Silimarin and Cancer.

BACKGROUND: Silimarin is the dry mixture of a whole family of natural substances, extracted after the addition of ethanol, methanol, and acetone. Silimarin consists mainly of silibin A and silibin B, as well as other less important compounds. METHODS: Silimarin has been demonstrated to "inhibit cell proliferation and to induce apoptosis, while also having anti-angiogenic properties." The induction of apoptosis in cancer cells has been mediated by the involvement of ER stress. RESULTS: Silibinin has the potential to operate as a STAT3-targeted inhibitor as well as an inhibitor of the upregulation of the immune checkpoint regulator PD-L1 and also EMT regulators, thus being a promising adjuvant in NSCLC. It has also been documented to suppress cancer cells be means of down- regulating actin cytoskeleton and PI3K / Akt molecular pathways. Several studies have demonstrated that silibinin exerts its protective potential partly through interacting with the tumor suppressor gene p53. CONCLUSIONS: It is noteworthy that research has been carried out on the enhancement of silimarin's bioavailability, especially by the preparation of specific nanoformulas, and its probable additional use together with the chemotherapeutic regimens in the near future.

Diabetic hepatosclerosis: True clinical entity or ghost disease?

Diabetic hepatosclerosis is a novel entity that has recently been introduced by reviewing archived liver biopsies as a non-cirrhotic form of peri-sinusoidal fibrosis with basement membrane formation. Diabetic hepatosclerosis is usually characterized by an indolent clinical course. Serum aminotransferase levels are normal or minimally elevated, but elevated alkaline phosphatase levels is usually present. Clinically relevant to DH is the co-existence of other diabetic microvascular complications in the same patient, such as ESRD on long-term dialysis or renal transplantation, retinopathy, or neuropathy. Although it seems that DH occurs in patients with type 1 more often than type 2 diabetes mellitus, the true prevalence of this entity still remains unknown. Future prospective studies should include long-term follow-up to examine the natural history and to explore treatment options for this form of hepatic micro-angiopathy disease.

Sodium glucose co-transporter 2 inhibitors and their nephroprotective potential
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Chronic kidney disease among patients with diabetes is on the rise. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose reabsorption in the kidney, thereby increasing glucosuria and decreasing serum glucose levels. Data suggest that they possess nephroprotective properties. It is noteworthy that the efferent glomerular arteriole is 10 - 100 times more sensitive to the vasoconstrictive properties of angiotensin II than the afferent one and this might account for the consequently higher intra-glomerular capillary pressure, which is believed to be the cornerstone of diabetic nephropathy. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1 - 7), which exerts vasodilatory and anti-inflammatory effects. In this review, the nephroprotective potential of this novel class of glucose-lowering drugs will be further discussed.
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SGLT-2 inhibitors: Their pleiotropic properties.

Type 2 diabetes mellitus has become a global pandemic. Nowadays, it is estimated that approximately 415 million people all over the world have diabetes. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose re-absorption in the kidney, thereby increasing glycosuria and decreasing serum glucose levels. Data suggest that apart from lowering HbA1c, they produce a small but significant weight loss and a small decrease in blood pressure. Also, they possess nephro-protective potential. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1-7), which exerts vasodilatory and anti-inflammatory effects. Their profile on cardiovascular events is still under investigation. In this review, the pleiotropic potential of this novel class of glucose-lowering levels will be discussed. Further research is warranted to determine their safety in the long term.

Potential anticancer properties and mechanisms of action of curcumin.

Curcumin, a yellow substance belonging to the polyphenols superfamily, is the active component of turmeric, a common Indian spice, which is derived from the dried rhizome of the Curcuma longa plant. Numerous studies have demonstrated that curcumin possesses anti-oxidant, anti-inflammatory and anticancerous properties. The purpose of this review is to focus on the anti-tumor effects of curcumin. Curcumin inhibits the STAT3 and NF-κB signaling pathways, which play key-roles in cancer development and progression. Also, inhibition of Sp-1 and its housekeeping gene expressions may serve as an important hypothesis to prevent cancer formation, migration, and invasion. Recent data have suggested that curcumin may act by suppressing the Sp-1 activation and its downstream genes, including ADEM10, calmodulin, EPHB2, HDAC4, and SEPP1 in a concentration-dependent manner in colorectal cancer cell lines; these results are consistent with other studies, which have reported that curcumin could suppress the Sp-1 activity in bladder cancer and could decrease DNA binding activity of Sp-1 in non-small cell lung carcinoma cells. Recent data advocate that ER stress and autophagy may as well play a role in the apoptosis process, which is induced by the curcumin analogue B19 in an epithelial ovarian tumor cell line and that autophagy inhibition could increase curcumin analogue-induced apoptosis by inducing severe ER stress. The ability of curcumin to induce apoptosis in tumor cells and its anti-angiogenic potential will be discussed in this review.

The therapeutic potential of milk thistle in diabetes.

Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.

Statins and cancer.

Statins have pleiotropic properties and might exert an effect even in the field of cancer. Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid. Specifically, inhibition of HMG-CoA reductase by statins has been proved to prevent the synthesis of mevalonic acid, a precursor of non-steroidal isoprenoids, which are lipid attachment molecules for small G proteins, such as Ras, Rho and Rac. Thus, statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins. In addition, statins exert pro-apoptotic, anti-angiogenic, and immunomodulatory effects, which may prevent cancer growth. Statins may inhibit the growth of a variety of cancer cell types, including breast, gastric, pancreatic, and prostate carcinoma, neuroblastoma, melanoma, mesothelioma and acute myeloid leukemia cells. They exert pro-apoptotic effects in a wide range of cancer cell lines, but with many differences in the sensitivity to statin-induced cell death among different cancer cell types. Regarding anti-angiogenic effects, multiple statin effects on blood vessel formation by inhibition of angiogenesis through down-regulation of pro-angiogenic factors, such as vascular endothelial growth factor, inhibition of endothelial cell proliferation and inhibition of adhesion to extracellular matrix by blocking intercellular adhesion molecules have been suggested. The molecular mechanisms of statin immunomodulation often implicate multiple pathways, regarding the regulation of genes encoding key molecules, which are involved in antigen presentation and subsequent immunomodulation. Another mechanism involves the down-regulation of the nuclear factor-kappa-B, which is responsible for the transcription of many genes involved in immunologic mechanisms, such as interferon-inducible protein-10, monocyte chemo-attractant protein 1 and cyclooxygenase-2. Statins have been associated with a significantly lower risk of breast, colorectal, ovarian, pancreatic, lung cancers and lymphoma in several observational studies. On the other hand, other studies, including meta-analyses have raised concerns about the safety of statins among elderly patients. A recent study upon the relationship between statin use (prior to cancer diagnosis) and cancer-related mortality in the entire Danish population from 1995-2009 in adults > 40 years of age has been conducted. As compared to statin non-users, patients using statins prior to cancer diagnosis were 15% less likely to die from any cause or cancer specifically. Further investigation is needed to elaborate on their mode of action as well as their true significance on cancer prevention and perhaps as an adjuvant to cancer chemotherapy.

Resveratrol and diabetes.

Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.

Metformin and cancer.

Metformin is well-known as an anti-diabetic drug, but it seems to possess anti-cancerous properties as well. Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved regulator of the cellular response to the presence of low energy in all eukaryotic cells. It is considered a key sensor of the balance of cellular ATP and AMP concentrations. LKB1 serine/threonine kinase is a divergent yet evolutionarily well-conserved kinase, biochemically sufficient to activate AMPK in vitro and genetically required for AMPK activation. Because of this potent connection to AMPK, LKB1 may act as a central regulator of metabolism in vivo. Once activated, AMP kinase phosphorylates the transcriptional activator TorC2, thereby blocking its nuclear translocation and inhibiting the expression of genes involved in gluconeogenesis. Data suggest that LKB1/AMPK signaling plays a role in protection from apoptosis, specifically in response to agents that increase the cellular AMP/ATP ratio. Active AMPK signaling offers a protective effect by providing the cell with time to reverse the aberrantly high ratio of AMP/ATP. If unable to reverse this ratio, the cell will eventually undergo cell death. These observations offer the provocative suggestion of a potential therapeutic window in which LKB1-deficient tumor cells may be acutely sensitive to AMP analogues or sensitized to cell death by other stimuli when treated in combination with agents that increase the AMP/ATP ratio. LKB1 therefore is a classical tumor suppressor. AMPK is a direct LKB1 substrate. A consequence of AMPK activation by LKB1 is the inhibition of the mammalian target of rapamycin (mTOR) C1 pathway. Metformin's anti-cancerous properties have been demonstrated in various cancer cells in vitro, such as lung, pancreatic, colon, ovarian, breast, prostate, renal cancer cells, melanoma, and even in acute lymphoblastic leukemia cells. To test metformin's action in vivo, mice were implanted with transformed mammary epithelial cells and treated with three cycles of metformin and with the anthracycline doxorubicin. When combined with doxorubicin, metformin wiped out tumors and prevented recurrence. Metformin alone had no effect, and doxorubicin as a single agent initially shrank tumors, but they regrew later. Virtually no cancer stem cells were recovered immediately after treatment and the complete response was sustained for nearly two months. Further studies are needed to assess the anti-cancerous potentials of metformin in vivo. This article reviews the current knowledge on the actions of LKB1/AMPK and the effectiveness of metformin in cancer, specifically in diabetes patients.