of ESCC cells were used to evaluate the anti-ESCC effect of Evo and assess the biosafety of Evo in vivo; RNAseq and Database of KEGG pathway analysis provided a direction for the mechanistic study of Evo; FACS was used to detect Evo-induced cell cycle arrest and cell apoptosis in ESCC cells; Western blot and QPCR were respectively used to detect the level of related genes and proteins in Evo-treated ESCC cells; SiRNA and other experimental techniques were used to identify the molecular mechanism of Evo-induced ESCC cell cycle arrest and cell apoptosis.Results: Evo significantly suppressed the growth of ESCC both in vitro and in vivo. Mechanistically, Evo induced M-phase cell-cycle arrest by inactivation of CUL4A E3 ligase, which mediates degradation blockage of p53 and transcriptional activation of p21. With the prolonged treatment time, Evo triggered both Noxa-dependent intrinsic and DR4-dependent extrinsic cell apoptosis in two ESCC cell lines.Conclusion: Our findings revealed the anti-tumor efficacy and mechanisms of Evo, providing a solid scientific basis for Evo as an attractive choice for ESCC treatment. [ABSTRACT FROM AUTHOR]

• Orai1 deficiency drastically decreases lipopolysaccharides (LPS)-induced TNF-α and IL-6 production in astrocytes. • Inhibition of CRACs or deficiency of Orai1 does not alter LPS-induced MAPK activation. • LPS exposure increases Orai1 protein expression vis NF-κB. • LPS exposure enhances basal Ca2+ level and SOCE. • Orai1 deficiency almost eliminates Ca2+ entry induced by elevating extracellular Ca2+ concentration, suggesting that Orai1 functions as a leak Ca2+ channel maintaining astrocytic Ca2+ homeostasis. Toll-like receptor 4 (TLR4) has been implicated in pathological conditions including chronic pain. Activation of astrocytic TLRs leads to the synthesis of pro-inflammatory cytokines like interleukin 6 (IL-6) and tumor necrosis factor-ɑ (TNF-α), which can cause pathological inflammation and tissue damage in the central nervous system. However, the mechanisms of TLR4-mediated cytokine releases from astrocytes are incomplete understood. Our previous study has shown that Orai1, a key component of calcium release activated calcium channels (CRACs), mediates Ca2+ entry in astrocytes. How Orai1 contributes to TLR4 signaling remains unclear. Here we show that Orai1 deficiency drastically attenuated lipopolysaccharides (LPS)-induced TNF-α and IL-6 production in astrocytes. Acute LPS treatment did not induce Ca2+ response and had no effect on thapsigargin (Ca2+-ATPase inhibitor)-induced store-dependent Ca2+ entry. Inhibition or knockdown of Orai1 showed no reduction in LPS-induced p-ERK1/2, p-c-Jun N-terminal kinase, or p-p38 MAPK activation. Interestingly, Orai1 protein level was significantly increased after LPS exposure, which was blocked by inhibition of NF-κB activity. LPS significantly increased basal Ca2+ level and SOCE after exposure to astrocytes. Moreover, elevating extracellular Ca2+ concentration increased cytosolic Ca2+ level, which was almost eliminated in Orai1 KO astrocytes. Our study reports novel findings that Orai1 acts as a Ca2+ leak channel regulating the basal Ca2+ level and enhancing cytokine production in astrocytes under the inflammatory condition. These findings highlight an important role of Orai1 in astrocytic TRL4 function and may suggest that Orai1 could be a potential therapeutic target for neuroinflammatory disorders including chronic pain. [Display omitted] [ABSTRACT FROM AUTHOR]

Background The avian influenza A H7N9 virus, previously unknown in humans, has infected humans in many areas of China since February 2013. Here we report on a clustering case of H7N9 in two little girls in one family in Dongyang city, Jinhua area, Zhejiang Province. Objectives To determine (1) whether the infections were due to person-to-person transmission or to co-exposure to poultry and (2) the prevalence of this novel H7N9 virus in Dongyang inferred by this family clustering case. Study design Samples were collected from patients and environment. We undertook detailed epidemiological investigations and laboratory work. Phylogenetic analyses were done based on the sequenced genomes. The concentration of cytokines and chemokines in the serum was detected by cytometric bead array analyses. Results A mixture of H7 and H9 was detected from the environmental sample. The three H7N9 viruses shared one infection source. The index patient who had significantly higher levels of IL-4, IL-8 and IL-10 suffered severe infection. Conclusions Based on a comparison with previous isolations of the virus in 2013, H7N9 has evolved different lineages through recombination with local H9N2 viruses. Determining whether it was human-to-human transmission or exposure to the same live poultry, since both patients had identical exposure histories, was ambiguous. The results from the cytokine analyses agreed with the conclusion that H7N9 severity is associated with a higher level of cytokines/chemokines. Long term influenza surveillance remains essential to allow for early warning of potential transmission events. [ABSTRACT FROM AUTHOR]

Cases of amyotrophic lateral sclerosis with pregnancy are quite rare. The aim of this case report is to present the successful use of total intravenous anesthesia without muscle relaxant for cesarean section in a parturient with amyotrophic lateral sclerosis at 35 weeks' gestation. The parturient presented with impaired neuromuscular function. Titrated general anesthesia with short-acting anesthetics was applied. During the procedure, no muscle relaxant was used. This strategy helped avoid prolonged ventilation and prevent maternal respiratory complications. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy (ART) controls viral replication but cannot eradicate an infected virus and restore the immune response of patients. The gene expression profiles of whole blood, PBMCs, CD4+ and CD8+ T cells were obtained from GSE108297. Coexpression analysis was carried out to evaluate differentially expressed genes (DEGs) between strong and weak responder HIV controllers (HICs). Enrichment analysis was used to explore the biological functions of DEGs. The key genes with common DEGs were screened using the Lasso Cox model. Then, the immune scores of HICs and HAART were calculated by ssGSEA. The content of CD4+ and CD8+ T cells, key genes were verified by flow cytometry, RT-PCR and Western blot analysis. DEGs were clustered into 24 coexpression modules. DEGs related to general immune responses had the highest correlation with strong responding HICs, while DEGs mainly related to the apoptotic process had the highest correlation with weak responder HICs. The hub genes CD8A and CCT2, as well as the key genes TMEM132C and S100A9, were DEGs in HICs and HARRT. The immune score and flow cytometry showed that CD4+ and CD8+ T cells of HICs were lower than those of HARRT in whole blood. Experiments confirmed the expression of key genes in HICs and HARRT. The key genes identified in this study highlight the strong responder HICs features that to help the immune system control HIV-1 infection. These results will be useful for developing therapeutic targets. [ABSTRACT FROM AUTHOR]

The objective of this case report is to present the successful use of regional cerebral oxygen saturation (rScO2) monitoring guided cerebral protection for cesarean delivery in a parturient with Takayasu's arteritis at 38weeks' gestation. The parturient presented with impaired cerebral and renal perfusion. Titrated epidural anesthesia was performed. During the procedure, we used rScO2 guided cerebral protection strategies, which helped to optimize cerebral oxygen delivery and prevent cerebral complications. [ABSTRACT FROM AUTHOR]

Abstract: IL-10 plays a critical role in controlling inflammation and the anti-inflammatory functions of IL-10 are regulated based on its coordinated expression from various cellular sources, most notably T cells. Although nearly all CD4+ subpopulations can express IL-10, surprisingly little is known about the molecular mechanisms which control IL-10 induction, particularly in humans. To examine the regulation of human IL-10 expression, we created the hIL10BAC transgenic mouse. As previously reported, we observed conservation of myeloid-derived IL-10 expression but found that human IL-10 was only weakly expressed in splenic CD4+ T cells from hIL10BAC mice. Since DNA methylation is an important determinant of gene expression profiles, we assessed the patterns of DNA methylation in the human and mouse IL10 genes in naïve and activated CD4+ T cells. Across mouse and human IL10 there were no obvious patterns of CpG methylation in naïve CD4+ T cells following polyclonal activation. Overall however, the human IL10 gene had significantly higher levels of DNA methylation. Interestingly, coculture with the IL-10-inducing cytokine IL-27 lead to a site-specific reduction in methylation of the mouse but not human IL10 gene. Demethylation was specifically localized to an intronic site adjacent to a known regulatory region. Our findings indicate that while the mouse and human IL10 genes undergo variable changes in DNA methylation during CD4+ T cell activation, IL-27 appears to influence DNA methylation in a particular intronic region thus associating with IL-10 expression. [ABSTRACT FROM AUTHOR]