Potential Mode Of Action Research Articles

Probiotics: mechanisms and established effects

The definition for probiotics has gradually changed with increasing understanding of the mechanisms by which they influence human health. Health effects related to changes in the intestinal microflora also accompany or are related to adhesion and immune system effects, competitive exclusion or metabolic and nutritional effects, with an increasing array of other potential modes of action. Most clinically documented and validated health effects have been studied using either fermented milks containing viable cultures or viable pure cultures. Specific targets for the future include controlled studies comparing foods containing viable strains to those containing non-viable strains and to assess the combined effects of multiple probiotics.

Role of Models in Assessing New Agents for Caries Prevention—Non-Fluoride Systems

While fluoride is an effective anti-caries agent, the search for more effective alternative therapies continues. A wide range of non-fluoride anti-caries agents has been postulated, and this paper reviews some of the pre-clinical models that have been utilized in their evaluation and some of the pitfalls that must be avoided. Using data on the potential anti-caries efficacy of phosphopeptides obtained from casein, the caution that must be applied in extrapolating laboratory data to predict clinical performance is discussed. Evaluation strategies that focus on only one potential mode of action (e.g., inhibition of demineralization) may overestimate the true clinical efficacy which may arise from a combination of two or more effects (e.g., inhibition of demineralization and stimulation of remineralization). Although laboratory and in situ data predict anti-caries efficacy for sodium trimetaphosphate in combination with fluoride, this was not found in three-year clinical trials. A possible reason for this, the lack of suitable calibration methods, is discussed. Finally, some comments on the appropriateness of laboratory evaluation strategies are made.

Regulation of endothelin-1 synthesis in cultured guinea pig airway epithelial cells by various cytokines

To study regulatory mechanisms influencing the synthesis and release of ET-1, a potent bronchoconstrictor, epithelial cells from guinea pig tracheas were cultured to test various cytokines for the synthesis of ET-1 and its precursor, big ET-1. Cytokines tested were divided into 4 groups, based on their potential modes of action. IL-8, TNF alpha and TGF beta transiently increased the synthesis of ET-1, while EGF, PDGF and GM/CSF promoted proliferation of ET-1 synthesizing cells. IL-1 enhanced the synthesis of ET-1 precursor without mitogenesis, whereas IL-2, IL-6 and IGF-1 induced both the synthesis of big ET-1 and mitogenesis. These observations suggest that cytokines involved in damage, inflammation and repair of the airway epithelial layer regulate the synthesis and release of ET-1 by multiple mechanisms, thereby influencing airway muscle tone.

Morphological alterations accompanying the effect of peptaibiotics, α-aminoisobutyric acid-rich secondary metabolites of filamentous fungi, on Culex pipiens larvae

The effect of different representatives of the group of peptaibiotics, α-aminoisobutyric acid rich secondary metabolites of filamentous fungi, on Culex pipiens larvae was studied. Light and transmission electron microscopy techniques were used to localize the intracellular damage and to determine the target organells for the mode of action of peptaibols in mosquito larvae. Though different in insecticidal activity, all tested compounds induced the same type of tissue damage, which was characterized by heavy challenge of mitochondria followed by partial swelling, crystaeolysis and destruction of mitochondrial walls. It is concluded that the mode of action of peptaibols in mosquito larvae is mediated through the damage of mitochondria. The structure-mosquitocidal effect of these compounds, their potential mode of action and role in the natural fungal entomopathogenic process are briefly discussed.

Hypercalcaemia of malignancy.

Hypercalcaemia in malignancy is a major clinical problem. It contributes significantly to morbidity and mortality and can present difficult diagnostic and management dilemmas. Direct bony invasion by tumour cells rather than humorally mediated hypercalcaemia is probably the most common cause of malignant hypercalcaemia. Yet even in this situation the mechanism of bone resorption or the reason that the normal homeostatic mechanisms cannot cope with the calcium load are poorly understood. It is likely that the humoral and paracrine factors produced by tumours which result in hypercalcaemia or in osteosclerotic bone metastases, are interposing themselves into the normal regulatory processes and deranging them. Humoral hypercalcaemia of malignancy is an important model for studying these questions, and it also provides some insight into the normal regulation of bone turnover. This review will examine the animal models and human syndromes of malignant hypercalcaemia and show how animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors. A most interesting recent development in this area is the description of a new hormone, the parathyroid hormone-related peptide, which may explain many of the cases of humoral hypercalcaemia of malignancy. It is also a useful model with multiple sites of action within the bone and calcium homeostatic process. The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, may also be involved in a small proportion of cases, but again it is a useful model of some of the factors that may operate. Of considerable interest are the tumour derived factors, such as the transforming growth factors, and the cytokines, such as tumour necrosis factors, interleukins, and haemopoietic colony stimulating factors. Prostanoids are seldom of major importance, but may be important in certain tumour types. Osteosclerotic metastases, although seldom associated with hypercalcaemia, may provide insight into osteoblast regulating factors. Treatment of hypercalcaemia is discussed to show ways in which response to treatment may shed light on underlying pathophysiological mechanisms. Most effective treatments have many potential modes of action, and further study of the interactions of these agents and tumour types may help to unravel some of the enigmas in this human syndrome. The major advances in this complex problem involve the realisation of the necessity of multiple sites of action, including renal calcium handling as well as relative increases in bone resorption and/or intestinal calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Action of Nedocromil Sodium and Sodium Cromoglycate on Cloned Human Allergen-Specific CD4+ T Lymphocytes

Nedocromil sodium (and sodium cromoglycate) are topical, prophylactic, anti-inflammatory agents used in reversible obstructive airways disease. To investigate their potential mode of action, the effects of these agents on specific allergen- or IL-2-induced proliferation of a human CD4+ house dust mite-specific T-cell clone isolated from an individual with perennial rhinitis was examined. Although strong proliferation was observed in control cultures, no inhibitory effect was observed with any of the drug concentrations tested. In contrast, dexamethasone was able to inhibit the T-cell proliferation. These observations suggest that the clinically observed suppression of the late-phase asthmatic response may not be due to an effect on CD4+ T lymphocytes.

The use of estrogens as postcoital contraceptive agents: Clinical effectiveness and potential mode of action

Tubal motility, oviduct flow, and ciliary activity are all influenced by estrogens. Tubal insufflation studies suggest that estrogens cause closure of the uterotubal junction in women. Estrogen action may reflect a release from modifications imposed by progesterone and may threaten the functional integrity of the corpus luteum under hypothalamic-hypophyseal control. Board and Bhatnagar have shown reduced progesterone levels with administration of diethylstilbestrol. Decrease of BBT following use of ethinyl estradiol and diethylstilbestrol support the theory of the luteolytic action of estrogen. After nidation, estrogens have no effect. Haspels reported on 2000 women treated with ethinyl estradiol (2-5 mg) or diethylstilbestrol (25-50 mg) administered for 5 consecutive days. Method failure was reported with 3 mg/day ethinyl estradiol and 25-30 mg/day diethylstilbestrol. No pregnancies were reported at 5 mg/day ethinyl estradiol and 50 mg/day diethylstilbestrol. Kuchera reported on 1000 cases with no pregnancies following treatment with 50 mg diethylstilbestrol administered within 72 hours of unprotected coitus (for a pregnancy rate of 2.5/1000). Other estrogens have been used successfully as postcoital contraceptive agents. Use of conjugated equine estrogens administered orally or intravenously within 72 hours of exposure prevented pregnancy. Dienestrol and dienestrol combined with ethynodiol acetate (progestogen) prevented pregnancy. Depot estradiol administered to 12 patients resulted in 2 ectopic pregnancies. Slow release of this estrogen could account for its high failure rate, although results suggest an effect on zygote transport. It is concluded that the best protection against pregnancy will be obtained by administering estrogen as soon as possible after coitus (preferably within 24 hours, no later than 72 and continued for 5 consecutive days).

Pregnancy maintenance with corticosterone in protein-depleted rats: a study on fetal protein composition.

A pregnancy maintenance of only 8% was obtained when rats were fed a protein free diet throughout gestation. Administration of 5 mg corticosterone on each of days S to 9 improved pregnancy maintenance to 62%. In comparison with fully fed rats, fetal weight and fetal protein (concentration and total) were significantly less in the corticosterone maintained protein deprived animal. However, fetal hepatic protein, RNA and DNA concentrations compared favorably with those of the full fed animal; total content of each of these constituents was subnormal in protein deficiency. Thus total cell numbers were fewer but cell size (P/DNA) was normal. Corticosterone may serve to mobilize amino acids and to release prolactin as a potential mode of action. (Endocrinology 90: 318, 1972)