Synergistic Effects of Adjuvants, Endotoxin, and Fasting on Induction of Diabetes With Multiple Low Doses of Streptozocin in Rats

Diabetes ◽  
1988 ◽  
Vol 37 (1) ◽  
pp. 112-118 ◽  
Author(s):  
J. R. Wright ◽  
P. E. Lacy
2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13169-13169
Author(s):  
B. Spaenkuch ◽  
S. Heim ◽  
E. Kurunci-Csacsko ◽  
C. Lindenau ◽  
M. Kaufmann ◽  
...  

13169 Background: A central role for polo-like kinases (PLK) in regulating mitosis has been shown in different species. Overexpression of PLK1 is observed in various human tumors, and it is a negative prognostic factor in patients suffering from diverse cancers. In order to reduce side-effects exerted by commonly used anti-neoplastic agents and to enhance chemosensitivity of different breast cancer cell lines, we used phosphorothioate antisense oligonucleotides (ASOs) targeted against PLK1 together with Paclitaxel, Carboplatin and Herceptin. Methods: We used different HER2-positive and -negative breast cancer cell lines (BT-474, MCF-7, MDA-MB-435) to define the role of reduced PLK1 expression for the necessary dose of anti-neoplastic agents. After transfection with PLK1-specific ASOs these agents were added and cell proliferation, cell cycle distribution, and apoptosis were measured. Results: We observed synergistic effects after combination of very low doses of PLK1-specific ASOs with Paclitaxel and Herceptin. Using Carboplatin we could only observe a synergistic effect in MDA-MB-435 cells. Downregulation of PLK1 levels led to an elevated percentage of cells in G2/M. Apoptosis and G2/M arrest were increased after combination of PLK1-specific ASOs with Paclitaxel in MDA-MB-435 cells. In a human Xenograft experiment using MDA-MB-435 cells the combination of PLK1-ASOs with Paclitaxel led to synergistic reduction of tumor growth after three weeks treatment compared to either agent alone. Conclusion: This study suggests that antisense inhibitors against PLK1 at well tolerated doses may be considered as cancer therapeutic agents which elevate chemosensitivity especially against Paclitaxel in very low doses with a significant better outcome than each agent alone. No significant financial relationships to disclose.


1987 ◽  
Author(s):  
M J Powling ◽  
R M Hardisty

In a medium containing 1 mM extracellular calcium (Ca2+o), sub-threshold concentrations of thrombin (0.01-0.02 u/ml) and PAF (0.1-0.2 nM) induced shape change but not aggregation and raised [Ca2+i] about 200 nM above the basal level of 80 nM. Addition of 0.5 uM adrenaline (which produced no effect alone) 15-30 seconds before those concentrations of second agonist induced rapid aggregation and substantial ATP secretion. In parallel, the rate and magnitude of the Ca2+i flux were both increased: each approximately doubled in response to thrombin while in response to PAF the rate increased about 2.5 fold and the maximum response by about 50%. In the presence of Fab fragments of Ml48, a monoclonal antibody against GPIIb/IIIa, adrenaline produced the same effect on the Ca2+i response although aggregation and ATP secretion were completely abolished.In the presence of 2 mM EGTA ([Ca2+o] = <100 nM) the threshold concentrations of PAF and thrombin raised the [Ca2+i] from 60 nM only to about 110 nM. Under these conditions pre-incubation with 0.5 uM adrenaline did not induce aggregation or ATP secretion, nor was there a significant increase in the maximal extent of Ca2+i flux.The rate of Ca2+i mobilization, however, was approximately doubled in response to thrombin and increased by about 50% in response to PAF.Blockade of cyclo-oxygenase with aspirin did not inhibit the adrenaline-induced potentiation of Ca2+i mobilization whether Ca2+o was 1 nM or <100 nM.It appears that adrenaline may exert its synergistic effects on low doses of other agonists by accelerating Ca2+ influx and intracellular mobilization.


2021 ◽  
pp. 1-34
Author(s):  
Ivan E. Wang ◽  
Shana Yi ◽  
Robert C. Block ◽  
Shaker A. Mousa

Abstract Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA resistant or diabetic patients. EPA and DHA deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are “V-shaped” such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location and subtype specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however ultra-low doses (30 mg/d) can also reduce thrombosis. EPA to DHA ratio is also important with regards to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation, however high dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.


2021 ◽  
Vol p5 (5) ◽  
pp. 3003-3011
Author(s):  
Kannan Mani ◽  
Priyanka K. Dighde ◽  
Sheetal Agrawal ◽  
Ashish Agrawal

Parada Murchana (Mercurial Preparations) forms the backbone of Rasashastra which signifies the formulations of mercury after Shodhan (purification) termed as Rasachikitsa which includes Kharaliya, Parpati Kupipakwa & Pottali Rasayanas. Amongst them, Kupipakwa Rasayana (KPR) & Pottali Rasayana (PTR) are unique pharmaceutical preparations designed to achieve potential therapeutic efficacy by stabilizing the stronger bonds between ingredients. Judicial utilization of these mercurial preparations provides quicker action and synergistic effects with suitable Anupana (adjuvants), Kala (time) at low doses without producing toxic effects. KPR and PTR give miraculous results in Complicated, Chronic as well as Acute conditions. In the present era, people hesitate to use these medicines due to a lack of knowledge & awareness. This review aims to bring into the limelight the importance of KPR & PTR in the modern era where modern medicines have failed or attained resistance against diseases and also to overcome difficulties that may arise because of the extinction of many herbal drugs. Keywords: Kupipakwa, Pottali, Rasayana, Rasachikitsa, Murchana, Mercurial preparations


1995 ◽  
Vol 147 (1) ◽  
pp. 103-110 ◽  
Author(s):  
M Nakamura ◽  
K Nakamura ◽  
S Igarashi ◽  
M Tano ◽  
K Miyamoto ◽  
...  

Abstract The acquisition of FSH receptor during preantral folliculogenesis is believed to be a key step in the subsequent development of follicles. We examined the interaction between activin and cAMP in FSH receptor induction in rat granulosa cells by measuring 125I-FSH binding and FSH receptor mRNA. In the 125I-FSH binding study, 0·2 mm 8-Br-cAMP and 1 μm forskolin were maximally effective in FSH receptor induction (169 and 220% respectively of control), while higher concentrations gave attenuated responses. It appears that cAMP has ambivalent effects on FSH receptor induction depending on the concentration and length of exposure. Activin alone dramatically increased the number of FSH receptors (314% of control). Moreover, synergistic effects of activin and 8-Br-cAMP or forskolin were observed on FSH receptor induction: a combination of activin (80 ng/ml) and low doses of 8-Br-cAMP (0·2 mm) or forskolin (1 μm) was most effective (160 or 140% of that induced by activin alone) and receptor levels reached a maximum at 24 h. These levels then markedly decreased after 72 h of incubation. Northern blot analysis revealed that the combination of activin (80 ng/ml) and 8-Br-cAMP (0·2 mm) or forskolin (1 μm) increased FSH receptor mRNA to about 140% of that induced by activin alone. These results indicate that activin and cAMP induced FSH receptor synergistically. However, activin did not enhance the production of cAMP induced by forskolin. In addition, a protein kinase A inhibitor (H89) (2 μm), which inhibited the effects of forskolin, had no effect on the action of activin. Taken together, the present findings suggest that the action of activin is not via a cAMP pathway, and that activin works co-operatively with cAMP on folliculogenesis. Journal of Endocrinology (1995) 147, 103–110


Author(s):  
D.E. Philpott ◽  
W. Sapp ◽  
C. Williams ◽  
J. Stevenson ◽  
S. Black ◽  
...  

Spermatogonial stem-cell survival after irradiation injury has been studied in rodents by histological counts of surviving cells. Many studies, including previous work from our laboratory, show that the spermatogonial population demonstrates a heterogeneous response to irradiation. The spermatogonia increase in radio-sensitivity as differentiation proceeds through the sequence As - Apr - A1 - A2 - A3 - A4 - In - B. The stem (As) cell is the most resistant and the B cell is the most sensitive. The purpose of this work is to investigate the response of spermatogonial cell to low doses (less than 10 0 rads) of helium particle irradiation.


Author(s):  
O. M. Faroon ◽  
R. W. Henry ◽  
M. G. Soni ◽  
H. M. Mehendale

Previous work has shown that mirex undergoes photolytic dechlorination to chlordecone (CD) (KeponeR) in the environment. Much work has shown that prior exposure to nontoxic levels of CD causes potentiation of hepatotoxicity and lethality of CCl4, BrCCl3 and other halomethane compounds. Potentiation of bromotrichloromethane hepatotoxicity has been associated with compounds that stimulate the activity of hepatic mixed-function oxidase (MFO). An increase in the metabolism of halomethane by the MFO to a free radical initiates peroxidative decomposition of membranal lipids ending in massive cellular injury. However, not all MFO inducers potentiate BrCCl3 hepatotoxicity. Potentiation by much larger doses of phenobarbital is minimal and th at by a more potent inducer of MFO, mirex, is negligible at low doses. We suggest that the CD and bromotrichloromethane interaction results in a depletion of cellular energy and thereby reducing the cellular ability to undergo mitosis.


Author(s):  
W.W. Adams ◽  
S. J. Krause

Rigid-rod polymers such as PBO, poly(paraphenylene benzobisoxazole), Figure 1a, are now in commercial development for use as high-performance fibers and for reinforcement at the molecular level in molecular composites. Spinning of liquid crystalline polyphosphoric acid solutions of PBO, followed by washing, drying, and tension heat treatment produces fibers which have the following properties: density of 1.59 g/cm3; tensile strength of 820 kpsi; tensile modulus of 52 Mpsi; compressive strength of 50 kpsi; they are electrically insulating; they do not absorb moisture; and they are insensitive to radiation, including ultraviolet. Since the chain modulus of PBO is estimated to be 730 GPa, the high stiffness also affords the opportunity to reinforce a flexible coil polymer at the molecular level, in analogy to a chopped fiber reinforced composite. The objectives of the molecular composite concept are to eliminate the thermal expansion coefficient mismatch between the fiber and the matrix, as occurs in conventional composites, to eliminate the interface between the fiber and the matrix, and, hopefully, to obtain synergistic effects from the exceptional stiffness of the rigid-rod molecule. These expectations have been confirmed in the case of blending rigid-rod PBZT, poly(paraphenylene benzobisthiazole), Figure 1b, with stiff-chain ABPBI, poly 2,5(6) benzimidazole, Fig. 1c A film with 30% PBZT/70% ABPBI had tensile strength 190 kpsi and tensile modulus of 13 Mpsi when solution spun from a 3% methane sulfonic acid solution into a film. The modulus, as predicted by rule of mixtures, for a film with this composition and with planar isotropic orientation, should be 16 Mpsi. The experimental value is 80% of the theoretical value indicating that the concept of a molecular composite is valid.


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