Near-infrared light and glucose dual-responsive cascading hydroxyl radical generation for in situ gelation and effective breast cancer treatment.

A general therapeutic strategy to treat breast cancer is attractive as different subtypes of breast cancers often exhibit distinct response to existing cancer therapeutics. To this end, we prepare a catalyst couple of glucose oxidase (GOx) and gallic acid-ferrous (GA-Fe) nanocomplexes, a type of near-infrared (NIR) absorbing Fenton catalyst, to enable NIR-trigger in-situ gelation and enhanced chemodynamic/starvation therapy that appears to be effective for different types of breast cancer cells. In this system, GOx is mixed with GA-Fe in a solution of N,N-dimethylacrylamide (DMAA) and poly (ethylene glycol) double acrylate (PEGDA). Upon intratumoral injection and NIR laser exposure, such GA-Fe show rapid temperature increase, which would simultaneously increase the catalytic efficiencies of GA-Fe and GOx. The cascade production of hydroxyl radicals (•OH) from glucose is then initiated to enable polymerization of DMAA and PEGDA to form a hydrogel at the injection site within the tumor. The continuous production of cytotoxic •OH together with glucose depletion by the intratumorally fixed catalyst couple would further confer effective destruction of breast cancer tumors by such chemodynamic/starvation therapy. Our work presents a hydrogel-based therapeutic strategy for local treatment of solid tumors with high tumor destruction efficacy and low systemic toxicity.

Improvement of glycemic control in streptozotocin-induced diabetic rats by Atlantic salmon skin gelatin hydrolysate as the dipeptidyl-peptidase IV inhibitor.

In our previous study, Atlantic salmon skin gelatin hydrolysed with flavourzyme possessed 42.5% dipeptidyl-peptidase (DPP)-IV inhibitory activity at a concentration of 5 mg mL(-1). The oral administration of the hydrolysate (FSGH) at a single dose of 300 mg per day in streptozotocin (STZ)-induced diabetic rats for 5 weeks was evaluated for its antidiabetic effect. During the 5-week experiment, body weight increased, and the food and water intake was reduced by FSGH in diabetic rats. The daily administration of FSGH for 5 weeks was effective for lowering the blood glucose levels of diabetic rats during an oral glucose tolerance test (OGTT). After the 5-week treatment, plasma DPP-IV activity was inhibited; the plasma activity of glucagon-like peptide-1 (GLP-1), insulin, and the insulin-to-glucagon ratio were increased by FSGH in diabetic rats. The results indicate that FSGH has the function of inhibiting GLP-1 degradation by DPP-IV, resulting in the enhancement of insulin secretion and improvement of glycemic control in STZ-induced diabetic rats.

First Report of the Root-Knot Nematode Meloidogyne arenaria Infecting Noni in China.

Noni (Morinda citrifolia) is an important medicinal plant and its fruit and root are of high value. In recent years, noni has been cultivated widely on Hainan Island, China. A survey of eight commercial noni fields in four counties found that most fields had plants with symptoms consistent with damage caused by root-knot nematodes. Above-ground symptoms included reduced vigor, plant stunting, and chlorosis. Affected roots were galled, swollen, cracked, and rotten. Fruit loss associated with diseased plants was quantified as 85%. In each field, three samples were taken consisting of 15 cm wide × 20 cm deep soil (containing roots). The nematode population was extracted and quantified according to Barker (1). Nematodes were found in all soil and root samples with population densities ranging from 450 to 835 eggs and second-stage juveniles (J2s) per 200 g subsample of soil, and 685 to 985 eggs and J2s per 10 g sub-sample of fresh roots. Three single egg masses were respectively hand-picked from one sample of diseased noni roots and inoculated onto tomato plants grown with sterilized soil at 20 to 28°C in the greenhouse. After 8 weeks, nematodes were extracted from the roots of tomato plants and identified by morphology, enzyme analysis, and molecular characterization. Morphology of the female perineal patterns showed a low dorsal arch with large lateral lines separating the striae of the dorsal and ventral sectors, leading to the tail terminus; and wavy, coarse striae with forking at lateral lines and short irregular striae near the lateral lines. Enzyme analysis of the esterase phenotype was also typical of the A1 phenotype in M. arenaria. Based on the perineal pattern and esterase phenotype, the Meloidogyne species was identified as M. arenaria (Est A1) (3). Total genomic DNA was extracted from ca. 10 µl of packed second-stage juveniles (J2s) using the method of Cenis (2). The primers C2F3 (5'-GGTCAATGTTCAGAAATTTGTGG-3') and 1108 (5'-TACCTTTGACCAATCACGCT-3') (4) was used to amplify the intergenic region between COII and LrRNA genes of the mtDNA and an amplification product (1,700 bp) was obtained, similar to M. hispanica, M. incognita, and M. javanica. Root-knot nematodes (Meloidogyne spp.) have been reported to be cause disease on noni in Hawaii. However, to our knowledge, this is the first report of M. arenaria (Est A1) infecting noni in China. References: (1) K. R. Barker. Pp. 19 in: An Advanced Treatise on Meloidogyne. Vol. II, Methodology. K. R. Barker et al. eds. North Carolina State University Graphics, Raleigh, 1985. (2) J. L. Cenis. Phytopathology 83:76,1993. (3) P. E. Esbenshade and A. C. Triantaphyllou. J. Nematol. 17:6,1990. (4) T. O. Power and T. S. Harris J. Nematol. 25:1,1993.

Chronic electrical stimulation of four acupuncture points on rat diabetic neuropathy.

The main purpose of this study is to investigate the effects of chronic electrical stimulation of acupuncture points on rat diabetic neuropathy. Diabetes mellitus was induced by a single dose of intravenous streptozotocin. The efficacies of several different protocols of electrical stimulation were compared. The evaluation measures included nerve conduction velocity, tactile threshold and blood perfusion on eye and footpad. Electrical stimulation was administered 30 min/day for 4 weeks. On the 4th weekend of stimulation, when compared with the control group, the stimulated groups showed differential benefits on different evaluation measures. The results indicated that chronic electrical stimulation could reduce the functional deficits of diabetic neuropathy.

Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese.

p53 mutations are etiologically associated with the development of oral squamous cell carcinomas (OSCCs) or are associated with exposure to specific carcinogens. In this study, we used PCR-single strand conformation polymorphism and DNA sequencing to analyze the conserved regions of the p53 gene (exons 5-9) in OSCC tumor specimens from 187 patients with varied histories of betel quid, tobacco and alcohol use. Ninety-one of the 187 OSCCs (48.66%) showed p53 gene mutations at exons 5-9. The incidence of p53 mutations was not associated with age, sex, TNM stage, status of cigarette smoking or betel quid chewing. However, alcohol drinkers exhibited a significantly higher incidence (57/101, 56.44%) of p53 mutations than non-users (39.53%, 34/86) (P = 0.02). The effect of alcohol on the incidence of p53 mutations was still statistically significant (RR = 2.24; 95% CI, 1.21-4.15) after adjustment for cigarette smoking and betel quid (BQ) chewing. G:C to A:T transitions were the predominant mutations observed and associated with BQ and tobacco use. Alcohol drinking could enhance these transitions. After adjustment for cigarette smoking and BQ chewing, alcohol drinking still showed an independent effect on G:C to A:T transitions (RR = 2.41; 95% CI, 1.01-5.74). These findings strongly suggest an important contributive role of tobacco carcinogens to p53 mutation in this series of Taiwanese OSCCs and alcohol might enhance these mutagenic effects. As safrole-DNA adducts have been detected in 77% (23/30) of the OSCC tissues from Taiwanese oral cancer patients with a BQ chewing history, we cannot rule out the possibility that safrole or other carcinogens present in the BQ may cause a similar pattern of mutagenesis. Determination of the role of safrole and other carcinogens present in BQ on the pattern of p53 gene mutation in OSCC will require further study.

Activation of the hypothalamus characterizes the acupuncture stimulation at the analgesic point in human: a positron emission tomography study.

We performed a positron emission tomography study, using regional cerebral blood flow as the index of brain activity, to address the specificity of brain activation pattern by acupuncture stimulation of short duration at the classical analgesic point. Needling manipulation at 2 Hz was performed at a classical point of prominent analgesic efficacy (Li 4, Heku) and a near-by non-classical/non-analgesic point, respectively, in normal subjects. Regions activated by acupuncture stimulation at Li 4 included the hypothalamus with an extension to midbrain, the insula, the anterior cingulate cortex, and the cerebellum. Of note, it was only the stimulation at Li 4 that activated the hypothalamus under the similar psychophysical ratings of acupuncture sensation (deqi) as elicited by the stimulation at the two points, respectively. The data suggested that the hypothalamus might characterize the central expression of acupuncture stimulation at the classical analgesic point and serve as one key element in mediating analgesic efficacy of acupuncture stimulation.

Enhanced biodegradation of petrochemical wastewater using ozonation and BAC advanced treatment system.

The characteristics of degradation/conversion of bio-refractory and the growth of a biofilm are investigated in laboratory-scale pre-ozonation and lifted moving-bed biological activated carbon (BAC) advanced treatment processes treating phenol, benzoic acid, aminobenzoic acid and petrochemical industry wastewater which contains acrylonitrile butadiene styrene (ABS). The optimal reaction time and ozone dosage of pre-ozonation for bio-refractory conversion were determined to be 30 min and 100-200 mg O3/hr, respectively. After pre-ozonation of 30 min treatment, BOD5/COD ratio of influent and effluent increased apparently from 20 to 35%, approximately. However, the change of pH in pre-ozonation was inconspicuous. The optimal flow rate of influent and air were controlled at 1.6 l/h and 120-150 nl/min in lifted moving-bed BAC advanced treatment reactor. A COD removal efficiency of 85-95% and 70-90% may be maintained by using an organic loading of 3.2-6.3 kg COD/m3 day and 0.6-1.6 kg-COD/m3 day with an HRT of 6.0 h as secondary and advanced treatment system, respectively. The time required for the BAC bed is be regenerated by a thermal regeneration is prolonged 4-5 times more than that of GAC system. It can be estimated that the enhanced COD removal capability of the biofilm was not only due to the increase in the COD removal capability of acclimated bacteria, but also due to species succession of bacteria in bio-film ecosystem.

Randomized comparison of local versus epidural anesthesia for tension-free vaginal tape operation.

PURPOSE: We determine the difference between local anesthesia and epidural blockade for the tension-free vaginal tape operation. MATERIALS AND METHODS: Between November 1995 and November 1997, 73 women who had genuine stress incontinence in the absence of pelvic prolapse underwent a prospective randomized study. The study was conducted using a standardized protocol for different types of anesthesia for the tension-free vaginal tape procedure. A formal pain scale was used to determine the pain score for the patients during the operation. Additionally an anxiety scale was used to measure the anxiety level of the subjects immediately after admission to the ward and before discharge from the hospital. RESULTS: One woman was excluded from study due to loss at followup. The comparisons of pain score, duration of procedure and anxiety level of the 2 different types of anesthesia were not significantly different in the 72 study subjects. There was no significant difference in the amount of blood loss, while initial spontaneous voiding occurred significantly earlier (3.5 +/- 2.3 versus 5.8 +/- 0.1 hours, p <0.01), the number of patients in whom initial spontaneous voiding occurred more than 6 hours postoperatively was fewer (2 versus 10, p =0.01), amount of post-void residual during hospitalization was significantly less (98 +/- 63 versus 155 +/- 56 ml., p <0.01) and length of hospital stay was significantly shorter (3.4 +/- 1.4 versus 5.5 +/- 1.6 days, p <0.01) in the local anesthesia compared to epidural group. Subjective and objective success rates were not significantly different in these 2 groups. CONCLUSIONS: Both anesthetic methods can be equally effectively used for the tension-free vaginal tape operation. Local may be better than epidural anesthesia but its clinical significance needs to be proved by further study.

Actions of Ginkgo Biloba related to potential utility for the treatment of conditions involving cerebral hypoxia.

Neuronal hypoxia results from a variety of cerebrovascular accidents or 'normal' age-associated anatomic changes. The consequences vary from mild deficits in neurologic function to massive neuropathology. Present pharmacotherapeutic therapy is not ideal. Two apparently disparate approaches to the search for better treatment or prevention-one involving reassessment of herbal remedies as 'alternative' medicine and the other one involving the desirability of increased structural diversity in HTS (high-throughput screening) libraries and as combinatorial chemistry templates-have converged in a rekindling of interest and a reevaluation of the pharmacologic properties of substances such as extract from the leaves of Ginkgo biloba Linne (form. Salisburia adiantifolia Sm.). There are reports of positive results from a small number of controlled clinical trials (albeit with small numbers of patients) sufficient to suggest that 'Ginkgo' might have therapeutic benefit in some situations or subset of patients. The pharmacologic mechanism by which Ginkgo might be able to provide the observed effect is not clear. However, it is believed that the flavonoid and terpenoid components of Ginkgo extract might produce beneficial therapeutic effects through mechanisms acting separately or in concert, such as the antagonism of PAF (platelet activating factor), antioxidant and metabolic actions, and effects on neurotransmitters. These mechanisms are reviewed in this article.

Induction of p21(CIP1/Waf1) and activation of p34(cdc2) involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells.

The biological activity of retinoic acid (RA) was examined in human hepatoma Hep3B cells. Under serum-deprived conditions, RA induced S/M-phase elevation and mitotic index increase within 24 h, followed by apoptosis. This RA-induced apoptosis was accompanied by p53-independent up-regulation of endogenous p21(CIPI/Waf1) and Bax proteins, as well as activation of p34(cdc2) kinase, and increase of Rb2 protein level and phosphorylation pattern. In addition, RA had no effect on the levels of Bcl-XL; Bcl-XS; cyclins A, B, D1, D3, or E; or Rb1 expression but markedly down-modulated Cdk2 kinase activity and reduced Cdk4 expression. RA also slightly delayed p27(Kip1) expression. Olomoucine, a potent p34(cdc2) and Cdk2 inhibitor, effectively blocked RA-mediated p34(cdc2) kinase activation and prevented RA-induced apoptosis. Furthermore, antisense oligonucleotide complementary to p21(CIP2/Waf1) and p34(cdc2) mRNA significantly rescued RA-induced apoptosis. Our data indicate that p21(CIP2/Waf1) overexpression may not be the only regulatory factor necessary for RA-induced apoptosis in human hepatoma Hep3B cells. RA treatment leads to Rb2 hyperphosphorylation, and p34(cdc2) kinase activation is coincident with an aberrant mitotic progression, followed by appearance of abnormal nucleus. This aberrant cell cycle progression appeared requisite for RA-induced cell death. These findings suggest that inappropriate regulation of the cell cycle regulators p21(CIP2/Waf1) and p34(cdc2) is coupled with induction of Bax and involved in cell death with apoptosis when Hep3B cells are exposed to RA.

Benzodiazepine binding site-interactive flavones from Scutellaria baicalensis root.

A benzodiazepine binding assay directed separation led to the identification of 3 flavones baicalein (1), oroxylin A (2), and skullcapflavone II (3) from the water extract of Scutellaria baicalensis root. Compounds 1, 2, and 3 interacted with the benzodiazepine binding site of GABAA receptors with a Ki value of 13.1, 14.6 and 0.36 micromol/L, respectively.

[Experience of surgical treatment for colorectal endometriosis: report of 6 cases].

Endometriosis is a common disease with 8-15% occurrence in women during their reproductive period. Involvement of the bowel wall occurs rather frequently and probably presents in 12-34% of patient with pelvic endometriosis. However, it is classically asymptomatic and difficult to find out. From 1977 to 1987, we had six patients of colorectal endometriosis with mainly bowel symptoms. Five of them were located at rectum and sigmoid colon, one at the hepatic flexure of colon. All of the cases developed constipation or diarrhea, and four of them had severe abdominal pain. Four cases developed rectal bleeding. Previous operation for pelvic endometriosis was noted in two cases. The detailed examination included digital examination, endoscopy, barium enema and CT scan. Suspected malignancy was the indication for surgery in 4 cases and one in rectal stenosis. Low diagnostic rate was due to the fact that endometrial tissue rarely infiltrates the mucosa. Therefore, pathology of biopsied specimen often reveals non-conclusive finding to prevent differential diagnosis. However bowel resection offers conclusive diagnosis and chances of cure. In our study, only one suspected endometriosis case received bilateral oophorectomy. The stenotic segment of rectum restored to normal caliber after operation.

Vascular effects of tetramethylpyrazine: direct interaction with smooth muscle alpha-adrenoceptors.

The interaction of tetramethylpyrazine, a vasoactive ingredient of a Chinese traditional medicinal plant, with the vascular muscle alpha 1-adrenoceptors was investigated by a direct radioligand binding technique using [3H]prazosin and vascular smooth muscle microsomes isolated from dog aorta and mesenteric artery. Tetramethylpyrazine inhibited the binding of [3H]prazosin to vascular muscle membranes in a concentration-dependent manner at a suboptimal concentration of prazosin. Scatchard analysis of the effect of tetramethylpyrazine on the saturation profile of [3H]prazosin binding to vascular muscle microsomes of either arterial muscle indicated a substantial increase of Kd values (the affinity for prazosin) without a change in Bmax (maximal binding sites for prazosin). Thus, the present results provide supporting evidence that the inhibitory effect of tetramethylpyrazine on the vasoconstriction of dog mesenteric artery induced by phenylephrine in the earlier studies may be, at least, in part due to a direct action at the recognition sites of alpha 1-adrenoceptors. Amiloride and amiloride-related compounds, which shares a common pyrazine ring structure with tetramethylpyrazine and other related derivatives, also inhibits the binding of [3H]prazosin to aortic muscle microsomal membranes. Functional studies of dog saphenous vein also indicated that both tetramethylpyrazine and its ethyl derivatives inhibited the responses induced by phenylephrine and B-HT 920 in the presence and absence of extracellular Ca2+. Together with our earlier findings that amiloride also inhibits [3H]prazosin and [3H]rauwolscine binding to vascular muscle alpha 1- and alpha 2-adrenoceptors, the present radioligand binding study in canine arteries and functional study in saphenous veins suggest that the above compounds containing the pyrazine nucleus indeed interacted at the alpha-adrenoceptor sites.

Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging.

Manganese(II)-N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis (phosphate) (MnDPDP) is a paramagnetic complex designed for use as a hepatobiliary agent. The T1 relaxivity of MnDPDP (2.8 [mmol/L]-1.sec-1 in aqueous solution) was similar to that of gadolinium diethylenetriaminepentaacetic acid (DTPA) (4.5 [mmol/L]-1.sec-1) and gadolinium tetraazocyclodecanetetraacetic acid (DOTA) (3.8 [mmol/L]-1.sec-1). However, in liver tissue the T1 relaxivity of MnDPDP (21.7 [mmol/L]-1.sec-1) was threefold higher than that reported for Gd-DOTA (6.7 [mmol/L]-1.sec-1). Maximum liver T1 relaxation enhancement occurred 30 minutes after injection of MnDPDP, at which time 54MnDPDP biodistribution studies indicated that 13% of total body activity was in the liver. Enhanced (MnDPDP, 50 mumol/kg) MR images showed a fivefold increase in tumor-liver contrast-to-noise ratio over baseline unenhanced images. Results of the authors' acute and subchronic toxicity studies suggest that MnDPDP will be safe at the doses necessary for clinical imaging; at 10 mumol/kg, the safety factor (LD50/effective dose) for MnDPDP is 540, significantly greater than the safety factor of Gd-DTPA (ie, 60-100).

Inhibition of vasoconstriction by tetramethylpyrazine: does it act by blocking the voltage-dependent Ca channel?

Using dog mesenteric arterial ring preparations, we studied the in vitro vascular effects of tetramethylpyrazine (TMP, also known as Ligustrazine), a vasoactive component derived from Ligustium Wollichii Franchat; a widely used ingredient in Chinese herbal medicine for the treatment of cardiovascular diseases. TMP had no effect on the resting force of the vascular muscle, but it caused a dose-dependent inhibition of vascular contractile responses to KCl and phenylephrine (PHE). These inhibitory effects of TMP were reversible and more prominent at lower agonist concentrations. TMP also inhibited the responses to PHE in Ca-free medium containing 50 microM EGTA suggesting the action on the release of intracellular Ca2+. Therefore, TMP is not a specific Ca-channel blocker as claimed previously. Its vasodilatory effect is mediated by the inhibition of Ca influx, as well as the release of intracellular Ca2+.

[Is synchronous hemorrhoidectomy with colonoscopy a worthwhile procedure?].

There were 201 patients receiving preoperative colonoscopy prior to hemorrhoidectomy in the meanwhile at MMH from July 1984 to June 1988. Other than rectal bleeding, they had colonic symptoms such as anemia, abdominal pain, familiar history of cancer and change of bowel habit etc. The study included 114 male and 87 female with ages ranging from 15 to 74 years (Median, 42 years). Three patients with colonic cancer and twenty-eight patients with neoplastic polyps were found by colonoscopic examination. Three cancer patients all received cancer surgery instead of hemorrhoidectomy as quickly as possible in a short time. One patient died for advanced stage and the other two patients got good results. The literatures were reviewed and discussed in accordance with the colonoscopic finding, operative time, hospital stay, post-operative morbidity and complication. There were not increase the postoperative morbidity in this series which compare with that of other series. The advantages of this procedure included: 1) Preventing suffer from twice colon preparations. 2) Preventing waiting period for Barium enema. 3) Preventing delay diagnosis of colorectal lesions especially colon cancer or precancer lesions of neoplastic polyps. 4) Performing examination and surgery at the same time-money-saving and time-saving. We thought synchronous hemorrhoidectomy with colonoscopy is a worthwhile clinical procedure.