Biomedical subjects
Publications and source records attributed to Z X Chen.
During our screening program for natural product drugs effective against multidrug-resistant mammalian cells, we have discovered a new delta lactone FD-211 from the fermantation broth of Myceliophthora lutea TF-0409. FD-211 had a broad spectrum activity against cultured tumor cell lines, including adriamycin-resistant HL-60 cells.
Wu Lin powder (WLP) is a prescription that causes urination to remove dampness. In order to elucidate its mechanism of action, the effect of WLP on atrial natriuretic factor (ANF) was observed. The results showed that the level of ANF was significantly higher in the plasma of mice after giving WLP as well as giving Alisma orientalis or Cinnamomum cassia orally, compared with control, P < 0.05, 0.01 and 0.001 respectively. The effect was most evident at 45 minute after giving WLP (P < 0.05). It is suggested that ANF might play an important role in therapeutic action of WLP.
Retinoids, including retinoic acid (RA), are naturally occurring and synthetic analogs of vitamin A that inhibit cell growth and induce cell differentiation in many experimental tumor models. Differentiation of the human myelogenous leukemia cell line HL-60 by RA led to the finding that cells from patients with acute promyelocytic leukemia (APL) are terminally differentiated by RA. One mechanism for the activity of RA in a variety of cell types involves the RA nuclear receptors (RA receptors [RARs] and retinoid X receptors), which have specific high-affinity binding sites for RA and some of its metabolites. Other mechanisms may also be involved in RA-induced differentiation. Recent studies suggest that RA acylation (retinoylation) may be involved in the RA induction of differentiation in leukemia cells. Combinations of RA with cyclic adenosine monophosphate (cAMP)-elevating agents led to synergistically induced differentiation of HL-60 cells. The lower doses of RA needed in combination therapy are unlikely to lead to RA resistance, a major limitation of RA therapy in APL. In vitro studies suggest that combinations of RA with either PGE or the butyric acid (BA) prodrug tributyrin (TB) may be useful in differentiation therapy for APL and other malignancies. This is a US government work. There are no restrictions on its use.
The gingiva samples were obtained from 40 patients with chronic periodontitis after flap operation and 20 cases having healthy gingiva after ectopic wisdom tooth extraction. We investigated the oxytalan fibers by light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). The results demonstrated that under normal conditions numerous oxytalan fibers were widely and evenly distributed throughout the periodontal tissues. There was marked degeneration of the oxytalan fibers in chronic peridontitis. The predominant features were disintegration, fragmentation or disappearance of the oxytalan fibers under the basement membrane. Around the blood vessels, the oxytalan fibers decreased in density with fragmentation of the fibers and sometimes they disappeared almost completely. These results indicated that degeneration and destruction of the oxytalan fibers were closely correlated with the chronic periodontitis process, leading to reduced function occlusion of teeth.
All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL. Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA.(ABSTRACT TRUNCATED AT 250 WORDS)
The zero-order derivative absorption spectra of aspirin, paracetamol and caffeine are closely overlapping. In this paper, a zero-crossing derivative spectrophotometry combined with simultaneous equations is proposed for the determination of the three components in a mixture without the need of prior separation. Satisfactory results were obtained. The method is reproducible, accurate and rapid. Calculation is not complicated. This method could be applied to biological fluid analysis.
Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.
Photosynthesis-deficient mutant 45-3B of the green alga Chlamydomonas reinhardtii contains a chloroplast mutation that causes valine-331 to be replaced by alanine within the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. This amino acid substitution occurs in loop 6 of the alpha/beta-barrel active site, three residues distant from catalytic lysine-334. The mutation reduces the specific activity of the enzyme and also reduces its CO2/O2 specificity factor by 42%, but the amount of holoenzyme is unaffected. In a previous study, an intragenic-suppressor mutation, named S40-9D, was selected that causes threonine-342 to be replaced by isoleucine, thereby increasing the CO2/O2 specificity of the mutant enzyme by 36%. To determine which other residues might be able to complement the original mutation, nine additional genetically independent revertants have now been analyzed. Another intragenic suppressor, represented by mutation S61-2J, causes glycine-344 to be replaced by serine. This change increases the CO2/O2 specificity of the mutant enzyme by 25%. Of the revertants recovered and analyzed, the mutant enzyme was improved only due to true reversion or by intragenic suppression mediated by substitutions at residues 342 or 344. Changes in the physical properties of the two pairs of complementing substitutions indicate that steric effects within loop 6 are responsible for the observed changes in the CO2/O2 specificity of the enzyme.
1. Effects of oral administration of synthetic tetrandrine (TD) derivatives (20 mg/kg per day) for 9 weeks on blood pressure, heart rate, plasma renin concentration (PRC) and vascular reactivities to pressor substances were studied in spontaneously hypertensive (SHR) rats. 2. 7-O-Ethyl fangchinolin (7-O-EFC) and 7-O-isopropyl fangchinolin (7-O-IFC) produced a significant and sustained reduction in blood pressure from the first week of administration. 7-O-EFC reduced heart rate when determined under restraint conditions, but not under unanesthetized, freely moving conditions. 3. TD derivatives produced no effect on PRC. 4. Pressor response to phenylephrine was reduced significantly whereas the response to angiotensin II was enhanced after prolonged administration of 7-O-EFC and 7-O-IFC. 5. These results demonstrate that TD derivatives are potential antihypertensive drugs, and that attenuation of the pressor response to phenylephrine may contribute at least in part to its antihypertensive effect.
Proteolytic enzymes from the organism Porphyromonas gingivalis are believed to be involved in the development of periodontitis. Studies on both crude extracts and purified trypsinlike enzymes from this organism indicate that substantial stimulation of both amidase and proteinase activities can be obtained during incubation with glycine-containing compounds. We postulate that P. gingivalis may have developed this unusual property to take advantage of the glycine-rich environment which occurs during the periodontitis-associated degradation of gingival collagen. The finding of such a stimulation in crevicular fluids from discrete periodontal sites has been correlated with the presence of P. gingivalis and could be utilized for the early detection of infection by this organism during the onset of periodontitis.
The function of the microtubules (MTs) beneath the postsynaptic membrane was studied in the isolated non-uniform stretched muscle preparation of rat diaphragm with the use of colchicine. After exposure to this drug, the amplitude of miniature endplate potential (MEPP), the mean quantal contents and mean amplitude of endplate potentials (EPPs) elicited by 10 Hz and 50 Hz stimulation and the amplitude of acetylcholine potentials (AChP) were decreased significantly, but the frequency of MEPP, membrane potential and the time course of EPP and AChP remained unchanged. These results indicate that colchicine suppresses the responses of acetylcholine receptors (AChR). No such effects were observed with colchicine's isomer lumicolchicine. It is suggested that the MTs beneath the postsynaptic membrane may be involved in the responsive process of AChR.
A completely serum-free culture system for L-CFU assay in vitro on 5 cases of acute non-lymphocytic leukemia (ANLL) is reported. Several agents were tested for the requirement of L-CFU assay in order to substitute the animal or human serum in the conventional culture medium. The results showed that fraction V of bovine serum albumin (2 x 10(-4) mol/L), iron saturated human transferrin (400 micrograms/ml), insulin (1 U/ml), and cholesterol (20 micrograms/ml) were indispensible components for the growth of ANLL L-CFU. Colonies of larger size could be obtained by adding 2-mercaptoethanol. HTB9-CM as the source of growth stimulating factor was used in all experiments. This method is useful for the study of L-CFU proliferation regulated by the human hemopoietic growth factors and the standardization of L-CFU assay.
Modulation of a number of protooncogene expression occurs during differentiation of eukaryotes. Changes in expression of c-myb and c-myc during the HMBA-induced terminal differentiation of murine erythroleukemia cells were characterized by an early decrease (within 4 hrs), followed by the recovery of c-myc mRNA by 10 hrs, and the retention of suppression of c-myb expression for the rest of the induction period. Two MELC variants were used to further define the relationship between the differentiation and the protooncogene expression. R1 was a MELC variant completely resistant to HMBA, and R1 (VCR), a vincristine resistant R1, became inducible by HMBA again. The cell differentiation and the c-myb and c-myc expression were determined on R1 or R1 (VCR) cultured with HMBA respectively. The results demonstrated that the c-myc mRNA increased and remained relatively high as the cells grew to a saturated density regardless of the induction of differentiation. The R1 (VCR) cultured with HMBA displayed an early decrease in c-myb mRNA and a subsequent suppression of its expression, while the R1 cultured with HMBA showed a stable level of c-myb mRNA. These results suggest that the c-myb expression, rather than c-myc expression, is closely related to the HMBA-induced terminal differentiation.
Suppressive effect on tumor cells of high energy shock waves (HESW) has aroused the interest of physicians in recent years. We assessed experimentally the cytotoxic effects of HESW on tumor cells both in vitro and in vivo and determined whether a Chinese domestic lithotriptor is capable of generating effective HESW, which has the potential to break tumor cells, reduce cell viability, retard cell growth, delay doubling time, impair cell attachment and cell clonogenicity. In nude rats, HESW was able to delay tumor growth and reduce tumor size without evidence of metastasis. The nature of HESW in the induction of cell damage and its clinical application need to be further investigated.
The in vitro differentiation of cultured primary bone marrow cells from patients with acute promyelocytic leukemia (M3) and chronic myelocytic leukemia (CML) induced by retinoic acid (RA) and TPA was studied. The results indicated that both the M3 and CML bone marrow cells bipotently differentiated into either myeloid or macrophage-monocytic lineage in response to the inducers. On M3 cells the effect of TPA was more potent than RA, and TPA could inhibit the phenotype of myeloid terminal differentiation induced by RA but not vice versa. However, RA could overcome the TPA-induced inhibition of myeloid terminal differentiation of CML cells. These experiments provide a useful model for studying the molecular mechanism of hematopoietic cell differentiation.
The Chlamydomonas reinhardtii temperature-sensitive mutant 68-4PP results from a mutation within the chloroplast gene that encodes the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. When grown at the permissive temperature (25 degrees C), the mutant has a reduced level of holoenzyme protein, and the purified enzyme has a lower CO2/O2 specificity than the wild-type enzyme. At the nonpermissive temperature (35 degrees C), the holoenzyme level is greatly reduced, and the mutant is unable to grow photosynthetically. When photosynthesis-competent revertants of 68-4PP were selected at 35 degrees C, a nuclear mutation was identified that suppresses the temperature-sensitive phenotype by enhancing both the activity and amount of the mutant enzyme. More significantly, the reduced CO2/O2 specificity of the 68-4PP enzyme is restored to the wild-type value. However, the nuclear suppressor mutation alone does not produce a phenotype different from wild type, and the CO2/O2 specificity of the suppressor strain's enzyme is normal. We have cloned and completely sequenced the two small-subunit genes from the suppressor strain, but no mutation has been found. These results suggest that some other nuclear-encoded protein is able to influence the structure of the holoenzyme, which in turn influences the CO2/O2 specificity factor.
1. Structure and hypotensive activity relationships of tetrandrine (TD), an alkaloid isolated from the Chinese herb Radix stephaniae tetrandrae and its derivatives were investigated in conscious stroke-prone spontaneously hypertensive rats (SHRSP). 2. Derivatives substituted at the 7-O position with various types of alkyl group produced varying degrees of hypotensive effect. 3. While the demethylated derivative, fangchinoline (FC), and its acetylated compound had no effect on blood pressure, 7-O-methyl FC (TD), and 7-O-ethyl and 7-O-isopropyl FC at oral doses of 25 and 50 mg/kg produced a gradual and sustained hypotensive effect without any significant effects on heart rate and plasma renin concentration. 4. Substitution at the 7-O position with longer side chains such as n-propyl, n-butyl and n-pentyl groups reduced both the degree and duration of hypotensive activity. 5. Substitution of N-methyl groups at the 2 and 2' positions with quaternary ammonium or N-oxide attenuated the hypotensive activity. 6. The results of this study suggest a possibility that 7-O-ethyl and 7-O-isopropyl derivatives as well as TD can be considered as potential antihypertensive drugs because of the gradual onset and long duration of their hypotensive action in SHRSP.
Gossypol acetic acid was administered orally to 35 male volunteers at a dose of 20 mg once a day for 52-70 days in the loading phase and twice a week for 22 months in the maintenance phase. Sperm counts and the serum concentrations of LH, FSH, prolactin, testosterone and oestradiol were monitored regularly during treatment and for a follow-up period of 12 months. At around 90 days after treatment, all treated participants approached or attained azoospermia and remained at this level throughout the maintenance phase. By the end of the follow-up phase, eight treated men were still azoospermic, while sperm counts in the other 27 men were restored to normal levels. The only hormone that changed significantly during and after the treatment was FSH. From the 6th month of the treatment to the end of the follow-up phase, serum concentrations of FSH in the eight participants that reached irreversible azoospermia were significantly higher than in the other 27 men or in controls. It is suggested that monitoring of FSH levels might be of diagnostic use for identifying those participants with irreversible azoospermia during gossypol treatment.