Oral intake of bucillamine, carvedilol, metformin, or phenformin does not protect against UVR-induced squamous cell carcinomas in hairless mice.

Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice.

Regulation of bioenergetics through dual inhibition of aldehyde dehydrogenase and mitochondrial complex I suppresses glioblastoma tumorspheres.

Background: Targeted approaches for treating glioblastoma (GBM) attempted to date have consistently failed, highlighting the imperative for treatment strategies that operate on different mechanistic principles. Bioenergetics deprivation has emerged as an effective therapeutic approach for various tumors. We have previously found that cancer cells preferentially utilize cytosolic NADH supplied by aldehyde dehydrogenase (ALDH) for ATP production through oxidative phosphorylation (OxPhos). This study is aimed at examining therapeutic responses and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM. Methods: For inhibition of ALDH and OxPhos, the corresponding inhibitors, gossypol and phenformin were used. Biological functions, including ATP levels, stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). Gene expression profiles were analyzed using microarray data. In vivo anticancer efficacy was examined in a mouse orthotopic xenograft model. Results: Combined treatment of GBM TSs with gossypol and phenformin significantly reduced ATP levels, stemness, invasiveness, and cell viability. Consistently, this therapy substantially decreased expression of genes associated with stemness, mesenchymal transition, and invasion in GBM TSs. Supplementation of ATP using malate abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting that disruption of ALDH-mediated ATP production is a key mechanism of this therapeutic combination. In vivo efficacy confirmed remarkable therapeutic responses to combined treatment with gossypol and phenformin. Conclusion: Our findings suggest that dual inhibition of tumor bioenergetics is a novel and effective strategy for the treatment of GBM.

An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis.

The mitochondrial electron transport chain (ETC) enables many metabolic processes, but why its inhibition suppresses cell proliferation is unclear. It is also not well understood why pyruvate supplementation allows cells lacking ETC function to proliferate. We used a CRISPR-based genetic screen to identify genes whose loss sensitizes human cells to phenformin, a complex I inhibitor. The screen yielded GOT1, the cytosolic aspartate aminotransferase, loss of which kills cells upon ETC inhibition. GOT1 normally consumes aspartate to transfer electrons into mitochondria, but, upon ETC inhibition, it reverses to generate aspartate in the cytosol, which partially compensates for the loss of mitochondrial aspartate synthesis. Pyruvate stimulates aspartate synthesis in a GOT1-dependent fashion, which is required for pyruvate to rescue proliferation of cells with ETC dysfunction. Aspartate supplementation or overexpression of an aspartate transporter allows cells without ETC activity to proliferate. Thus, enabling aspartate synthesis is an essential role of the ETC in cell proliferation.

[Effect of phenformin hydrochloride on pharmacokinetics of puerarin in rats].

OBJECTIVE: To study the effect of phenformin hydrochloride that may be illegally added in traditional Chinese medicine preparations on the pharmacokinetics of puerarin in rats. METHOD: Rats were randomly divided into the single pueraria group and the phenformin hydrochloride combined with pueraria group. After oral administration in the two groups, their bloods were sampled at different time points to determine the drug concentration of puerarin in rat blood and calculate pharmacokinetic parameters. RESULT: After oral administration with pueraria extracts and phenformin hydrochloride combined with pueraria extracts, the two groups showed main pharmacokinetic parameters as follows: Cmax were (2.39 +/- 1.01), (1.03 +/- 0.35) mg x L(-1), respectively; Tmax were (0.50 +/- 0.09), (1.5 +/- 0.5) h, respectively; Ke were (0.153 +/- 0.028), (0.172 +/- 0.042) h(-1), respectively; t(1/2) were (4.65 +/- 0.86), (4.20 +/- 0.81) h, respectively; AUC(0-t), were (5.73 +/- 2.60), (5.45 +/- 1.81) mg x h x L(-1), respectively; AUC(0-infinity) were (6.72 +/- 2.89), (6.26 +/- 1.88) mg x h x L(-1), respectively. Compared with the single puerarin group, the Cmax was significantly decreased (P < 0.05) and the Tmax was markedly longer (P < 0.01) than the hydrochloride combined with pueraria group. CONCLUSION: Phenformin hydrochloride can slow down the absorption process of puerarin and change the pharmacokinetic process of puerarin to some extent.

Antihyperglycemic activity of Euphrasia officinale leaves.

The effects of the aqueous extract of the leaf of Euphrasia officinale on blood glucose levels in normal and alloxan-diabetic rats were investigated. The treatment of alloxan-induced diabetic rats brought down the raised glucose levels, while the extract was devoid of hypoglycemic effect in normal rats.

Longevity effect of chromium picolinate--'rejuvenation' of hypothalamic function?

The first rodent longevity study with the insulin-sensitizing nutrient chromium picolinate has reported a dramatic increase in both median and maximal lifespan. Although the observed moderate reductions in serum glucose imply a decreased rate of tissue glycation reactions, it is unlikely that this alone can account for the substantial impact on lifespan; an effect on central neurohormonal regulation can reasonably be suspected. Recent studies highlight the physiological role of insulin as a modulator of brain function. I postulate that aging is associated with a reduction of effective insulin activity in the brain, and this contributes to age-related alterations of hypothalamic functions that result in an 'older' neurohormonal milieu; consistent with this possibility, diabetes leads to changes of hypothalamic regulation analogous to those seen in normal aging. Conversely, promoting brain insulin activity with chromium picolinate may help to maintain the hypothalamus in a more functionally youthful state; increased hypothalamic catecholamine activity, sensitization of insulin-responsive central mechanisms regulating appetite and thermogenesis, and perhaps trophic effects on brain neurons may play a role in this regard. Since both the pineal gland and thymus are dependent on insulin activity, chromium may aid their function as well. Thus, the longevity effect of chromium picolinate may depend primarily on delay or reversal of various age-related changes in the body's hormonal and neural milieu. A more general strategy of hypothalamic 'rejuvenation' is proposed for extending healthful lifespan.

Homologous physiological effects of phenformin and chromium picolinate.

The insulin-sensitizing drug phenformin, in addition to its clinical utility in type II diabetes, has been reported to lower blood lipids, reduce body fat, enhance cellular immunity, and--in rodents--to increase mean lifespan and retard the development of growth of cancer. Initial studies with the insulin-sensitizing nutrient chromium picolinate indicate that it aids glucose tolerance in type II diabetes, lowers elevated LDL cholesterol, reduces body fat while increasing lean mass, and--in rats--increases median lifespan. These effects are thus analogous to those reported for phenformin; chromium picolinate should be tested to determine whether it likewise has a favorable impact on cellular immunity and cancer risk. The ability of both phenformin and chromium picolinate to increase lifespan suggests that age-related insulin resistance may play a profound role in the aging process. It may not be coincidental that caloric restriction--the best documented technique for increasing lifespan--markedly increases insulin sensitivity. Safe, appropriate measures for promoting lifelong insulin sensitivity include a low-fat diet, exercise training, and supplemental chromium picolinate.

Effects of jambolan seed treatment on blood sugar, lipids and urea in streptozotocin induced diabetes in rabbits.

In New Zealand rabbits a single intravenous injection of streptozotocin (STZ 65 mg/kg) elevated the levels of blood sugar to 340 mg percent, which was associated with glycolysis, ureamia, hypercholesterolemia, hypertriglyceridemia and loss of body weight. Oral administration of jambolan seed (1 g/kg) in casein diet significantly lowered the elevated postmeal (1 1/2 hr after) values of blood sugar, cholesterol, FFA and triglyceride down to levels comparable to phenformin. Jambolan seed treatment failed to check ureamia. Weight loss was checked by phenformin and jambolan seed but the gain was not equivalent to that recorded in nondiabetic control. Like phenformin, jambolan seed too failed to control glycogenolysis in STZ-induced diabetes.

[Hypolactatemic effect of sodium difluoroacetate]. / Etude de l'effet hypolactatémiant du difluoroacétate de sodium.

In the anesthetized rat, the intraperitoneal injection of 40 mg/kg sodium difluoroacetate (DFA), an activator of the pyruvate dehydrogenase, counteracted the hyperlactatemia induced by a high dose of phenformin (40 mg/kg) injected concomitantly. In the normal conscious dog, the administration of 150 mg/kg by gastric intubation decreased the blood lactate and pyruvate levels; however, this effect was less marked than that produced by the same dose of sodium dichloroacetate (DCA).

[Endogenous hyperlactatemia and insulin secretion]. / Hyperlactatémies endogènes et insulino-sécrétion.

In the normal anesthetized dog, the endogenous hyperlactatemia induced either by intense muscular work or by a high dose of phenformin (20 mg/kg subtucaneously) is followed by an increase in the pancreaticoduodenal insulin output. A previous perfusion of sodium dichloroacetate (50 mg/kg. h) opposes the hyperlactatemia, and reduces or suppresses the increase in insulin output.

[An increase in hypothalamic sensitivity to the inhibiting effects of estrogens caused by use of L-DOPA, diphenine, epithalamin and phenformin in old rats]. / Povyshenie chuvstvitel'nosti gipotalamusa k ingibiruiushchemu deistviiu éstrogenov, vyzvannoe primeneniem L-DOFA, difenina, épitalamina i fenformina u starykh krys

Daily treatment of hemicastrated young rats with 0.57 mug of stilbestrol inhibited compensatory ovarian hypertrophy (COH) by 48% in the 3-month animals and by 3% only in the 18-month animals. Administration of L-DOPA, dilantin, epithalamin or phenoformin with the same dose of estrogen to old rats suppressed the COH by 65-98%. L-DOPA and epithalamin were effective when administered into the 3rd cerebral ventricle. A functional nature of the age changes in the hypothalamic sensitivity to the estrogen action is suggested.

Hypoglycaemic effects of onion, Allium cepa Linn. on diabetes mellitus - a preliminary report.

Hypoglycaemic fractions of A. cepa Linn (onion) have been separated. After 7 days treatment, the more active hypoglycaemic fraction was about half as active as Phenformin in lowering the fasting blood sugar of alloxan-diabetic rabbits. Oral administration of the hypoglycaemic fraction to alloxan-diabetic rabbits improved their glucose tolerance also. Juice expressed residue of onion, when fed to diabetic patients along with their food, controlled the hyperglycaemia effectively.

The effect of phenformin-HCl on patients with diabetes mellitus, studied under strict balance conditions.

Under strict balance conditions we studied the effect of phenformin in 5 patients with diabetes mellitus. In all cases phenformin lowered the blood glucose values, and all patients showed a reduction of glycosuria. Contrary to other reports body weight increased during phenformin treatment. This was accompanied by positive nitrogen, phosphorus and calcium balances. The weight gain can be explained by the positive caloric balance, mainly caused by the diminished glycosuria. No change in B.M.R. or R.Q. was seen. During phenformin treatment there was a drop in cholesterol and total lipid levels in 4 patients. No conclusions could be drawn about the effect of phenformin on triglycerides, phospholipids and lipoprotein spectra. Phenformin treatment did not affect the disappearance of glucose, nor the insulin levels after intravenous glucose loading. During oral glucose loading phenformin caused a significant fall in blood glucose levels, accompanied by an increased insulin response in one patient. In the other 4 patients phenformin had no effect on either parameter.