Diffuse cystic lung disease caused by tuberculosis infection: Case series.

Diffuse cystic lung disease (DCLD) is a complex disease that can be caused by various reasons. Although the chest CT scan plays a vital role in suggesting the etiology of DCLD, it is apt to lead to misdiagnosis simply based on the CT image of the lung. Here, we report a rare case of DCLD caused by tuberculosis and misdiagnosed as pulmonary Langerhans cell histiocytosis (PLCH). A 60-year-old female DCLD patient with a long-term smoking history was admitted to the hospital because of a dry cough and dyspnea, and the chest CT scan showed diffuse irregular cysts in both lungs. We considered the patient to be PLCH. To alleviate dyspnea, we chose to give her intravenous glucocorticoids. However, she developed a high fever during the use of glucocorticoids. We performed flexible bronchoscopy and bronchoalveolar lavage. Mycobacterium tuberculosis (specific sequence reads: 30) was detected in BALF. She was finally diagnosed with pulmonary tuberculosis. Tuberculosis infection is one of the rare causes of DCLD. We have discovered thirteen similar cases by searching Pubmed and Web of Science. For DCLD patients, glucocorticoids should not be used blindly unless the existence of a tuberculosis infection is ruled out. TBLB for pathology and bronchoalveolar lavage fluid (BALF) for microbiological detection are helpful for diagnosis.

Oridonin attenuates LPS-induced early pulmonary fibrosis by regulating impaired autophagy, oxidative stress, inflammation and EMT.

CONTEXT: Oridonin (Ori) possesses anti-inflammatory, antioxidant and antitumor properties. However, the effects of Ori on Lipopolysaccharide (LPS)-induced early pulmonary fibrosis remain unclear. OBJECTIVE: We evaluated the protective effects of Ori on the mice model of pulmonary fibrosis. MATERIALS AND METHODS: The BALB/C mice were given LPS (1 mg/kg) or Ori (20 mg/kg) according to experimental grouping. Then the left lung tissues were used for HE, immunohistochemical and Masson staining, and the right lung tissues were used for hydroxyproline measurement and western blot experiments. Bronchoalveolar lavage fluid was collected for Giemsa staining. RESULTS: The high levels of hydroxyproline induced by LPS were reduced by Ori treatment. Immunohistochemical staining and western blot analysis showed that Ori inhibited the increased levels of fibrosis-related proteins (α-smooth muscle actin, transforming growth factor-ß, Collagen Ⅰ and phosphorylated-smad). Additionally, Ori treatment increased E-cadherin levels and decreased in Snail and Slug levels. Besides, Ori could suppress LPS-induced the infiltration of neutrophils and activation of the NLRP3 inflammasome. In addition, LPS caused the upregulation of NADPH oxidase 4 and exacerbated lung fibrosis. As the activator of NF-E2 related factor-2, Ori exerted protective effects in this animal model. Moreover, Ori reversed the LPS-triggered increases in Beclin-1, P62/sequestosome 1, autophagy related 3 and LC3. CONCLUSIONS: These findings suggested that Ori protected against LPS-induced early pulmonary fibrosis by inhibiting NLRP3-dependent inflammation, NADPH oxidase 4-dependent oxidative stress, the impaired autophagy and epithelial mesenchymal transformation.

Long-term study of heavy metal pollution in the northern Hangzhou Bay of China: temporal and spatial distribution, contamination evaluation, and potential ecological risk.

Coastal ecosystem is vulnerable to heavy metal contamination. The northern Hangzhou Bay is under intensifying impact of anthropogenic activities. To reveal the heavy metal pollution status in the coastal environment of the Hangzhou Bay, a long-term investigation into the heavy metal contamination during 2011 to 2016 was initiated. Seawater and sediment samples of 25 locations depending on the sewage outlet locations in the northern Hangzhou Bay were collected to analyze the concentrations and temporal and spatial distribution of Cu, Pb, Zn, Cd, Hg, and As. Pollution condition, ecological risk, and potential sources were additionally analyzed. Results show that the annual mean concentrations of Cu, Pb, Zn, Cd, Hg, and As were 2.13-4.59, 0.212-1.480, 7.81-20.34, 0.054-0.279, 0.026-0.090, and 1.08-2.57 µg/L in the seawater, and were 16.34-28.35, 16.25-26.33, 67.32-97.61, 0.084-0.185, 0.029-0.061, and 6.09-14.08 µg/L in the sediments. A decreasing trend in Cu, Pb, Zn, Cd, and Hg concentrations and an increasing trend in As of the seawater were observed. However, in the sediment, the heavy metals demonstrated a rising trend, except for Hg. The single-factor pollution index showed an increasing trend in Cd and As in the seawater, depicting an enhanced pollution of Cd and As, while in the sediments, Cu, Pb, and As were in pollution-free level (average Geo-accumulation index (Igeo) values below 0) in general, and only occasional slight pollution occurred in individual years, e.g., As with 0.403 in 2016. The mean Igeo values of Cd ranged from - 0.865 to 0.274 during 2011 to 2016, indicating that the pollution level of Cd was slight, but is likely to increase in the forthcoming years. The level of heavy metal contamination in sediments was low in 2011 (5.853) and 2012 (5.172), and moderate during 2013 to 2016 (in the range of 6.107 to 7.598), while the degree of potential ecological risk was low in the study period, except moderate in 2013 (125.107). The highest contamination degree and potential ecological risk appeared in 2013 (Cd = 7.598; RI = 125.107), while Cd and Hg contributed over 75% of the ecological risk. Overall, the results show low pollution level and low potential ecological risk in the northern Hangzhou Bay; however, more attention should be paid to the potential ecological risk due to Hg and Cd. Graphical abstract Spatial distribution of the heavy metal levels in the sediment of the coastal environment of the northern Hangzhou Bay on a long-term basis.

Pterostilbene prevents LPS-induced early pulmonary fibrosis by suppressing oxidative stress, inflammation and apoptosis in vivo.

Early pulmonary fibrosis after acute lung injury leads to poor prognosis and high mortality. Pterostilbene (Pts), a bioactive component in blueberries, possesses anti-inflammatory, antioxidative and antifibrotic properties. However, the effects of Pts on lipopolysaccharide (LPS)-induced pulmonary fibrosis are still unknown. In our study, the Pts group showed lower lung injury and fibrosis scores, and lower levels of hydroxyproline and protein (collagen I and transforming growth factor-ß) than the scores and levels in mice treated with LPS. MMP-1 was the degrading enzyme of collagen I and LPS caused the inhibition of MMP-1, disturbing the degradation of collagen. Additionally, Pts remarkably reversed the LPS-induced inhibition of interleukin-10 and the release of tumor necrosis factor-α, interleukin-6 and interleukin-1ß. In terms of cellular pathways, Pts treatment ameliorated LPS-activated nuclear factor kappa B (NF-κB) and NOD-like receptor NLRP3 signaling. Besides, LPS-induced low levels of A20 could be activated by Pts. In addition, Pts treatment reversed the high levels of Caspase-3, poly ADP-ribose polymerase (PARP) and Bcl2-associated X protein (Bax) expression and the low levels of B cell lymphoma/lewkmia-2 (Bcl2) that had been induced by LPS. Moreover, oxidative stress is also involved in the pathogenesis of fibrosis. Our findings indicate that LPS injection triggered the production of myeloperoxidase (MPO) and malondialdehyde (MDA) and the depletion of superoxide dismutase (SOD) and glutathione (GSH), and that these effects were notably reversed by treatment with Pts. In addition, Pts induced the dissociation of Kelch-like epichlorohydrin-associated protein-1 (Keap-1) and NF-E2 related factor-2 (Nrf2) and the activation of downstream genes (heme oxygenase-1, NAD(P)H:quinine oxidoreductase, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modifier). In conclusion, oxidative stress, apoptosis and inflammation are involved in early pulmonary fibrosis and Pts exerts a protective effect by activating Keap-1/Nrf2, inhibiting caspase-dependent A20/NF-κB and NLRP3 signaling pathways.

Isoliquiritigenin exerts antioxidative and anti-inflammatory effects via activating the KEAP-1/Nrf2 pathway and inhibiting the NF-κB and NLRP3 pathways in carrageenan-induced pleurisy.

Pleurisy refers to a pleural disease caused by pathogenic factors that stimulate the pleura associated with pleural inflammation and oxidative stress. Isoliquiritigenin (ISL), a flavonoid from the liquorice compound, possesses antioxidative and anti-inflammatory properties. In the current study, we investigated the protective effects of ISL on carrageenan-induced pleurisy and lung injury in mice. The mice were intraperitoneally injected with ISL (30 mg kg-1) twice (each time interval of 12 h), followed by exposure to Car 1 h after the second dose of ISL. Our results indicated that ISL treatment significantly alleviated carrageenan-induced histopathological damage and increased levels of inflammatory cell exudation, protein leakage, and pro-inflammatory mediators. Meanwhile, ISL inhibited reactive oxygen species (ROS) generation, MDA and MPO formation, and SOD and GSH depletion induced by carrageenan. In addition, it decreased the GSSG level and GSSG-to-GSH ratio. In terms of the mechanism, ISL inhibited NOX2 and NOX4 levels, caused the dissociation of KEAP-1 and Nrf2, and activated the downstream genes HO-1, NQO1, GCLC and GCLM, thus decreasing oxidative stress. In addition, ISL exerts protective effects against inflammation by suppressing the NOD-like receptor protein 3 (NLRP3)/NF-κB pathway and the high levels of iNOS and COX-2. In summary, our results reinforce the hypothesis that ISL exerts protective effects on carrageenan-induced pleurisy and lung injury in a manner that can be attributed to Nrf2-mediated antioxidative activities and NLRP3/NF-κB-mediated anti-inflammatory activities.

Oridonin attenuates carrageenan-induced pleurisy via activation of the KEAP-1/Nrf2 pathway and inhibition of the TXNIP/NLRP3 and NF-κB pathway in mice.

The classic NLRP3 inflammasome and NF-κB molecular pathways are activated in many inflammatory-related diseases, such as pleurisy. Because oridonin (Ori) has been indicated as a covalent NLRP3 inhibitor with strong anti-inflammasome activity, we herein aimed to assess the effects of Ori in a mouse model of carrageenan (CAR)-induced pleurisy. The results showed that CAR caused hemorrhaging and exudation of lung tissues and the release of inflammatory factors (TNF-α, IL-6 and IL-1ß), effects that were significantly reduced by treatment with Ori. In addition, increased neutrophil infiltration, protein concentrations and volumes were found in the exudates of the CAR group, and these phenomena were suppressed by Ori treatment. Regarding cellular pathways, Ori could alleviate the CAR-activated NF-κB and TXNIP/NLRP3 pathways. Additionally, oxidative stress was shown to be involved in the pathogenesis of pleurisy, but possible mechanisms remain to be explored. Herein, Ori reversed the CAR-induced depletion of GSH and SOD and the CAR-induced increases in ROS, MPO and MDA levels. Furthermore, Ori inhibited NOX-4 levels, initiated the dissociation of KEAP-1 from Nrf2, activated the downstream genes HO-1 and exerted antioxidative effects on CAR-induced pleurisy. In conclusion, Ori conferred protection against CAR-induced pleurisy via Nrf2-dependent antioxidative and NLRP3-dependent anti-inflammatory properties.

Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux.

Background: Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA in vitro and in vivo. Methods: The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth in vivo. Results: Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity. Conclusion: Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.

Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells.

AMPK-mediated autophagy and Akt/mTOR pathways play important roles in current cancer treatments. Oridonin (Ori), an ent-kaurane diterpenoid isolated from Isodon rubescens, exerts extensive anti-tumor potential and controversial effects on autophagy. In this study, we investigated the effect of Ori on the autophagy, apoptosis, and AMPK/Akt/mTOR pathways and determined whether Ori was related to the increased cisplatin sensitivity observed in A549 cells. First, we found that Ori suppressed Akt/mTOR, Bcl2 and autophagy flux with enhanced levels of Atg3, P62, and LC3II, which was also shown as the accumulation of autophagosomes. AMPK and pro-apoptotic proteins (caspase3, Bax, and PARP) were activated in Ori-treated cells. With the pretreatment of compound c (AMPK inhibitor), the activation of autophagosomes, apoptosis and the inhibition of Akt/mTOR pathways induced by Ori were all reversed. The Ori-activated apoptosis-related markers mentioned previously and the cell-killing effect were restrained by 3-MA (inhibitor of autophagosomes) treatment. Therefore, we hypothesized that the Ori-induced pro-apoptotic effect was mediated by AMPK/Akt/mTOR-dependent accumulation of impaired autophagosomes. Furthermore, Ori could increase the sensitivity of cisplatin through its increased cell-killing, autophagy-suppressing and apoptosis-inducing activities. In addition to sensitizing cisplatin, Ori also alleviated cisplatin-induced acute renal injury in vivo, manifested as depleted BUN, CRE, kidney index, and weight loss compared to the cisplatin group. In summary, apart from its protective effect on cisplatin-induced nephrotoxicity, Ori enhanced cisplatin sensitivity via its pro-apoptotic activity mediated by AMPK/Akt/mTOR-dependent autophagosome activation, which may be a potential therapeutic target for non-small cell lung cancer.

Oridonin protects LPS-induced acute lung injury by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-κB pathways.

BACKGROUND: Oxidative stress and the resulting inflammation are essential pathological processes in acute lung injury (ALI). Nuclear factor erythroid 2-related factor 2 (Nrf2), a vital transcriptional factor, possesses antioxidative potential and has become a primary target to treat many diseases. Oridonin (Ori), isolated from the plant Rabdosia Rrubescens, is a natural substance that possesses antioxidative and anti-inflammatory effects. Our aim was to study whether the anti-inflammatory and antioxidant effects of Ori on LPS-induced ALI were mediated by Nrf2. METHODS: MTT assays, Western blotting analysis, a mouse model, and hematoxylin-eosin (H & E) staining were employed to explore the mechanisms by which Ori exerts a protective effect on LPS-induced lung injury in RAW264.7 cells and in a mouse model. RESULTS: Our results indicated that Ori increased the expression of Nrf2 and its downstream genes (HO-1, GCLM), which was mediated by the activation of Akt and MAPK. Additionally, Ori inhibited LPS-induced activation of the pro-inflammatory pathways NLRP3 inflammasome and NF-κB pathways. These two pathways were also proven to be Nrf2-independent by the use of a Nrf2 inhibitor. In keeping with these findings, Ori alleviated LPS-induced histopathological changes, the enhanced production of myeloperoxidase and malondialdehyde, and the depleted expression of GSH and superoxide dismutase in the lung tissue of mice. Furthermore, the expression of LPS-induced NLRP3 inflammasome and NF-κB pathways was more evident in Nrf2-deficient mice but could still be reversed by Ori. CONCLUSIONS: Our results demonstrated that Ori exerted protective effects on LPS-induced ALI via Nrf2-independent anti-inflammatory and Nrf2-dependent antioxidative activities.

Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A.

Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2-/- mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.

Farrerol Ameliorates APAP-induced Hepatotoxicity via Activation of Nrf2 and Autophagy.

Farrerol has been shown to have antioxidative potential via Nrf2 activation, which in turn is involved in the prevention of hepatotoxicity. The purpose of the current study was to explore the protective effect of farrerol against acetaminophen-induced hepatotoxicity and its underlying mechanisms. Mice were used to evaluate the hepatoprotective effect of farrerol on liver injury induced by acetaminophen in vivo. HepG2 cells were utilized to further determine the functional role and mechanisms by which Nrf2 and autophagy are involved in the hepatoprotective effect of farrerol in vitro. We found that treatment with farrerol leads to a significant reduction in acetaminophen-induced hepatotoxicity by decreasing mortality, histopathological liver changes, and ALT and AST levels. Furthermore, farrerol effectively suppressed mitochondrial dysfunction by reducing JNK phosphorylation, Bax mitochondrial translocation, AIF and cytochrome c release. Further investigations revealed that the activation of Nrf2 and the induction of autophagy via the AMPK/AKT pathway by farrerol contributed to its hepatoprotective activity in vitro. In addition, farrerol inhibited acetaminophen-induced the mortality and histopathological changes in WT mice were evidently alleviated but not abrogated in Nrf2 -/- mice, which attributed to the induction of autophagy. Together, farrerol has protective potential against acetaminophen-induced hepatotoxicity which may be associated with activation of Nrf2 and autophagy.