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Xiang-Dong Wang

Publications and source records attributed to Xiang-Dong Wang.

17 recordsLinked to original sources
PubMed2021

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.

Aged↗
PubMed2006

Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer.

Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer. Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated. To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke. Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions. The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans. In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions. Furthermore, the expression of proliferating cellular nuclear antigen increased markedly in both gross tumors and preneoplastic lesions in the lungs. In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer.

Adenocarcinoma↗
PubMed2005

Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential.

Chronic alcohol consumption depletes hepatic vitamin A stores. However, vitamin A supplementation is hepatotoxic, which is further potentiated by concomitant alcohol consumption. It was suggested that polar retinol metabolites generated by alcohol-inducible cytochrome P4502E1 aggravate liver damage. However, experimental evidence supporting this hypothesis is lacking. To elucidate the effects of polar retinol metabolites on cultured HepG2 cells and primary rat hepatocytes, polar retinol metabolites were extracted from liver tissues of rats fed either an alcoholic or isocaloric control Lieber-DeCarli diet. Cell toxicity assays included morphology assessment, trypan blue exclusion test, and LDH/AST leakage. Staining for DAPI and acridine orange, FACS analysis, and Western blot for cleaved caspase-9 and -3 were used to detect apoptosis. Polar retinol metabolites caused marked cytotoxicity in a concentration- and time-dependent manner in both cell types reflected by morphological changes, a dramatic increase in trypan blue positive cells, and LDH/AST leakage. Toxicity was due to apoptosis, as demonstrated by a time-dependent increase of sub-G1 cellular events, a rapid loss of mitochondrial membrane potential, and a time-dependent activation of caspase-9 and -3. No toxicity was found with equivalent doses of the control extract from nonalcoholic rats. We demonstrate that polar retinol metabolites cause marked hepatocyte death through the induction of apoptosis.

Animals↗
PubMed2005

Alcohol, vitamin A, and cancer.

Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid "cross-talk" with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A.

Animals↗
PubMed2004

The effect of dietary glutathione and coenzyme Q10 on the prevention and treatment of inflammatory bowel disease in mice.

Because reactive oxygen species have been implicated as mediators of inflammatory bowel disease (IBD), we evaluated the potential preventive and therapeutic effects of two dietary antioxidants, glutathione (GSH) and coenzyme Q10 (CoQ10) on dextran sulfate sodium (DSS)-induced colitis in mice. Fifty female 8-wk old Swiss-Webster mice were randomly assigned to 4 groups for a pre-treatment "prevention" study: (1) GSH (1% of diet); (2) CoQ10 (200 mg/kg/d); (3) DSS only (3% of drinking water); (4) control (no treatment). The mice in groups 1 and 2 were fed with GSH or CoQ10 for 21 wks, and the mice in groups 1, 2 and 3 were provided DSS from wk 7 for 4 cycles (1 cycle = 1 wk DSS followed by 2-wk water). Another 50 mice were randomly assigned to 4 groups for a 21-wk "treatment" study where the mice in groups 1, 2, and 3 were administered DSS for 6 cycles (18 wks) to induce colitis. GSH and CoQ10 were added from wk 7 until the completion of the protocol. Loose stools and hemocult positivity were modestly but significantly reduced with GSH or CoQ10 at several periods during the intervention in both the prevention and treatment studies. In contrast, histological evaluation revealed increases in colonic dysplasia and ulceration with GSH or CoQ10. Thus, in this mouse model, GSH and CoQ10 appear to have a beneficial effect on acute signs of IBD, but may have an adverse impact on the chronic pathophysiology of the disease. Further studies using additional animal models are required to determine whether GSH or CoQ10 provide a favorable or unfavorable benefit:risk ratio in the prevention or treatment of IBD.

Analysis of Variance↗
PubMed2004

Low dose beta-carotene supplementation of ferrets attenuates smoke-induced lung phosphorylation of JNK, p38 MAPK, and p53 proteins.

We demonstrated previously that smoke exposure and/or high-dose beta-carotene supplementation decreases levels of retinoic acid and retinoic acid receptor beta (RARbeta) protein, but increase levels of c-Jun and proliferating cellular nuclear antigen protein in the lungs of ferrets. In contrast, low-dose beta-carotene can prevent the decreased lung retinoic acid and the smoke-induced lung lesions. In the present study, we investigated whether smoke exposure and/or beta-carotene supplementation could affect Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p53 in the lungs of ferrets. Ferrets were subjected to cigarette smoke exposure and either a high or low dose of beta-carotene (2 x 3 factorial design) for 6 mo. There were greater protein levels of phosphorylated JNK, p38, and c-Jun, but lower levels of MAPK phophatase-1 (MKP-1) in groups exposed to smoke and/or high dose beta-carotene. Both phosphorylated-p53 and total p53 were substantially increased in the lungs of these groups. In contrast, low-dose beta-carotene greatly attenuated the smoke-induced phosphorylation of JNK, p38, c-Jun, p53, and total p53, accompanied by upregulated MKP-1. Smoke exposure increased MAPK kinase-4 (MKK4) phosphorylation regardless of beta-carotene supplementation. These data indicate that restoration of retinoic acid and MKP-1 by low-dose beta-carotene in the lungs of ferrets may prevent the smoke-induced activation of the JNK-dependent signaling pathway, p38 MAPK, and the associated phosphorylation of p53, thereby lowering the risk of the smoke-related lung lesions. These data provide supportive evidence that the beneficial vs. detrimental effects of beta-carotene supplementation are related to the dosage of beta-carotene administered.

Animals↗
PubMed2004

Alcohol-reduced plasma IGF-I levels and hepatic IGF-I expression can be partially restored by retinoic acid supplementation in rats.

Chronic and excessive ethanol intake in rats results in low levels of hepatic retinoic acid (RA) either by inhibiting the biosynthesis of RA or by enhancing its catabolism of RA. Chronic ethanol intake also decreases both hepatic expression of insulin-like growth factor-I (IGF-I) and plasma IGF-I concentration in rats. It is not known whether RA supplementation in alcohol-fed rats can restore plasma IGF-I concentrations and hepatic IGF-I expression. In the present study, we examined both plasma IGF-I level and hepatic IGF-I mRNA expression in alcohol-fed rats with or without RA (100 microg/kg body weight) supplementation for 6 mo. Hepatic IGF-I mRNA levels and plasma IGF-I concentration were decreased (84 and 29%, respectively) significantly in alcohol-fed rats compared with the control. In contrast, RA supplementation in ethanol-fed rats partially restored both hepatic IGF-I mRNA levels and plasma IGF-I concentration compared with rats fed ethanol alone. These data suggest that alcohol-impaired hepatic RA status contributes to the decreased plasma IGF-I level and hepatic IGF-I expression in alcoholics.

Animals↗
PubMed2004

Alpha-tocopherol and ascorbic acid decrease the production of beta-apo-carotenals and increase the formation of retinoids from beta-carotene in the lung tissues of cigarette smoke-exposed ferrets in vitro.

Previously, we found that exposing ferrets to cigarette smoke enhanced oxidative excentric cleavage of beta-carotene. In the present study, we examined whether alpha-tocopherol, ascorbic acid, or the two combined can prevent smoke-altered beta-carotene metabolism. In vitro incubation of beta-carotene (10 micro mol/L) with lung postnuclear fractions from ferrets exposed to cigarette smoke was carried out in the absence or presence of alpha-tocopherol (50 micro mol/L), ascorbic acid (10 or 50 micro mol/L), or both vitamins to evaluate their effects on the production of beta-apo-carotenals and retinoids from beta-carotene. The oxidative cleavage metabolites of beta-carotene, beta-apo-carotenals (beta-apo-14', beta-apo-12', beta-apo-10', and beta-apo-8'), retinoic acid (RA), and retinal were analyzed by HPLC. We found that the smoke-enhanced production of individual beta-apo-carotenals was significantly decreased by 36-77% when alpha-tocopherol (50 micro mol/L) and ascorbic acid (50 micro mol/L) were added together to the incubation mixture. alpha-Tocopherol alone had a modest effect. Ascorbic acid in the presence of alpha-tocopherol inhibited the production of beta-apo-carotenals in a dose-dependent manner, although ascorbic acid alone had no effect. In contrast, the production of RA and retinal among smoke-exposed ferrets was substantially increased ( approximately 3-fold, P < 0.05) when both alpha-tocopherol and ascorbic acid were added to the incubation mixtures. However, when ascorbic acid or alpha-tocopherol alone was added, the production of RA among smoke-exposed ferrets increased only modestly (80%, P < 0.05) and did not differ from the RA levels in control ferrets. In conclusion, these data indicate that alpha-tocopherol and ascorbic acid may act synergistically in preventing the enhanced oxidative excentric cleavage of beta-carotene induced by smoking exposure, thereby facilitating the conversion of beta-carotene into RA and retinal.

Analysis of Variance↗
PubMed2004

Beta-carotene and beta-apo-14'-carotenoic acid prevent the reduction of retinoic acid receptor beta in benzo[a]pyrene-treated normal human bronchial epithelial cells.

Low-dose beta-carotene (BC) supplementation, such as would be provided by daily consumption of approximately 5-9 servings of fruits and vegetables, has no apparent detrimental effects, but rather appears to have a protective effect against cigarette smoke-induced lung lesions in ferrets. In the present study, we investigated the effects of BC, beta-apo-14'-carotenoic acid (14'CA), or benzo[a]pyrene (BP; a primary lung carcinogen from cigarette smoke) treatments, either alone or in combination, on cell growth and expression of the retinoic acid receptor (RAR) of normal human bronchial epithelial (NHBE) cells. We found that both BC and 14'CA inhibited the growth of NHBE cells (P < 0.05) with or without BP. The level of RARbeta, a tumor suppressor, but not RARalpha or RARgamma, was reduced by 50% in the NHBE cells treated with BP. However, treatment with either BC or 14'CA significantly induced the expression of RARbeta in the NHBE cells, and prevented the reduction of RARbeta by BP. Furthermore, 14'CA transactivated the RARbeta promoter primarily via its conversion to retinoic acid (RA). In the presence of 3-mercaptopropionic acid, an inhibitor of fatty acid oxidation, both RA formation and transactivation activity from 14'CA were decreased. These observations indicate that the growth inhibitory effects of BC and beta-apo-carotenoic acid are through their conversion to RA and upregulation of RARbeta.

Benzo(a)pyrene↗
PubMed2004

Intraductal ultrasonography and endoscopic retrograde cholangiography in diagnosis of extrahepatic bile duct stones: a comparative study.

BACKGROUND: Intraductal ultrasonography (IDUS) is highly accurate in detection of extrahepatic bile duct stones. This study was to compare the accuracy of IDUS and endoscopic retrograde cholangiography (ERC) in the diagnosis of extrahepatic bile duct stones. METHODS: Thirty patients suspected of extrahepatic bile duct stones on B ultrasonography, CT, or MRI were enrolled for study. ERC was performed using a Fujinon duodenoscope (ED-410XT, ED-410Xu), then IDUS was done by inserting a Fujinon microprobe (PL2220-15) through the endoscopic biopsy channel to detect the extrahepatic bile duct. Finally stones in the extrahepatic bile duct were detected and extracted by endoscopic sphincterotomy (EST). RESULTS: Among the 30 patients, 26 were diagnosed as having cholelithiasis accurately through ERC. In one patient the stone detected by ERC was really floccule. Misdiagnosis happened in 2 patients with extrahepatic bile duct stones. So the overall accuracy and sensitivity of ERC in the diagnosis of extrahepatic bile duct stones were 86.7% (26/30) and 92.9% (26/28) respectively. In contrast, IDUS showed the results of diagnosis were in consistent with those of EST stone extraction. Its accuracy and sensitivity in the diagnosis of extrahepatic bile duct stones were 100% (30/30) and 100% (28/28) respectively. CONCLUSION: IDUS which is superior to ERC in diagnosing extrahepatic bile duct stones can avoid the visual error of ERC.

Adult↗
PubMed2003

Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets.

Higher intake of lycopene is related to a lower risk of lung cancer in human studies. Lung cancer risk is associated with higher plasma levels of insulin-like growth factor I (IGF-I) and/or lower levels of IGF-binding protein 3 (IGFBP-3). However, little is known regarding whether lycopene can inhibit cigarette smoke-induced lung carcinogenesis through modulation of IGF-I/IGFBP-3, cell proliferation, and apoptosis. We investigated the effects of lycopene supplementation at a low dose (1.1 mg/kg/day, which is equivalent to an intake of 15 mg/day in humans) and a high dose (4.3 mg/kg/day, which is equivalent to 60 mg/day in humans) on plasma IGF-I/IGFBP-3 levels, histopathological changes, proliferating cellular nuclear antigen (PCNA) expression, BAD phosphorylation, and apoptosis (caspase 3 assay) in lungs of ferrets with or without cigarette smoke exposure for 9 weeks. We found that ferrets supplemented with lycopene and exposed to smoke had significantly higher plasma IGFBP-3 levels (P < 0.01) and a lower IGF-I/IGFBP-3 ratio (P < 0.01) than ferrets exposed to smoke alone. Both low- and high-dose lycopene supplementations substantially inhibited smoke-induced squamous metaplasia and PCNA expression in the lungs of ferrets. No squamous metaplasia or PCNA overexpression were found in the lungs of control ferrets or those supplemented with lycopene alone. Furthermore, cigarette smoke exposure greatly increased BAD phosphorylation at both Ser(136) and Ser(112) and significantly decreased cleaved caspase 3 in the lungs of ferrets, as compared with controls. The elevated phosphorylation of BAD and down-regulated apoptosis induced by cigarette smoke in the lungs of ferrets was prevented by both low- and high-dose lycopene supplementations. Lycopene levels were increased in a dose-dependent manner in both plasma and lungs of ferrets supplemented with lycopene alone. However, lycopene levels were markedly lower in both plasma and lungs of ferrets supplemented with lycopene and exposed to smoke. Furthermore, smoke exposure increased cis isomers (26% for 13-cis and 22% for 9-cis) of lycopene in the lungs of ferrets, compared with that of ferrets supplemented with lycopene alone (20% for 13-cis and 14% for 9-cis). In conclusion, lycopene may mediate its protective effects against smoke-induced lung carcinogenesis in ferrets through up-regulating IGFBP-3 and down-regulating phosphorylation of BAD, which promote apoptosis and inhibit cell proliferation.

Animals↗
PubMed2003

Exposing ferrets to cigarette smoke and a pharmacological dose of beta-carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes.

In our previous studies, we found lower levels of retinoic acid (RA) in the lungs of ferrets exposed to cigarette smoke and/or a pharmacological dose of beta-carotene. To determine whether this is involved in excessive catabolism of RA via cytochrome P450 (CYP) induction, we carried out in vitro incubations of RA with the lung microsomal fractions of ferrets with or without CYP inhibitors and antibodies against CYP. The polar metabolites (4-oxo-RA and 18-hydroxy-RA) of RA metabolism after the incubation were analyzed by HPLC. Expressions of CYP (1A1, 1A2, 2E1 and 3A1) were examined using Western blot analysis. Incubation of various concentrations of RA with the lung microsomal fraction from ferrets exposed to cigarette smoke, a pharmacological dose of beta-carotene or their combination dose-dependently increased the levels of 4-oxo-RA and 18-hydroxy-RA compared with that of the control ferrets. At all RA concentrations, this increase was the greatest in lung tissue from the combined treatment group. Furthermore, this enhanced RA catabolism was substantially (approximately 80%) inhibited by nonspecific CYP inhibitors (disulfiram and liarozole), but was partially (approximately 50%) inhibited by resveratrol (CYP1A1 inhibitor), alpha-naphthoflavone (CYP1A2 inhibitor) and antibodies against CYP1A1 and CYP1A2. Cigarette smoke exposure and/or pharmacological doses of beta-carotene increased levels of CYP1A1 and 1A2 by three- to sixfold but not levels of 2E1 and 3A1 in ferret lung tissue. These findings suggest that low levels of RA in the lung of ferrets exposed to cigarette smoke and/or pharmacological doses of beta-carotene may be caused by the enhanced RA catabolism via induction of CYP, CYP1A1 and CYP1A2 in particular, which provides a possible explanation for enhanced lung carcinogenesis seen with pharmacological doses of beta-carotene supplementation in cigarette smokers.

Analysis of Variance↗
PubMed2003

Retinoids and alcohol-related carcinogenesis.

Chronic and excessive alcohol intake is associated with an increased incidence of a variety of cancers (e.g., liver, oral cavity, esophagus, colorectal and breast). Long-term alcohol intake results in impaired nutritional status of retinoic acid (RA), the most active derivative of vitamin A, which may provide a promoting environment for tumor formation. Recent studies demonstrate that chronic alcohol-induced hepatocellular proliferation, which may convert hepatocytes from a state of resistance to a carcinogen to a state of high susceptibility, is due to alcohol-impaired RA metabolism and signaling and crosstalk with the Jun N-terminal kinases-dependent signaling pathway. Further, the restoration of hepatic RA homeostasis by treatment with either RA supplementation or inhibitors of RA catabolism can suppress alcohol-induced hepatocyte hyperproliferation and restore alcohol-deregulated apoptosis, thereby reducing the risk of alcohol-promoted hepatocellular carcinogenesis. These studies indicate the importance of RA actions in the prevention and/or treatment of alcohol-related carcinogenic process in the liver and other organs.

Alcoholism↗
PubMed2002

Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats.

Retinoic acid (RA) supplementation suppresses ethanol-enhanced hepatocyte hyperproliferation in rats; however, little is known about the mechanism(s). Here, we investigated whether RA affects the protein kinase signaling pathways in the liver tissues of rats fed with a high dose of ethanol for a prolonged period of time (6 months). Results show that there were greater levels of phosphorylated Jun N-terminal kinase (JNK) and phosphorylated c-Jun protein, but not total JNK protein, in livers of ethanol-fed rats vs those of controls. Moreover, ethanol feeding to rats increased the levels of phosphorylated mitogen-activated protein kinase kinase-4 (MKK-4) and decreased the levels of mitogen-activated kinase phosphatase-1 (MKP-1) in liver tissue. However, hepatic levels of phosphorylated-p38 protein and total-p38 protein were not altered by the ethanol treatment. In contrast, all-trans-RA supplementation at two doses in ethanol-fed rats greatly attenuated the ethanol-induced hepatic phosphorylation of MKK-4, phosphorylated-JNK and c-Jun proteins. The level of MKP-1 was increased in ethanol-fed rats supplemented with all-trans-RA. Further, ethanol-induced hepatocyte hyperproliferation, measured by immunostaining for proliferating cell nuclear antigen, were markedly decreased by all-trans-RA supplementation. Interestingly, hepatic apoptosis in the liver of ethanol-fed rats after 6 months of treatment decreased significantly. This decrease of hepatic apoptosis in ethanol-fed rats was prevented by all-trans-RA supplementation in a dose-dependent manner. The results from these studies indicate that restoration of RA homeostasis is critical for the regulation of JNK-dependent signaling pathway and apoptosis in the liver of ethanol-fed rats.

Animals↗
PubMed2002

Chlormethiazole treatment prevents reduced hepatic vitamin A levels in ethanol-fed rats.

BACKGROUND: Chronic ethanol intake results in decreased hepatic vitamin A levels through both enhanced degradation of vitamin A via a cytochrome P450 enzyme (CYP)-dependent process and increased mobilization of vitamin A from the liver into the circulation. This study investigated whether treatment with chlormethiazole, a CYP inhibitor, restores vitamin A in the livers of ethanol-fed rats. METHODS: Ethanol-exposed and non-ethanol-exposed rats were treated with or without chlormethiazole (10 and 100 mg/kg body weight) for 1 month. Liver and plasma levels of retinol and retinyl palmitate were analyzed by high-performance liquid chromatography. Expressions of hepatic lecithin:retinol acyltransferase (LRAT) and cellular retinol-binding protein were analyzed with reverse transcription-polymerase chain reaction. Hepatic retinol esterification by LRAT was examined by using incubations of the microsomal fractions of livers with exogenous sources of retinol. RESULTS: Ethanol-feeding in rats for a month resulted in lower hepatic levels of retinol and retinyl palmitate than those found in controls and the occurrence of several polar retinoid metabolites. In contrast, treatment with chlormethiazole at two different doses in ethanol-fed rats completely blocked the formation of hepatic retinoid polar metabolites and restored hepatic levels of retinol and hepatic retinyl palmitate in a dose-dependent manner. Furthermore, increased plasma concentrations of retinyl palmitate in rats fed with ethanol, which indicate increased mobilization of vitamin A, were partially inhibited by chlormethiazole treatment. However, neither ethanol nor chlormethiazole treatment altered the expression and activity of LRAT in the liver of rats. Hepatic expression of cellular retinol-binding protein increased significantly in ethanol-fed rats with or without chlormethiazole treatment compared with control rats. CONCLUSIONS: These data suggest that chlormethiazole can restore both hepatic retinol and retinyl ester concentrations to normal levels in ethanol-fed rats through blocking enhanced both degradation of vitamin A and mobilization of vitamin A from the liver into the circulation.

Alcohol Drinking↗
PubMed2002

Emphysematous lung destruction by cigarette smoke. The effects of latent adenoviral infection on the lung inflammatory response.

This study was designed to test the hypothesis that cigarette smoke-induced inflammation and emphysema are amplified by the presence of latent adenoviral (Ad) infection, and to determine whether this emphysematous process can be reversed by all-trans-retinoic acid (RA) treatment. The results confirm that in guinea pigs, chronic cigarette-smoke exposure caused lesions similar to human centrilobular emphysema. They also show that latent Ad infection combined with cigarette-smoke exposure caused an excess increase in lung volume (P < 0.001), air-space volume (P < 0.001), and lung weight (P < 0.01), and further decrease in surface-to-volume ratio (P < 0.001) compared with smoke exposure alone. RA treatment failed to reverse these emphysematous changes. Analysis of inflammatory response in parenchymal and airway tissue showed that smoking caused an increase of polymorphonuclear leukocytes (PMNs) (P < 0.0002), macrophages (P < 0.001), and CD4 cells (P < 0.0009), and that latent Ad infection independently increased PMNs (P < 0.001), macrophages (P = 0.003), and CD8 cells (P < 0.001). We conclude that latent Ad infection amplifies the emphysematous lung destruction and increases the inflammatory response produced by cigarette-smoke exposure. In this study, the increase in CD4 was associated with cigarette smoke and the increase in CD8 cells with latent Ad infection.

Adenoviridae↗