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Biomedical subjects

M F McCarty

Publications and source records attributed to M F McCarty.

At least 91 records · Page 5Linked to original sources
PubMed1998

Vascular nitric oxide may lessen Alzheimer's risk.

Estrogen deficiency, hyperinsulinemia, type II diabetes, atherosclerosis, and a past history of elevated blood pressure may be associated with increased risk of Alzheimer's disease (AD). Common to all of these risk factors is a diminished capacity of vascular endothelium to generate nitric oxide (NO). Vascular NO has the potential to enhance the membrane polarization of cerebral neurons by increasing the open probability of calcium-activated potassium channels; this may protect neurons from the excessive calcium influx, potentiated by beta-amyloid peptides that is thought to mediate neuronal damage in AD. The possibility that NO/cyclic guanosine 3', 5'-phosphate (cGMP) may modulate the synthesis or processing of the amyloid precursor protein, also merits evaluation. Practical measures for promoting vascular NO production may include increased intakes of arginine, potassium, antioxidants, and fish-oil, as well as lifestyle measures that typically lower elevated blood pressure; potential benefits of chromium, glucosamine, and silicon should also be explored. In hypertensives, angiotensin-converting enzyme (ACE) inhibitors and sodium restriction may favorably influence endothelial function. Fish-oil should have the additional benefit of antagonizing the contribution of interleukin-1 to AD pathogenesis. Ancillary anti-excitotoxic measures such as magnesium, taurine, phenytoin, and vasodilators targeting ATP-dependent potassium (KATP) channels, may likewise reduce AD risk. Most of the nutritional measures suggested here would in any case be recommendable for preservation of vascular health.

Alzheimer Disease↗
PubMed1998

A central role for protein kinase C overactivity in diabetic glomerulosclerosis: implications for prevention with antioxidants, fish oil, and ACE inhibitors.

The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.

Angiotensin II↗
PubMed1998

Selenium, calcium channel blockers, and cancer risk--the Yin and Yang of apoptosis?

It is increasingly clear that apoptosis plays a crucial role in the promotional phase of cancer development. Initiated pre-neoplastic clones in rat liver experience a high rate of apoptosis, and this rate has an important impact on the survival and growth of these clones. Suppression of apoptosis appears to be a universal property of cancer promoters, suggesting conversely that agents which inhibit cancer induction during the promotional phase increase the rate of apoptosis in initiated cells. Modulation of apoptosis is a likely explanation for recent striking evidence that use of calcium channel blockers substantially increases, whereas supplemental selenium substantially decreases, human cancer incidence. Non-genotoxic measures which are likely to upregulate apoptosis in pre-neoplastic/neoplastic cells--and thus may be useful in prevention and/or therapy--include selenium, retinoids/carotenoids, green tea polyphenols, caloric restriction, downregulation of IGF-I activity, high-dose tamoxifen and other protein kinase C antagonists, withdrawal or blockade of trophic hormones, isoflavones, limonene, vitamin D and cholecalciferol analogs, dietary fiber/sodium butyrate, hyperthermia, benzaldehyde derivatives, and creatine.

Animals↗
PubMed1998

Nitric oxide deficiency, leukocyte activation, and resultant ischemia are crucial to the pathogenesis of diabetic retinopathy/neuropathy--preventive potential of antioxidants, essential fatty acids, chromium, ginkgolides, and pentoxifylline.

Impaired microcirculatory perfusion appears to be crucial to the pathogenesis of both neuropathy and retinopathy in diabetics. This in turn reflects a hyperglycemically mediated perturbation of vascular endothelial function that entails overactivation of protein kinase C, reduced availability of nitric oxide, increased production of superoxide and endothelin, impaired insulin function, diminished synthesis of prostacyclin/PGE1, and increased activation and endothelial adherence of leukocytes. These dysfunctions may be addressed with a supplementation program that includes high-dose antioxidants, fish oil, gamma-linolenic acid, chromium, arginine, carnitine, and ginkgolides. Pharmaceuticals likely to be of benefit in this regard include pentoxifylline, probucol, replacement estrogens, and inhibitors of angiotensin converting enzyme and aldose reductase.

Animals↗
PubMed1998

Vascular heparan sulfates may limit the ability of leukocytes to penetrate the endothelial barrier--implications for use of glucosamine in inflammatory disorders.

Oral glucosamine has anti-inflammatory activity in rodents, and anecdotal evidence suggests that it may be clinically useful in inflammatory bowel disorders. A possible explanation is that supplemental glucosamine increases production of heparan sulfate (HS) proteoglycans by the vascular endothelium, thereby improving the endothelium's barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of HS. Heparin can inhibit neutrophil activation, adhesion, and chemotaxis, and--like glucosamine--has been reported effective for managing inflammatory bowel syndromes. Cytokine-mediated loss of endothelial HS may be a key factor in the coordinated inflammatory response. These considerations suggest that glucosamine may have clinical utility in a range of inflammatory disorders, and should be assessed with regard to its impact on cancer metastasis and peripheral ischemic disease. In inflammatory bowel disease, fish oil, ginkgolides, and enteric-coated 5-aminosalicylic acid may safely complement the efficacy of glucosamine.

Animals↗
PubMed1998

Enhanced synovial production of hyaluronic acid may explain rapid clinical response to high-dose glucosamine in osteoarthritis.

Anecdotal reports of rapid symptomatic response to high-dose glucosamine in osteoarthritis are not credibly explained by the traditional view that glucosamine promotes synthesis of cartilage proteoglycans. An alternative or additional possibility is that glucosamine stimulates synovial production of hyaluronic acid (HA), which is primarily responsible for the lubricating and shock-absorbing properties of synovial fluid. Many clinical and veterinary studies have shown that intra-articular injections of high-molecular-weight HA produce rapid pain relief and improved mobility in osteoarthritis. HA has anti-inflammatory and analgesic properties, and promotes anabolic behavior in chondrocytes. The concentration and molecular weight of synovial fluid HA are decreased in osteoarthritis; by reversing this abnormality, high-dose glucosamine may provide rapid symptomatic benefit, and in the longer term aid the repair of damaged cartilage.

Animals↗
PubMed1998

Polyphenol-mediated inhibition of AP-1 transactivating activity may slow cancer growth by impeding angiogenesis and tumor invasiveness.

Certain polyphenols, capable of activating transcription via antioxidant response elements, potently induce Fra-1/Fra-2, thereby antagonizing the transactivating activity of AP-1 complexes. Since AP-1 is crucial to the induction of matrix proteases required for angiogenesis and tumor invasion, it is reasonable to suspect that adequate intakes of appropriate polyphenols would have utility in cancer therapy. Indeed, green tea polyphenols have reduced tumor growth rate and/or metastatic capacity in several animal studies. Additional measures for down-regulating AP-1 activity may include fish oil, heparin, and the drug LY290181. Down-regulation of AP-1 activity as a general therapeutic strategy merits further consideration.

Animals↗
PubMed1997

Promotion of interleukin-2 activity as a strategy for 'rejuvenating' geriatric immune function.

The age-related decline in immune capacities is largely attributable to a decrease in the ability of activated T lymphocytes to achieve efficient clonal expansion. This in turn reflects a decrease in the expression of both interleukin-2 and its receptor. Nutritional/hormonal measures which up-regulate such expression may thus have a 'rejuvenatory' impact on geriatric immune function. Such measures may include: subtoxic selenium intakes, which increase the inducibility of interleukin-2 receptor; high-dose vitamin E and possibly chromium, which may counteract the down-regulatory effect of cAMP on interleukin-2 activity; as well as carotenoids and ascorbic acid. Restoring more youthful serum levels of the hormones DHEA and melatonin may also have a positive effect in this regard. In addition to their likely value for boosting geriatric immune defenses, these measures deserve evaluation as adjuvants to cancer immunotherapies and to drug treatments for HIV infection.

Aging↗
PubMed1997

Glucosamine for psoriasis?

Amphiregulin and transforming growth factor-alpha, agonists for the epidermal growth factor receptor, are the major autocrine growth factors for cultured keratinocytes, and their substantial overexpression in psoriatic lesions suggests that they are crucial to the basal hyperplasia that characterizes psoriasis. Amphiregulin binds to heparin and related highly sulfated polysaccharides, and exogenous heparin blocks its growth factor activity, rationalizing previous reports that psoriasis responds to heparin therapy. Differentiating keratinocytes produce increased amounts of protein-bound as well as free-chain heparan sulfates, which may function physiologically as amphiregulin antagonists. By promoting keratinocyte synthesis of these heparan sulfates, glucosamine administration may inhibit amphiregulin function and thus provide therapeutic benefit in psoriasis. Concurrent ingestion of fish oil, by impeding the excessive activation of protein kinase C, may decrease keratinocyte production of amphiregulin and other autocrine growth factors, thus complementing the postulated benefits of glucosamine.

Amphiregulin↗
PubMed1997

Up-regulation of IGF binding protein-1 as an anticarcinogenic strategy: relevance to caloric restriction, exercise, and insulin sensitivity.

The mitotic rate of stem cells is a major determinant of cancer risk. Insulin-like growth factors (IGFs) are virtually obligate stimulants of cell turnover in nearly every tissue. IGF activity is subject to rapid modulation by hepatic release of IGF binding protein-1 (IGFBP-1), a factor whose synthesis is suppressed by insulin and increased by glucagon. Up-regulation of IGFBP-1 production can be expected to decrease IGF activity and thereby diminish cancer risk. Measures that sensitize peripheral tissues to insulin, and thereby down-regulate insulin secretion, can be expected to increase IGFBP-1 synthesis, provided that they do not unduly sensitize hepatocytes as well. Prolonged aerobic exercise and caloric restriction also increase IGFBP-1 production. Since IGF-1 suppresses hepatic synthesis of sex hormone binding globulin (SHBG), down-regulation of IGF activity will increase SHBG levels and thus diminish the availability of free sex hormones--an effect that should further decrease cancer risk in sex hormone-responsive tissues. These considerations rationalize many findings in animal and epidemiologic studies, and suggest that non-diabetic insulin resistance may be a significant cancer risk factor. Increased IGF activity associated with insulin resistance may also promote benign hyperplasias-most notably atherosclerosis. Hyperinsulinemia stimulates intimal hyperplasia indirectly, via IGF.

Aging↗
PubMed1997

Subtoxic intracellular trivalent chromium is not mutagenic: implications for safety of chromium supplementation.

For reasons that are outlined, toxicologists have long suspected that intranuclear trivalent chromium mediates much if not all of the well-documented genotoxicity of hexavalent chromium. However, more recent evidence suggests that this genotoxicity is in fact attributable to free radical damage catalyzed by hexavalent chromium under reducing aerobic conditions. Subtoxic intranuclear concentrations of trivalent chromium, while they can be clastogenic in vitro, do not appear to induce point mutations and thus are unlikely to mediate the carcinogenicity of hexavalent compounds. Furthermore, there is considerable doubt that sublethal doses of trivalent chromium can produce tissue levels high enough to induce clastogenic damage in vivo. These considerations elucidate the virtual non-toxicity of orally-administered trivalent chromium in any dose, and strongly suggest that dietary supplementation with trivalent chromium in reasonable amounts is unlikely to carry any genotoxic risk. However, further animal studies are advisable to rule out the possibility of clastogenicity when grossly 'megadose' amounts are ingested.

Animals↗
PubMed1997

Thalidomide may impede cell migration in primates by down-regulating integrin beta-chains: potential therapeutic utility in solid malignancies, proliferative retinopathy, inflammatory disorders, neointimal hyperplasia, and osteoporosis.

A growing number of human inflammatory disorders are reported to respond to treatment with thalidomide, and recently this drug has been shown to inhibit angiogenesis in the rabbit, in doses which can elicit teratogenicity in this species. Studies in marmosets and humans indicate that thalidomide, and a teratogenic analogue, decrease the expression of beta integrin subunits, most notably beta 3 and the beta 2 produced by leukocytes. Since integrins are crucial for cell-matrix interactions, and the beta 2 integrins of leukocytes mediate adhesion to endothelium, it is reasonable to postulate that thalidomide inhibits cell migration in susceptible species, and that this accounts for its anti-inflammatory, anti-angiogenic, and teratogenic activity. This perspective suggests that thalidomide will show utility in the prevention or treatment of a wide range of disorders, including solid tumors, proliferative retinopathies, many inflammatory diseases, neointimal hyperplasia, and osteoporosis. It is likely that dietary fish oil-as well as selective inhibitors of urokinase, when and if they become clinically available-will complement the efficacy of thalidomide in most if not all of these applications.

Animals↗
PubMed1997

Exploiting complementary therapeutic strategies for the treatment of type II diabetes and prevention of its complications.

Impaired glycemic control in type II diabetes results from peripheral insulin resistance, hepatic insulin resistance, and a relative failure of beta cell function. Nutritional and pharmaceutical measures are now available for addressing each of these defects, presumably enabling a rational and highly effective clinical management of non-insulin-dependent diabetes mellitus. Peripheral insulin resistance, which usually responds to a very-low-fat diet, aerobic exercise training, and appropriate weight loss, can also treated with high-dose chromium picolinate, high-dose vitamin E, magnesium, soluble fiber, and possibly taurine; these measures appear likely to correct the diabetes-associated metabolic derangements of vascular smooth muscle, and thus lessen risk for macrovascular disease. Metformin's clinical efficacy is primarily reflective of reduced hepatic glucose output; this action should complement the benefits of peripheral insulin sensitizers. When these measures are not sufficient for optimal control, beta cell function can be boosted with second-generation sulfonylureas.

Complementary Therapies↗
PubMed1997

Reported antiatherosclerotic activity of silicon may reflect increased endothelial synthesis of heparan sulfate proteoglycans.

Silicon plays a physiologically essential but mechanistically obscure role in promoting the synthesis of mucopolysaccharides and collagen. In light of reports that increased silicon ingestion impedes cholesterol-induced atherogenesis in rabbits and may be associated epidemiologically with reduced cardiovascular risk, it is reasonable to speculate that supplemental silicon may stimulate endothelial production of heparan sulfate proteoglycans that inhibit intimal hyperplasia.

Animals↗