Biomedical subjects

M Baba

Publications and source records attributed to M Baba.

At least 127 records · Page 7Linked to original sources

PubMed1999

Effects of aging on central conduction in somatosensory evoked potentials: evaluation of onset versus peak methods.

OBJECTIVES: To investigate effects of aging on peripheral and central somatosensory conduction, and evaluate onset-to-onset and peak-to-peak measurements of each component and central conduction time (CCT) in somatosensory evoked potentials (SEPs). METHODS: We recorded SEPs with non-cephalic reference from the Erb's point, the posterior (cv 6) and anterior neck, and scalp (Fz and P4) after left median nerve stimulation in 138 normal subjects aged between 20 and 78 years. We determined onset or peak latencies of the Erb's potential (N9), the spinal N13-P13 in cv 6-to-anterior neck montage and the N20-P20 in scalp leads. Onset CCT was defined as a transit time from N13-P13 onset to N20-P20 onset. In each subject, interpeak latencies of the 'N13' component in cv 6-to-Fz montage and the N20-P20 in P4-to-Fz montage were also defined as conventional peak CCT. RESULTS: Using multiregression analysis, we found that the onset or peak latencies of each SEP component were correlated with the subject's height and age. So were the onset CCTs: Onset CCT (in ms) = 2.549+2.041x(height in meters) + 0.005 x (age in years) (P<0.0001). The conventional peak CCTs as well as onset-to-peak durations of the N20-P20 were correlated with the subject's age but not height: Peak CCT(in ms) = 5.458+0.012x (age in years) (P<0.0005). CONCLUSION: Conductive function is affected by normal aging in the central as well as peripheral somatosensory pathways. The peak CCT is more affected by aging than the onset CCT. However, the onset-to-peak duration of the N20-P20 increased by 0.8 ms between the 4th and 7th decades, suggesting that the peak CCT increase in older people reflects the age-related changes in N20-P20 profile but not in the fastest central conduction. We therefore conclude that the onset CCT measurement is preferable to the peak CCT measurement when assessing the central somatosensory conduction.

Adult↗

PubMed1999

Attenuation by all-trans-retinoic acid of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effect of prolonged administration of all-trans-retinoic acid (RA) on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labelling and apoptotic indices and immunoreactivity of transforming growth factor (TGF) alpha in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and subcutaneous injections of RA at doses of 0.75 or 1.5 mg kg(-1) body weight every other day. In week 52, oral supplementation with sodium chloride significantly increased the incidence of gastric cancers compared with the untreated controls. Long-term administration of RA at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral administration of sodium chloride. RA at both doses significantly decreased the labelling index and TGF-alpha immunoreactivity of gastric cancers, which were enhanced by administration of sodium chloride, and significantly increased the apoptotic index of cancers, which was lowered by administration of sodium chloride. These findings suggest that RA attenuates gastric carcinogenesis, enhanced by sodium chloride, by increasing apoptosis, decreasing DNA synthesis, and reducing TGF-alpha expression in gastric cancers.

Adenocarcinoma↗

PubMed1999

High prevalence of sensitization to cat allergen among Japanese children with asthma, living without cats.

BACKGROUND: Cat allergy is common among children with asthma. Many cat-allergic patients in Japan and elsewhere do not keep cats, but nonetheless become sensitized through environmental exposure to cat allergen. OBJECTIVE: To assess the frequency of cat allergy and cat-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) antibody responses in young Japanese patients with asthma in relation to self-reported cat exposure and Fel d 1 levels in dust samples. METHODS: Cat dander-specific IgE antibody was measured in sera from asthma patients using the CAP system. IgE and IgG antibody to Fel d 1 was measured by antigen binding radioimmunoassay and by chimeric enzyme immunoassay. Fel d 1 levels in dust samples from a subset of patients' homes were measured by monoclonal antibody-based enzyme immunoassay. RESULTS: Cat-specific IgE (CAP class>/=2) was found in sera from 70% of 44 patients who kept cats and 34% of 394 patients who had never kept cats. The prevalence of sensitization increased progressively to age 6 years (40%: positive), and then increased gradually to age 16 years (approximately 60%: positive) in patients who had never kept cats. There was an excellent correlation between cat CAP values and IgE levels to Fel d 1. The absolute amount of IgE antibody to Fel d 1 ranged from 0.01 to 15.6% of total IgE. Most patients who did not keep cats were exposed to Fel d 1 levels ranging from 0.07-8 microg/g dust. CONCLUSIONS: Sensitization to cat allergen is common among young asthmatic patients in Japan, even among patients who do not keep cats. Use of CAP and the chimeric enzyme-linked immunosorbent assay allows accurate diagnosis of cat allergy and quantification of specific IgE antibody levels.

Adolescent↗

PubMed1999

Reversible F-wave hyperexcitability associated with antibodies to potassium channels in Isaacs' syndrome.

We report a case of Isaacs' syndrome showing F-wave hyperexcitability which was reversible after either epidural block or plasmapheresis. A 14-year-old girl with progressive muscle cramp and myokymia in the legs showed high amplitude, long duration, polyphasic F-waves after either tibial nerve or peroneal nerve stimulation. Potassium current of PC-12 cell membrane was suppressed by her serum, IgM of which strongly reacted with proteins of approximately 50 kDa of the lysates of a PC-12 cell line. After an epidural nerve block with 1 per cent lidocaine 10 ml, the myokymia temporally improved, during which time the hyperexcitable F-waves became normalized. We treated her with double filtration plasmapheresis, which resulted in remarkable improvement of myokymia; simultaneously, the abnormal F-waves showed a decrease in amplitude, duration, and in the number of phases. We concluded that there was hyperexcitability of the proximal site of motor fibers in our patient, and possible immune mechanisms gave rise to the myokymia and unusual F-wave features.

Adolescent↗

PubMed1999

Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells.

NF-kappaB is a potent cellular activator of HIV-1 gene expression. Down-regulation of NF-kappaB activation is known to inhibit HIV replication from the latently infected cells. Gold compounds have been effectively used for many decades in the treatment of rheumatoid arthritis. We previously reported that gold compounds, especially aurothioglucose (AuTG) containing monovalent gold ion, inhibited the DNA-binding of NF-kappaB in vitro. In this report we have examined the efficacy of the gold compound AuTG as an inhibitor of HIV replication in latently infected OM10.1 and Ach2 cells. Tumor necrosis factor (TNF)-alpha-induced HIV-1 replication in OM10.1 or Ach2 cells was significantly inhibited by non-cytotoxic doses of AuTG (>10 microM in OM10.1 cells and >25 F.M in Ach2 cells), while 25 microM of the counter-anion thioglucose (TG) or gold compound containing divalent gold ion, HAuCl3, had no effect. The effect of AuTG on NF-kappaB-dependent gene expression was confirmed by a transient CAT assay. Specific staining as well as electron microscopic examinations revealed the accumulation of metal gold in the cells, supporting our previous hypothesis that gold ions could block NF-kappaB-DNA binding by a redox mechanism. These observations indicate that the monovalent gold compound AuTG is a potentially useful drug for the treatment of patients infected with HIV.

Anti-HIV Agents↗

PubMed1999

IgG1 production by sIgD+ splenic B cells and peritoneal B-1 cells in response to IL-5 and CD38 ligation.

CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induces proliferation, IL-5 receptor alpha chain expression and tyrosine phosphorylation of Bruton's tyrosine kinase. Furthermore, stimulation of splenic B cells with IL-5 together with CS/2 induces Blimp-1 expression and differentiation into Ig-producing cells. Here we examined the role of IL-5 in IgG1 and IgA production by B cells isolated from the spleen and peritoneal cavity. CD38 recognized by CS/2 was expressed in the follicular mantle B cells surrounding the germinal center, sIgD+ splenic B cells and peritoneal B cells. IL-5 induced IgG1 production in splenic sIgD+ B cells stimulated with CS/2, while it was ineffective to induce IgA production. Among the various cytokines tested, only IL-5 had a synergistic effect on IgG1 production with CS/2. IL-5 could induce the generation of S micro-Sgamma1 reciprocal recombination DNA products in CS/2-stimulated B cells. IL-4 was ineffective to induce either micro-gamma1 switch recombination or IgG1 secretion with CS/2, demonstrating that IL-5 promotes both micro-gamma1 switch recombination and IgG1 secretion in an IL-4-independent manner. The peritoneal B-2 cells exhibited both IgG1 and IgA production in response to IL-5 plus CS/2, while B-1 cells produced IgG1. These results imply that the pattern of differentiation to Ig-producing cells seen with peritoneal B cells is not identical to the pattern seen with splenic B cells and that peritoneal B-2 cells contain precursors of IgA-producing cells responding to IL-5 plus CS/2.

ADP-ribosyl Cyclase↗

PubMed1999

How the lymph node metastases toward cervico-upper mediastinal region affect the outcome of patients with carcinoma of the thoracic esophagus.

BACKGROUND: The aim of this study was to establish whether the site of lymph node metastasis influences the survival of patients with carcinoma of the thoracic esophagus. METHODS: A series of 159 patients with lymph node metastasis who underwent right transthoracic R0 esophagectomy was analyzed retrospectively. Sites of the nodal metastasis were divided into two regions; the neck and/or upper mediastinum above (upward metastasis) and the abdomen and/or lower mediastinum below (downward metastasis) the tracheal carina. RESULTS: Univariate analysis of prognostic factors revealed the tumor location, distant lymphatic metastasis, number of metastatic nodes and upward metastasis influenced survival, but downward metastasis did not. Multivariate analysis showed that the number of metastatic nodes and upward metastasis were also significant prognostic factors. Thirty-one (33.3%) of the 93 patients with, but only 6 (9.1%) without, upward metastasis had recurrences in the neck and/or upper mediastinum (P = 0.0002). Eighteen (60.0%) of the 30 patients with extranodal invasion in the neck and/or upper mediastinum had recurrence in these regions. CONCLUSIONS: Nodal metastasis in the neck and/or upper mediastinum was a significant risk factor for prognosis, the same as the number of metastatic nodes.

Esophageal Neoplasms↗

PubMed1999

Assessment of cervical lymph node metastasis in esophageal carcinoma using ultrasonography.

OBJECTIVE: To evaluate the efficacy of ultrasonography for the diagnosis of cervical lymph node metastasis in esophageal carcinoma. SUMMARY BACKGROUND DATA: Ultrasound (US) examination is useful for diagnosing lymph node metastasis. However, few reports have examined its role in the decision to perform cervical lymph node dissection in esophageal carcinoma. METHODS: Ultrasound examination was performed to evaluate cervical lymph node metastasis in 519 patients with esophageal carcinoma. The patients were divided into 5 groups according to treatment received: group 1, 153 patients who underwent curative resection of primary tumor by right thoracotomy and complete bilateral cervical lymphadenectomy; group 2, 112 patients who underwent curative resection of primary tumor by right thoracotomy but without cervical lymphadenectomy; group 3, 78 patients who underwent esophagectomy by left thoracotomy or blunt dissection with or without removal of cervical lymph nodes; group 4, 76 patients with palliative resection without cervical lymphadenectomy; and group 5, 100 patients without any surgical treatment. US diagnosis was compared with histologic findings or cervical lymph node recurrence. RESULTS: Lymph node metastasis was detected in 30.8% of patients (160/519). The sensitivity, specificity, and accuracy of US diagnosis in group 1 were 74.5%, 94.1%, and 87.6%, respectively. Cervical lymph node recurrence was seen in 7 patients (4.6%) in group 1, in 4 patients (3.6%) in group 2, and 3 patients (3.8%) in group 3. Although the incidence of cervical lymph node metastasis as determined by US examination was high in groups 4 and 5, almost none of the patients died of cervical lymph node metastasis. CONCLUSIONS: Ultrasound examination plays a useful role in the decision to perform cervical lymph node dissection in patients with esophageal carcinoma, particularly in those with potentially curative dissection.

Esophageal Neoplasms↗

PubMed1999

Significance of anaerobic preincubation of Helicobacter pylori for measuring metronidazole susceptibility by the Etest.

The Etest is widely used for measuring the susceptibility of Helicobacter pylori to metronidazole. By using 55 H. pylori isolates from 55 patients and a standard H. pylori strain, NCTC11637, we compared metronidazole susceptibility results obtained from the Etest with or without anaerobic preincubation to those obtained from the agar dilution method. Mueller Hinton agar plates supplemented with 5% horse blood were used for both methods. For the Etest, plates were incubated for 72 hr at 35 C under microaerophilic conditions after 0-, 4- or 24-hr periods of anaerobic preincubation. For the agar dilution method, the plates were incubated at the same microaerophilic conditions as those for the Etest. Without anaerobic preincubation for the Etest, 39 of the 56 (70%) H. pylori isolates were categorized as resistant to metronidazole (minimal inhibitory concentration>8 mg/liter), whereas only one of the 56 (1.8%) isolates was resistant according to the agar dilution method. The resistant and susceptible agreement rate was 32%. Four-hour anaerobic preincubation did not alter the readings of the Etest significantly. However, when the Etest was performed with 24-hr anaerobic preincubation, the number of isolates categorized as resistant was reduced to six (11%), improving the agreement rate to 91%. For measuring the metronidazole susceptibility of H. pylori by the Etest, 24-hr anaerobic preincubation is necessary to agree with the results obtained by the agar dilution test.

Anaerobiosis↗

PubMed1999

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Aminobiphenyl Compounds↗

PubMed1999

Therapeutic effect of 1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyridine-1 M potassium oxonate (S-1) on liver metastasis of xenotransplanted human colon carcinoma.

S-1 [1 M tegafur (FT)-0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP)-1 M potassium oxonate (Oxo)], was developed as a new oral antineoplastic agent based on biochemical modulation of fluorouracil (5-FU) by CDHP and Oxo. The therapeutic effect of S-1 on human colon cancer xenografts (TK-13) with high metastatic potential to the liver was evaluated. Small pieces of TK-13 were sutured into the cecal wall of 52 nude mice, and the animals were randomly divided into 3 groups [control (n=17), UFT (combination of 1 M FT and 4 M uracil) (n=18) and S-1 (n=17)]. S-1 or UFT was administered orally at an equitoxic dose (S-1, 7.5 mg/kg; UFT, 17.5 mg/kg as FT) for 37 consecutive days beginning 10 days after the transplantation. S-1 showed higher tumor growth inhibition than UFT (P<0.05) and also showed a significant anti-metastatic effect on liver metastasis, while UFT did not. Liver metastasis developed in only 2 of the 17 mice (12%) in the S-1 group, whereas it developed in 9 of the 17 (53%) and 7 of the 18 (39%) in the control and UFT group, respectively. Analysis of AUC (area under the curve) revealed that S-1 yielded higher 5-FU levels in both tumor tissue (1.6 times) and plasma (2.5 times) than UFT. These results suggest that S-1 will show a higher clinical therapeutic effect against human colorectal cancer than UFT.

Animals↗

PubMed1999

Antitumor effect on human gastric cancer and induction of apoptosis by vascular endothelial growth factor neutralizing antibody.

Induction of apoptosis by antiangiogenic therapy has been suggested as a new anticancer strategy. To clarify the mechanism of the antitumor effect achieved by inhibition of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis, we used an orthotopic transplantation model of human gastric carcinoma line (MT2) treated with a monoclonal VEGF neutralizing antibody (VEGF Ab). We histologically examined the microvessel density (MVD) and the apoptotic index (AI) in this model. Transplanted tumor growth was significantly inhibited by the VEGF Ab (P = 0.03), and there was a significant decrease in the number of mice with liver metastasis (P = 0.004). The MVD detected by immunohistochemical staining with ER-MP12 antibody was 33.6 +/- 8.0 in the control group and 21.1 +/- 5.4 in the treated group, and the difference was significant (P < 0.0001). The AI values of the control and treated groups were 4.73 +/- 1.11 and 7.26 +/- 1.62, respectively, and this difference is also significant (P < 0.0001). However, the expression of VEGF mRNA in transplanted tumors did not show a significant difference between the control and treated groups. These results suggest that the antitumor effect of the VEGF Ab on human gastric carcinoma is exerted by inducing mild hypoxia followed by apoptosis, which does not influence VEGF mRNA expression in the carcinoma.

Adenocarcinoma↗

PubMed1999

Increase in apoptosis and decrease in ornithine decarboxylase activity of the gastric mucosa in patients with atrophic gastritis and gastric ulcer after successful eradication of Helicobacter pylori.

OBJECTIVE: Recent reports have shown that patients infected with Helicobacter pylori (H. pylori) have a higher risk of gastric cancer. However, the mechanism of this increased risk is still unclear. In the gastric mucosa, the size of a continuously renewed population of cells is determined by the rates of cell production and of cell loss. Ornithine decarboxylase (ODC) activity is elevated in various gastrointestinal cancers and serves as a marker of mucosal proliferative activity. Apoptosis occurs throughout the gut and is associated with cell loss. Both cell proliferation and cell loss have important roles in H. pylori-associated gastric carcinogenesis. Therefore, we investigated the effect of H. pylori eradication on ODC activity and apoptosis in the gastric mucosa of patients with atrophic gastritis and gastric ulcers. METHODS: Biopsy specimens of the gastric antrum were obtained at endoscopy from 17 H. pylori-positive gastric ulcers patients and 15 H. pylori-positive gastritis patients before and 4 wk after eradication therapy with amoxicillin, omeprazole, and a new anti-ulcer agent, ecabet sodium, and from 10 gastric ulcer patients in whom ulcer healed but H. pylori was left untreated. ODC activity and induction of apoptosis were determined immunohistochemically. RESULTS: H. pylori was successfully eradicated with the triple therapy in 12 (80%) of 15 gastritis patients and 13 (76%) of 17 gastric ulcer patients. ODC activity was present in the gastric mucosa in 21 (84%) patients before eradication but in only four (16%) patients after successful eradication (p = 0.0005). The apoptotic index increased significantly (p = 0.0006) from 4.2% +/- 0.4% before treatment to 7.4% +/- 0.5% after successful eradication. CONCLUSIONS: Successful eradication of H. pylori decreases mucosal ODC activity and increases apoptosis in the gastric mucosa. These findings indicate that by decreasing mucosal cell proliferation and increasing epithelial cell loss, H. pylori eradication may help decrease the subsequent risk of gastric cancer.

Adult↗

PubMed1999

Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations.

OBJECTIVE: Telomerase activity is reported to be specific and very frequent in human malignancy. K-ras mutations are also very frequently detected in pancreatic cancer, but their specificity for pancreatic cancer is controversial. We examined the telomerase activity and K-ras mutations in pancreatic juice from patients with pancreatic disease. METHODS: Pancreatic juice was obtained endoscopically at endoscopic retrograde pancreatography from 10 patients with pancreatic cancer, three with chronic pancreatitis, and three with a normal pancreas. The telomerase activity in pancreatic juice was assayed by telomeric repeat amplification protocol. K-ras mutations in exon 1 codon 12 were examined by the two-step polymerase chain reaction combined with restriction enzyme digestion, followed by single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Telomerase activity of >5.0 was detected in eight of 10 (80%) subjects with pancreatic cancer, but in none with chronic pancreatitis or normal pancreas. K-ras mutations were detected not only in eight of 10 (80%) subjects with pancreatic cancer but also in two of three with chronic pancreatitis and in one of three with a normal pancreas. CONCLUSIONS: It was shown that the detection of telomerase activity in pancreatic juice is a more useful diagnostic tool for pancreatic cancer than that of K-ras mutations.

Aged↗

PubMed1999

Inhibition of human immunodeficiency virus type 1 replication in acutely and chronically infected cells by EM2487, a novel substance produced by a Streptomyces species.

In a search for effective HIV-1 transcription inhibitors, we have evaluated more than 75,000 compounds for their inhibitory effects on Tat-induced human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven reporter gene expression and found that EM2487, a novel small-molecule substance produced by a Streptomyces species, is a potent and selective inhibitor of HIV-1 replication in both acutely and chronically infected cells. Its 50% effective concentration for acute HIV-1 infection was 0.27 microM in peripheral blood mononuclear cells (PBMCs), while the 50% cytotoxic concentration for mock-infected PBMCs was 13.3 microM. EM2487 proved inhibitory to a variety of HIV-1 strains and HIV-2 in acutely infected T-cell lines (MOLT-4 and MT-4). The compound could suppress tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 production in latently infected cells (OM-10.1 and ACH-2) as well as constitutive viral production in chronically infected cells (MOLT-4/III(B) and U937/III(B)) without showing any cytotoxicity. EM2487 did not affect early events of the HIV-1 replication cycle, as determined by proviral DNA synthesis in acutely infected MOLT-4 cells. In contrast, the compound selectively prevented viral mRNA synthesis in OM-10.1 cells, suggesting that HIV-1 inhibition occurs at the transcriptional level. Furthermore, EM2487 did not inhibit TNF-alpha-induced HIV-1 LTR-driven reporter gene expression but did inhibit that induced by Tat, irrespective of the presence or absence of the nuclear factor kappaB binding sites in the LTR. These results suggest that the mechanism of action is attributable in part to the inhibition of Tat function.

Anti-HIV Agents↗

PubMed1999

Inhibition of human immunodeficiency virus type 1 replication by combination of transcription inhibitor K-12 and other antiretroviral agents in acutely and chronically infected cells.

8-Difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyp hen yl)-1- piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor kappa B inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.

Alkaloids↗

PubMed1999

Marked suppression of T cells by a benzothiophene derivative in patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

In a search for new anti-autoimmune agents that selectively suppress activation of autoreactive T cells, one such agent, 5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (CI-959-A), was found to be effective. This compound, which is known to suppress tumor necrosis factor alpha (TNF-alpha)-induced CD54 expression, inhibited the primary proliferative response of the T cell to antigen (Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs), autologous Epstein-Barr virus-infected B cells, and human T lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T cells from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their activation is reported to be associated with CD54 expression. The spontaneous proliferation of T cells from patients with HAM/TSP was entirely blocked by CI-959-A. However, in this study, the T-cell proliferation in 15 patients with HAM/TSP was found to depend more extensively on major histocompatibility complex (MHC) class II and CD86 than on CD54 Ags. Since most important APCs for the development of HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on DC generation and on the expression of surface molecules on activated T cells is examined. CI-959-A suppressed recombinant granulocyte-macrophage colony stimulating factor (GM-CSF)- and recombinant interleukin-4-dependent differentiation of DCs from monocytes and inhibited the expression of CD54 and, more extensively, MHC class II and CD86 Ags. CI-959-A showed little toxicity toward lymphoma or HTLV-I-infected T-cell lines or toward monocytes and cultured DCs. These results suggest that CI-959-A might be a potent anti-HAM/TSP agent.

Adult↗

PubMed1999

T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure.

T22, an analog of polyphemusin II (18 amino acid residues), was found to block T-tropic human immunodeficiency virus type 1 (HIV-1) entry into target cells as a CXCR4 inhibitor. We synthesized T134, a small analog (14 amino acid residues) of T22 with reduced positive charges. T134 exhibited highly potent activity and significantly less cytotoxicity in comparison to that of T22. T134 prevents the anti-CXCR4 monoclonal antibody from binding to peripheral blood mononuclear cells but has no effect on the binding of anti-CCR5 monoclonal antibodies. Since T134 inhibits the binding of stromal cell-derived factor-1 (SDF-1) to MT-4 cells, it seems that T134 prevents HIV-1 entry by binding to CXCR4. The bicyclam AMD3100 has also been shown to block HIV-1 entry via CXCR4 but not via CCR5. Both T134 and AMD3100 are CXCR4 antagonists and low-molecular-weight compounds but have different structures. Our results indicate that T134 is active against wild-type T-tropic HIV-1 strains and against AMD3100-resistant strains.

Anti-HIV Agents↗