Inhaled isobutyl nitrite produced lung inflammation with increased macrophage TNF-alpha and nitric oxide production.
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Administration, Inhalation↗
Biomedical subjects
L W Chang
Publications and source records attributed to L W Chang.
Radiation protection and radiation recovery with essential metalloelement chelates.
Understanding essential metalloelement metabolism and its role in tissue maintenance and function, as well as the roles of essential metalloelement-dependent enzymes in responding to injury, offer a new approach to decreasing and/or treating radiation injury. This review presents the roles of some essential metalloelement-dependent enzymes in tissue maintenance and function, and their responses to radiation injury in accounting for radiation protection and recovery effects observed for nontoxic doses of essential metalloelement compounds. Effects of biochemicals including water undergoing bond radiolysis and the effects of free radicals derived from diatomic oxygen account for the acute and chronic aspects of radiation injury. Recognized biochemical roles of essential metalloelement-dependent enzymes and the observed pharmacological effects of small-molecular mass chelates predict the therapeutic usefulness of essential metalloelement complexes in decreasing and/or treatment of radiation injury. Copper chelates have radiation protection and radiation recovery activities and cause rapid recovery of immunocompetency and recovery from radiation-induced histopathology. Mice treated with Cu(II)2(3,5-diisopropylsalicylate)4[Cu (II)2(3,5-DIPS)4] had increased survival and corresponding increases in numbers of myeloid and multipotential progenitor cells early after irradiation and earlier recovery of immune reactivity. Examination of radiation-induced histopathology in spleen, bone marrow, thymus, and small intestine also revealed Cu(II)2(3,5-DIPS)4-mediated rapid recovery of radiation-induced histopathology. Most recently, Fe, Mn, and Zn complexes have also been found to prevent death in lethally irradiated mice. These pharmacological effects of essential metalloelement chelates can be understood as due to facilitation of de novo synthesis of essential metalloelement-dependent enzymes which have roles in preventing the accumulation of pathological concentrations of oxygen radicals or repairing biochemical damage caused by radiation-induced bond homolysis. Essential metalloelement chelates offer a physiological approach to prevention and/or treatment of radiation injury.
Animals↗
Purification and characterization of a raw-starch digesting amylase from a soil bacterium--Cytophaga sp.
A newly isolated bacterium from soil, identified as Cytophaga sp. was found to produce raw-starch digesting amylase. The enzyme was purified from 24-hr cultured medium through ammonium sulfate fractionation, DEAE-Sepharose CL 6B ion exchange chromatography and Sephacryl S-200 gel filtration. The preparation was proved to be homogeneous by SDS-PAGE. The subunit molecular weight determined by SDS-PAGE was 59 KD. The optimum temperature was 50 degrees C on soluble starch and 60 degrees C on raw starch. The optimum pH was in the range of 4.5 to 6.5 on soluble starch and 6.5 to 9.5 on raw starch. In the presence of Mn+2, Cu+2 or Zn+2, the enzyme activity on either substrate was inhibited. Dinitrofluorobenzene, N-bromosuccinimide and trinitrobenzene sulfonic acid all showed inhibitory effect on the enzyme acting on both substrates.
Ammonium Sulfate↗
Cutaneous side effects associated with interferon-alpha therapy: a review.
Interferon-alpha is a unique biological protein whose clinical use, both in dermatology and other fields of medicine, has greatly increased over the past several years. We present a review of the cutaneous side effects reported with the use of interferon-alpha.
Antineoplastic Agents↗
Macromolecular adducts: biomarkers for toxicity and carcinogenesis.
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Animals↗
Experimental podophyllotoxin (bajiaolian) poisoning: III. Biochemical bases for toxic effects.
The biochemical mechanism underlying the toxicity of podophyllotoxin is investigated. Previous studies from our laboratories suggested that hepatocytes were extremely sensitive to the toxicity of podophyllotoxin and a disruption of protein synthesis was suspected. Dose-response and time-course studies on the effects of podophyllotoxin on protein. RNA, and DNA syntheses on hepatocellular cultures were made. Inhibitions of protein, RNA, and DNA syntheses were demonstrated, and a direct correlated dose-response relationship on such effects was also evident. Inhibition of protein synthesis appeared to be a direct toxic effect of podophyllotoxin and occurred independently from that of RNA. The reduction of DNA synthesis was reflected by a reduction of H3-thymidine incorporation, which is believed to be the consequence of inhibition on the mitotic activity by podophyllotoxin.
Cells, Cultured↗
Hybridoma stability.
Hybridoma stability issues include mutations, chromosome losses, and the potential effects of process variables on the yield, quality and homogeneity of the Monoclonal Antibody (MAb) product. MAb production by murine hybridomas is typically unstable in the early stages after fusion but repeated cloning normally produces stable clones. The stability of hybridomas and the consistency of the MAbs produced during extended high density perfusion cultures at Xoma Corporation were evaluated. Cell stability was assessed by recovering cells from the bioreactors at different intervals and comparing their growth and product formation kinetics and yields to those of cells started fresh from the corresponding Manufacturer's Working Cell Banks. Product consistency was evaluated in the crude harvests and in the corresponding purified MAb lots by biochemical and functionality tests including: SDS-PAGE (reducing and non-reducing), IEF, HPLC (size exclusion and cation exchange), peptide mapping, N-terminal sequencing, carbohydrate composition and binding assays. Several murine hybridomas were studied during runs lasting several months and found to be stable by all criteria employed. Such results support the viability of extended hollow fiber perfusion cultures for reproducible production of murine MAbs. Selecting stable clones and understanding the effects of process variables on the quantity and quality of the MAbs are keys to controlling hybridoma stability during the manufacturing process.
Animals↗
Differential responses in cyclic GMP formation induced by excitatory amino acids (EAA) and sodium nitroprusside (SNP) in various regions of the brain and of rats of varied age.
1. Sodium nitroprusside (SNP, 100 microM) caused a rapid and great increase of formation of cGMP in rat cerebellar slices. This effect was not blocked by L-NMMA (a NO synthetase inhibitor) or antagonists of the NMDA receptor complex (e.g. AP5 or MK 801). 2. Similarly, NMDA (100 microM) and glutamate (1 mM) caused a rapid but less significant increase of cGMP formation. This increase was blocked by NMDA receptor complex blockers (e.g. AP5, MK801 and kynurenate), and L-NMMA and L-nitroarginine. 3. In rats aged 12 days, both NMDA and kainate (at 100 microM) caused significantly increased levels of cGMP in the cerebellum, pons and medulla areas, whereas no significant alterations were found in the cerebral cortex, hippocampus or midbrain areas. 4. NMDA (100 microM) and SNP (300 microM) induced greater increases of cGMP in cerebellar slices in young (aged 13 days) animals than older ones of either sex. This effect decreased greatly after 35 days of age. In adult (2 months) animals the effect of NMDA had virtually disappeared whereas SNP was barely significantly present. 5. Our results suggest that brain region and age, but not sex, affected formation of cGMP induced by excitatory amino acids (EAA) and SNP. Furthermore, endogenous NO production is required by EAA, but not by SNP, in the formation of cGMP.
Aging↗
A reverse transcriptase-polymerase chain reaction assay for the detection and quantitation of murine retroviruses.
Specific hybridization primers for the PCR assay were developed to detect the presence of the ecotropic, xenotropic, and mink cell focus-forming classes of murine leukemia viruses (MuLVs) in samples derived from cultured cells and cell-free supernatants. The primers, which were tested against reference viruses from all three classes and two subclasses and accurately identified each class present, were used to characterize the endogenous expression of MuLV-related sequences in a number of murine and mink cell lines. Two murine/murine hybridomas were shown to contain expressed retroviral sequences from all three classes. The murine cell lines SC-1, Balb/c 3T3, and NIH 3T3, were found to constitutively express sequences from many of the MuLV classes. These MuLV-related sequences were not expressed in the Mus dunni or mink lung cell lines. When these primers were used in a quantitative PCR assay to determine the retroviral content of hybridoma supernatants, the values were less variable than those obtained by transmission electron microscopy (TEM). This assay can be adapted to detect and quantitate any viral contaminant in cell culture supernatants, ascites fluids, process validation samples, and final products.
3T3 Cells↗
Humoral factors that induce alterations of the pancreas in rats with obstructive jaundice.
This study was conducted to investigate the role of humoral factors in pancreatic alterations induced by obstructive jaundice (OJ) in rats. OJ in male Sprague-Dawley rats induced significant increases in pancreatic weight, DNA content, and RNA content of acinar cells. These changes were accompanied by enlargement of eosinophilic granules and compressed nuclei. Protein, amylase, and trypsinogen contents of pancreas were also increased in OJ rats. In addition, plasma levels of bilirubin, cholecystokinin (CCK), and estradiol increased in OJ rats and were correlated positively with each other and with pancreatic weights. Administration of a specific CCK receptor, L-364,718, to OJ rats partly attenuated the changes of the pancreas, indicating that CCK is involved in these changes. These findings suggest that estradiol may be involved in regulating the pancreatic changes induced by OJ in rats.
Amylases↗
Persistent annular erythema of infancy.
Annular erythema of infancy is an uncommon, nonpruritic, figurate erythema that begins in the first year of life. Biopsy specimens reveal a perivascular and interstitial lymphocytic infiltrate with numerous eosinophils. The cause of the disorder is unknown, but a hypersensitivity response to unrecognized antigens is suspected. The disorder is self-limited, but may last for many months. In our patient the eruption continued 19 months after its onset.
Biopsy↗
Retrieval and amplification of DNA from unstained histopathological sections.
Testing of compounds for carcinogenic potential in vivo involves various experimental designs. A few of these techniques are directed to demonstrate the genotoxicity and mutagenicity of the compound by histopathology. These changes shown by histochemical means include monoclonal antibody directed cellular markers. Development of the polymerase chain reaction technique (PCR) for amplification of DNA has facilitated the investigation of molecular events related to the formation of malignant neoplasms. We describe here a method for screening tissues for mutations of the H-ras gene using monoclonal antibodies directed toward normal and mutant p21 proteins. Formalin-fixed, paraffin-embedded tissue sections are used to subsequently confirm the gene mutation by PCR amplification of the H-ras gene. The results indicated a successful application of this technique to demonstrate the presence of p21 oncoprotein in the tissues tested.
Antibodies, Monoclonal↗
Tissue distribution of [3H]-nicotine in rats.
This study was conducted in adult male Sprague--Dawley rats to determine the distribution of [3H]-nicotine in blood and tissues following a bolus injection and a constant infusion of pure nicotine. The animals were anesthetized and injected with either 0.5 ml of nicotine solution or given a constant infusion of the same nicotine solution with identical amounts of radioactive nicotine. After sacrifice, blood, brain, trachea, salivary gland, esophagus, lung, heart, liver, fundus, antrum, spleen, pancreas, duodenum, jejunum, ileum, cecum, colon, kidneys, adrenal gland, and testes were collected and measured for radioactivity by scintillation counting. The distribution of nicotine was found highest in kidneys by both routes of administration. Higher accumulations were also found in salivary and adrenal glands, fundus, antrum, duodenum, jejunum, ileum and colon. Retention of nicotine via constant infusion was significantly higher in esophagus, fundus antrum, spleen, cecum, pancreas, testes, heart and muscle when compared with bolus injection. Six-fold increase in retention of blood levels of nicotine were found with constant infusion. (P < 0.05). The results indicate that longer retention of nicotine occurs in blood and other specific tissues such as esophagus, fundus, antrum, spleen, cecum, pancreas, testes, heart and muscle via constant exposure. These data may implicate the predisposition of these tissues to pathologic manifestations.
Animals↗
Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes.
An alkaline unwinding assay was used to quantitate the induction of DNA strand breaks (DNA SB) in the livers of rats and mice treated in vivo, in rodent hepatocytes in primary culture, and in CCRF-CEM cells, a human lymphoblastic leukemia cell line, following treatment with tri- (TCA), di- (DCA), and mono- (MCA) chloroacetic acid and their corresponding aldehydes, tri- (chloral hydrate, CH), di- (DCAA) and mono- (CAA) chloroacetaldehyde. None of the chloroacetic acids induced DNA SB in the livers of rats at 4 hr following a single administration of 1-10 mmole/kg. TCA (10 mmole/kg) and DCA (5 and 10 mmole/kg) did produce a small amount of strand breakage in mice (7% at 4 hr) but not at 1 hr. N-nitrosodiethylamine (DENA), an established alkylating agent and a rodent hepatocarcinogen, produced DNA SB in the livers of both species. TCA, DCA, and MCA also failed to induce DNA strand breaks in splenocytes and epithelial cells derived from the stomach and duodenum of mice treated in vivo. None of the three chloroacetaldehydes induced DNA SB in either mouse or rat liver. The continuous exposure of mice to 5 g/L DCA in the drinking water for 7 and 14 days did not induce appreciable hepatic DNA SB (< 10% at 14 days), although peroxisome proliferation, as evidenced by an increased cyanide-insensitive palmitoyl CoA oxidase (PCO) activity, was stimulated to 490% (7 days) and 652% (14 days) of control. Under this protocol, DENA (0.1 g/L) produced DNA damage after both 7 days (73% of control) and 14 days (57% of control). Similarly, long-term exposure of rats (30 weeks) to 2 g/L DCA in the drinking water, a level that increased PCO activity to 364% of the control value, exhibited no DNA damage. Both the chloroacetic acids and the chloroacetaldehydes were ineffective in inducing DNA SB in cultured rat and mouse hepatocytes at concentrations below those that yielded cytotoxicity. The chloroacetic acids were also ineffective in the CCRF-CEM cells. However, two of the chloroaldehydes, DCAA and CAA, did induce DNA SB in the CCRF-CEM cells at concentrations that did not decrease the cell viability after 2 hr of treatment. Prior incubation of DCAA and CAA with a rat S9 liver homogenate eliminated much of the DNA damaging activity. These studies provide further evidence that the chloroacetic acids lack genotoxic activity not only in rodent liver, a tissue in that they induce tumors, but in a variety of other roden tissues and cultured cell types.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetaldehyde↗
Induction of pancreatic acinar pathology via inhalation of nicotine.
This study was conducted to determine the effects of nicotine inhalation on the onset, progression, and sequential development of pancreatic lesions. Male Sprague-Dawley rats in groups of five were exposed to saline or nicotine aerosol twice daily for 15, 30, 45, and 60 min for 21 days. After sacrifice, blood samples were analyzed for plasma levels of nicotine, glucose, gastrin, and cholecystokinin. Pancreatic tissues were examined for pathological lesions. While there were no significant differences in plasma levels of glucose, gastrin, and cholecystokinin in all groups, there was a steady increase in plasma levels of nicotine with increased exposures to nicotine. Histopathological examination of pancreatic tissue revealed definitive pancreatic injuries that also appeared to be directly correlated with increased duration of nicotine exposure. The pathological changes of the pancreas were confined only to acinar cells of the exocrine pancreas. Two main types of cellular changes were observed: cellular swelling/vacuolation and nuclear condensation/cellular pyknosis. Both of these changes indicated tissue injuries in the pancreas. Transformation of the glandular acini to solid masses of epithelial cells was also observed. The results from our present study strongly suggest that the exocrine pancreas is very sensitive and susceptible to nicotine toxicity. Our data further indicate that early morphological changes in the pancreas induced by nicotine may occur without functional or metabolic alterations; however, such changes could occur at a later stage, when tissue and cellular changes become more extensive.
Administration, Inhalation↗
Experimental podophyllotoxin (bajiaolian) poisoning: I. Effects on the nervous system.
Bajiaolian, one of the species in the Mayapple family (Podophyllum pelatum), has been widely used as a traditional Chinese herbal medicine for the remedies of snake bites, general weakness, poisons, condyloma accuminata, lymphadenopathy, and certain tumors in China. In Western medicine, Podophyllum was first used medically as a laxative in the early 19th century. Since 1940, the resin of podophyllum has also been used topically for various skin lesions, such as warts and condyloma. Human poisonings have been reported. An animal model was established to investigate the neurotoxic effects of Bajiaolian. Podophyllotoxin, the major active ingredient in Podophyllum, was injected (ip) to young adult male rats at doses of 0, 5, 10, or 15 mg.kg-1 b.w.. The animals were sacrificed 72 h after injection. Neuronal changes were readily observable in animals treated with 10 or 15 mg.kg-1 of the toxin. Edematous changes of the anterior horn motoneurons were observed in the spinal cord. No neuronal necrosis was found. The type of neuronal swelling is believed to be only a transient change and would probably subside with time if no further assaults occur. More serious and perhaps longer term of changes were found in the dorsal ganglion neurons and the nerve fibers (axons) in the central and peripheral nervous system. Severe depletion of the Nissl substance (RNA/polyribosomes) was observed in the dorsal root ganglion neurons. Alterations in these sensory neurons would give rise to and correlate with the sensory disturbances experienced by the patients. Bodian staining also revealed a dose-related increase in the coarseness (thickness) of the nerve fibers (axons) in the cerebellum, cerebral cortex, brainstem, and spinal cord. This is the first scientific study showing the neurotoxicity of Bajiaolian, a commonly used Chinese herbal medicine. Toxicities on other organ systems by this drug certainly exist. Caution should be exercised in the dispensing and usage of this medicine.
Animals↗
Experimental podophyllotoxin (bajiaolian) poisoning: II. Effects on the liver, intestine, kidney, pancreas and testis.
Young male rats were orally intubated with podophyllotoxin: Group I, control animals, orally fed with vehicle only; Group II, fed with an initial dose of 5 mg.kg-1 b.w., followed by a daily dose of 1.67 mg.kg-1 b.w. for 7d. Group III, fed with an initial dose of 15 mg.kg-1 b.w., followed by a daily dose of 5 mg.kg-1 b.w. for 7d. All animals were sacrificed 72 h after the last dosing. Histopathological examination revealed dose-related fatty change of the liver, atrophy and degenerative changes of the intestinal epithelial linings and testicular seminiferous tubules. Depletion of the pancreatic acinar cell granules was also apparent in the Group III animals. No pathology, however, was observed in the kidneys. The present study demonstrated for the first time degenerative changes in the liver, intestine, testis, and pancreas of animals ingested podophyllotoxin. These pathological changes correlate well with the clinical signs/symptoms of abnormal liver function, abdominal pain and diarrhea, and reduced serum amylase in humans poisoned by podophyllum. Inhibition of protein synthesis and mitosis (disruption of microtubules) are believed to be the underlying mechanisms of these changes observed in the animals intoxicated by podophyllotoxin.
Animals↗
DNA strand breaks induced in cultured human and rodent cells by chlorohydroxyfuranones--mutagens isolated from drinking water.
Chlorohydroxyfuranones, by-products of chlorine disinfection and drinking water contaminants, are shown to produce DNA strand breaks in human and rodent cells. One chlorohydroxyfuranone, 3-chloro-4-dichloromethyl-5-hydroxy-2[5H]-furanone (MX), a potent bacterial mutagen, induces 232 +/- 89 DNA strand breaks.(cell-microM)-1 in human CCRF-CEM cells over a concentration range of 4.4 to 220 microM. This constitutes a DNA damage potency comparable to dimethylsulfate (DMS). By comparison, 3,4-dichloro-5-hydroxy-2[5H]-furanone (MA), another chlorohydroxyfuranone which is approximately four orders of magnitude less mutagenic than MX in Salmonella typhimurium strain TA100, is only about tenfold less potent as an inducer of DNA strand breaks in these cells, i.e., 18.2 +/- 3.1 strand breaks.(cell-microM)-1. The DNA strand-breaking potential of MX is inactivated by prior incubation with a rat liver S9 homogenate. In addition, both chlorohydroxyfuranones are ineffective at producing DNA strand breaks in primary rate hepatocytes (PRH) at concentrations below those which produce cytotoxicity as assessed by release of the cellular enzyme lactate dehydrogenase (LDH). Prior treatment of the PRH with 750 microM diethyl maleate, a glutathione-depleting agent, did not enhance the cytotoxicity nor the DNA strand-breaking potential of either chlorohydroxyfuranone. This could indicate that glutathione-glutathione-S-transferase is not an important mechanism for the detoxification of these compounds in PRH.
Animals↗