Lactate as a signaling molecule: Journey from dead end product of glycolysis to tumor survival.

Global metabolism of cancers exhibits a peculiar phenotype that is lactate acidosis (high lactate with acidic pH) in tumor microenvironment. Why tumor microenvironment becomes so responsive towards lactate is still not clear. In this review we have discussed lactate generation and recycling either exogenously, directly or indirectly by cancer cells via some transporters. Tumor cells in hypoxia use glucose rapidly and produce lactate while cells which have profuse oxygen supply take up lactate and use it for energy production which is referred as lactate shuttling between tumor cells. Escaping immune evasion which is also an emerging hallmark of cancer cells has also been discussed in this review with respect of lactate acidosis.

An Overview of Natural Plant Products in the Treatment of Hepatocellular Carcinoma.

BACKGROUND: Liver cancer is the fifth most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Among the liver cancers, hepatocellular carcinoma has been reported to be responsible for 85-90% of primary liver cancer and it is the second most common cause of cancer mortality with 700,000 deaths documented annually. The major risk factors of HCC include chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) virus, chronic liver diseases, alcoholism as well as dietary carcinogens, such as aflatoxins. Highest incidence rates are estimated to occur in Asia and Africa. OBJECTIVE: The effectiveness of current man-made agents in treating chronic liver disease is not satisfactory and they have uninvited side effects. Herbal medicines are extensively used all over the world; however, there is still a vast gap in their acceptance by the scientific community. Plants are rich in secondary metabolites and phytochemicals obtained from both, dietary and non-dietary sources. Natural plant products are potent therapeutic as well as chemopreventive agents for numerous chronic diseases like cardiovascular, metabolic, neurodegenerative and neoplastic diseases. RESULTS: Dietary phytochemicals such as curcumin, resveratrol, quercetin, silibinin, N-trans-feruloyl octopamine, lycopene, emodin, caffeine, urolithin A and Phloretin have been found to be useful for the treatment of HCC and other diseases. According to recent reports 60% of the anticancer medication in current use has been obtained from natural sources. CONCLUSION: Thus, derivatives from plants have played an essential role in cancer prevention due to their pleiotropic abilities to scavenge free radicals, inhibit cell growth and induce apoptosis.

Moderate grade hyperammonemia activates lactate dehydrogenase-4 and 6-phosphofructo-2-kinase to support increased lactate turnover in the brain slices.

Rapid metabolism of lactate is an important aspect of bioenergetic adaptation in the brain during non-physiological conditions. The low grade hyperammonemia (HA) is a common condition in the patients with chronic hepatic encephalopathy (HE); however, biochemistry of lactate turnover during low grade HA remains poorly defined. The present article describes profile of lactate dehydrogenase (LDH) isozymes vis-a-vis lactate level in the brain slices exposed with 0.1-0.5 mM ammonia, found to exist in the brain during chronic HE. A significant increment in LDH activity coincided with a similar increase in lactate level in the brain slices exposed with 0.5 mM ammonia. This was consistent with a selective increment of LDH-4 that synthesizes lactate from pyruvate with a concomitant decline in LDH-1 which catalyzes conversion of lactate to pyruvate; resulting into ~3-fold increase in LDH-4/LDH-1 ratio in those brain slices. The PFK2 domain of PFK2/FBPase2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) regulates glycolysis to maintain the pyruvate pool for lactate synthesis. The PFK2 expression was also observed to be increased ~2-fold (P < 0.001) in 0.5 mM ammonia treated brain slices. These findings provide enzymatic regulation of increased lactate turnover in the brain exposed with moderate HA.

Targetting cancer with Ru(III/II)-phosphodiesterase inhibitor adducts: a novel approach in the treatment of cancer.

Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer agents in current use. Due to effective biodistribution and multimodal cellular actions, during recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate (cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate delivery of the drugs/compounds to the tumor site. Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to administration of such complexes.

Moderate grade hyperammonemia induced concordant activation of antioxidant enzymes is associated with prevention of oxidative stress in the brain slices.

Acute hyperammonemia (HA) induced oxidative stress in the brain is considered to play critical roles in the neuropathology of end stage hepatic encephalopathy (HE). Moderate grade HA led minimal/moderate type HE is more common in the patients with chronic liver failure. However, implication of oxygen free radical ([Formula: see text]) based oxidative mechanisms remain to be defined during moderate grade HA. This article describes profiles of all the antioxidant enzymes Vis a Vis status of oxidative stress/damage in the brain slices exposed to 0.1-1 mM ammonia, reported to exist in the brain of animals with chronic liver failure and in liver cirrhotic patients. Superoxide dismutase catalyzes the first step of antioxidant mechanism and, with concerted activity of catalase, neutralizes [Formula: see text] produced in the cells. Both these enzymes remained unchanged up to 0.2-0.3 mM ammonia, however, with significant increments (P < 0.01-0.001) in the brain slices exposed to 0.5-1 mM ammonia. This was consistent with the similar pattern of production of reactive oxygen species in the brain slices. However, level of lipid peroxidation remained unchanged throughout the ammonia treatment. Synchronized activities of glutathione peroxidase and glutathione reductase regulate the level of glutathione to maintain reducing equivalents in the cells. The activities of both these enzymes also increased significantly in the brain slices exposed to 0.5-1 mM ammonia with concomitant increments in GSH/GSSG ratio and in the levels of total and protein bound thiol. The findings suggest resistance of brain cells from ammonia induced oxidative damage during moderate grade HA due to concordant activations of antioxidant enzymes.