[Mechanism of combined treatment of rhein and emodin in Rhubarb for ulcerative colitis].

This study aimed to explore the efficacy and mechanism of combined rhein and emodin in the treatment of ulcerative colitis(UC) from the aspects of network pharmacology, animal inflammation improvement and molecular mechanism. Network pharmacology predicted that combined rhein and emodin acted on 52 potential targets, mainly participating in signaling pathways such as cancer, PI3 K/AKT, microRNAs in cancer and apoptosis. PI3 K/AKT signaling pathway has been reported to be closely related to UC, and the optimal candidate pathway for combined therapy. The UC mice model was established by dextran sodium sulfate, and then the modeled mice were randomly divided into control group, model group, rhein group, emodin group, rhein+emodin group and sulfasalazine group. After administration, compared with the conditions in model group, body weight, disease activity index(DAI) score, colon length, TNF-α, IL-6, IL-1ß and myeloperoxidase(MPO) of mice in rhein+emodin group were improved(P<0.01); colonic mucosal injury was significantly reduced; the expression of p-PI3 K/PI3 K and p-AKT/AKT proteins were down-regulated(P<0.01). All the above indices were better than those in the rhein/emodin group alone. The Jin's Q-values of the effect of combined rhein and emodin on colon length, TNF-α, IL-6, IL-1ß, MPO, p-PI3 K/PI3 K and p-AKT/AKT were all greater than 1.15, which indicated that there was obvious synergistic effect between rhein and emodin. In all, rhein and emodin have synergistic effect in the treatment of UC, and the mechanism may be related to the inhibition of PI3 K/AKT signaling pathway and the down-regulation of proinflammatory factors. They are the new components in the treatment of UC, which is worthy of attention.

Corrigendum: Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice.

[This corrects the article DOI: 10.3389/fimmu.2021.594330.].

Lipid metabolism in asthma: Immune regulation and potential therapeutic target.

Asthma is a chronic inflammatory disease of the lungs that poses a considerable health and socioeconomic burden. Several risk factors work synergistically to affect the progression of asthma. Lipid metabolism, especially in distinct cells such as T cells, macrophages, granulocytes, and non-immune cells, plays an essential role in the pathogenesis of asthma, as lipids are potent signaling molecules that regulate a multitude of cellular response. In this review, we focused on the metabolic pathways of lipid molecules, especially fatty acids and their derivatives, and summarized their roles in various cells during the pathogenesis of asthma along with the current pharmacological agents targeting lipid metabolism.

Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice.

Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.

Enriched environment boosts the post-stroke recovery of neurological function by promoting autophagy.

Autophagy is crucial for maintaining cellular homeostasis, and can be activated after ischemic stroke. It also participates in nerve injury and repair. The purpose of this study was to investigate whether an enriched environment has neuroprotective effects through affecting autophagy. A Sprague-Dawley rat model of transient ischemic stroke was prepared by occlusion of the middle cerebral artery followed by reperfusion. One week after surgery, these rats were raised in either a standard environment or an enriched environment for 4 successive weeks. The enriched environment increased Beclin-1 expression and the LC3-II/LC3-I ratio in the autophagy/lysosomal pathway in the penumbra of middle cerebral artery-occluded rats. Enriched environment-induced elevations in autophagic activity were mainly observed in neurons. Enriched environment treatment also promoted the fusion of autophagosomes with lysosomes, enhanced the lysosomal activities of lysosomal-associated membrane protein 1, cathepsin B, and cathepsin D, and reduced the expression of ubiquitin and p62. After 4 weeks of enriched environment treatment, neurological deficits and neuronal death caused by middle cerebral artery occlusion/reperfusion were significantly alleviated, and infarct volume was significantly reduced. These findings suggest that neuronal autophagy is likely the neuroprotective mechanism by which an enriched environment promotes recovery from ischemic stroke. This study was approved by the Animal Ethics Committee of the Kunming University of Science and Technology, China (approval No. 5301002013855) on March 1, 2019.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

Inactivation of MTOR promotes autophagy-mediated epithelial injury in particulate matter-induced airway inflammation.

Particulate matter (PM) is able to induce airway epithelial injury, while the detailed mechanisms remain unclear. Here we demonstrated that PM exposure inactivated MTOR (mechanistic target of rapamycin kinase), enhanced macroautophagy/autophagy, and impaired lysosomal activity in HBE (human bronchial epithelial) cells and in mouse airway epithelium. Genetic or pharmaceutical inhibition of MTOR significantly enhanced, while inhibition of autophagy attenuated, PM-induced IL6 expression in HBE cells. Consistently, club-cell-specific deletion of Mtor aggravated, whereas loss of Atg5 in bronchial epithelium reduced, PM-induced airway inflammation. Interestingly, the augmented inflammatory responses caused by MTOR deficiency were markedly attenuated by blockage of downstream autophagy both in vitro and in vivo. Mechanistically, the dysregulation of MTOR-autophagy signaling was partially dependent on activation of upstream TSC2, and interacted with the TLR4-MYD88 to orchestrate the downstream NFKB activity and to regulate the production of inflammatory cytokines in airway epithelium. Moreover, inhibition of autophagy reduced the expression of EPS15 and the subsequent endocytosis of PM. Taken together, the present study provides a mechanistic explanation for how airway epithelium localized MTOR-autophagy axis regulates PM-induced airway injury, suggesting that activation of MTOR and/or suppression of autophagy in local airway might be effective therapeutic strategies for PM-related airway disorders.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; ALI: air liquid interface; AP2: adaptor related protein complex 2; ATG: autophagy related; BALF: bronchoalveolar lavage fluid; COPD: chronic obstructive pulmonary disease; CXCL: C-X-C motif chemokine ligand; DOX: doxycycline; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EPS15: epidermal growth factor receptor pathway substrate 15; HBE: human bronchial epithelial; H&E: hematoxylin & eosin; IKK: IKB kinase; IL: interleukin; LAMP2: lysosomal-associated membrane protein 2; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTEC: mouse tracheal epithelial cells; MTOR: mechanistic target of rapamycin kinase; MYD88: MYD88 innate immune signal transduction adaptor; NFKB: nuclear factor of kappa B; NFKBIA: NFKB inhibitor alpha; PM: particulate matter; PtdIns3K: phosphatidylinositol 3-kinase; Rapa: rapamycin; RELA: RELA proto-oncogene, NFKB subunit; SCGB1A1: secretoglobin family 1A member 1; siRNA: small interfering RNAs; SQSTM1: sequestosome 1; TEM: transmission electronic microscopy; TLR4: toll like receptor 4; TSC2: TSC complex subunit 2.

Conversion to resectability using transcatheter arterial chemoembolization alternating with mFOLFOX6 in patients with colorectal liver metastases.

BACKGROUND: Colorectal cancer is one of the most common malignancies in the world, and about 25% of colorectal cancer patients present with colorectal cancer liver metastases (CRCLM) even at new diagnosis. The study was to evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) alternating with mFOLFOX6 in Chinese patients with unresectable CRCLM. MATERIALS AND METHODS: In this study, by combining the systemic and regional treatment, the resectability rate, overall survival, and progression-free survival were measured with addition of TACE. Included patients had Eastern Cooperative Oncology Group performance status 0-2. Sixty-two patients received mFOLFOX6 plus one TACE after 2 weeks of chemotherapy; after 2 weeks, the next periodical treatment repeated. Patients received operation when the liver metastases were converted to resectability or severe tumor-associated complications occurred. RESULTS: We found that 28 patients (45.2%) patients received operation after the treatment of TACE combined with systemic chemotherapy. The median time from initial treatment to the operation was 6 months. The median follow-up period was 41 months in all the patients. The 3-year survival rate of resected patients and unresected patients was 54% and 17%, respectively. Post-TACE syndrome was the major adverse reaction (81%). Other adverse reactions were neutropenia, nausea, and neurotoxicity. No patient died of the adverse reactions. The resection rate was related to hepatic segments and vasculature involvement. CONCLUSION: Taken together, TACE alternating with mFOLFOX6 has been proved to be safe and effective for CRCLM treatment to improve resection rate and prolong the survival time.

[Smoking in Middle School Students in Priority Areas for HIV Control in Liangshan].

OBJECTIVE: To determine the prevalence and determinants of smoking in middle school students in priority areas for HIV control in Liangshan of Sichuan Province. METHODS: Students were randomly selected in all of the schools located in the priority areas for HIV control in Liangshan. A questionnaire survey was conducted,collecting data in relation to socio-demographic characteristics of the participants,their smoking behavior,drug abuse in family members,and HIV infections in family members. Risk factors associated with smoking were identified using univariate and multivariate statistical analyses. RESULTS: About 21.3% of respondents were smoking at the time of survey; 33.4% attempted smoking; 5% were heavy smokers; and 16.8% started smoking before 13 years old. The Logistic regression analysis identified male gender,senior high school students,poor academic records,low household income,rural residency,family drug abuse and HIV infections as predictors of attempted smoking. Male gender,minority ethnicity,average academic records,broken family,medium and high household income,family drug abuse and HIV infections were identified as predictors of smoking. Male gender,senior high school students,low or medium academic records,rural residency,and family drug abuse were identified as predictors of heavy smoking. Male gender,broken family,average academic records,medium or high household income,family drug abuse and HIV infections were associated with smoking before thirteen. CONCLUSION: Smoking rate in middle school students in the priority areas for HIV control in Liangshan is high. They start smoking at a young age. School smoking control programs should place priorities on those who are in the groups of boys,minority ethnicity,senior high school students,rural residency,poor academic records,and those with family drug abuse and HIV infections.

Osteoblast responses to thin nanohydroxyapatite coated on roughened titanium surfaces deposited by an electrochemical process.

PURPOSE: The purpose of this study was to investigate in vitro osteoblast responses to the thin nano-hydroxyapatite (HA) coating on porous implant surfaces. MATERIALS AND METHODS: Surface characteristics of nano-HA coating were evaluated by x-ray diffractometer (XRD) and Fourier transform infrared spectroscopy (FTIR). Murine preosteoblast cell (MC3T3-E1) proliferation, alkaline phosphatase (ALP) activity, and osteocalcin release on nano-HA coated surfaces were compared with HA-coated surfaces. RESULTS: The XRD pattern demonstrated that the peak of nano-HA coating matched well with the standard HA patterns. FTIR spectra also showed that the coating consisted of pure HA crystals. Significant increases in cell proliferation, total protein on day 7, ALP activity on day 14 and day 21, and osteocalcin production on day 21 (P < .05) were observed for nano-HA coated surfaces. CONCLUSIONS: It was concluded that thin nano-HA coating, deposited by the electrochemical process, improved proliferation and differentiation of osteoblasts.

E-cadherin promotes proliferation of human ovarian cancer cells in vitro via activating MEK/ERK pathway.

AIM: E-cadherin is unusually highly expressed in most ovarian cancers. This study was designed to investigate the roles of E-cadherin in the carcinogenesis and progression of ovarian cancers. METHODS: Human ovarian adenocarcinoma cell line SKOV-3 was examined. E-cadherin gene CDH1 in SKOV-3 cells was knocked down via RNA interference (RNAi), and the resultant variation of biological behavior was observed using CCK-8 and colony formation experiment. E-cadherin-mediated Ca(2+)-dependent cell-cell adhesion was used to study the mechanisms underlying the effects of E-cadherin on the proliferation and survival of SKOV-3 cells. The expression levels of E-cadherin, extracellular signal-related kinase (ERK), phosphorylated ERK (P-ERK) were measured using Western blot assays. RESULTS: Transfection with CDH1-siRNA for 24-96 h significantly suppressed the growth and proliferation of SKOV-3 cells. E-cadherin-mediated calcium-dependent cell-cell adhesion of SKOV-3 cells resulted in a rapid increase of P-ERK, but did not modify the expression of ERK protein. The phosphorylation of ERK in the cells was blocked by pretreatment with the MEK1 specific inhibitor PD98059 (50 µmol/L), but not by the PI3K inhibitor wortmannin (1 µmol/L) or PKA inhibitor H89 (10 µmol/L). CONCLUSION: E-cadherin may function as a tumor proliferation enhancer via activating the MEK/ERK pathway in development of ovarian epithelial cancers.