Cisplatin in cancer treatment.

Cisplatin is a widely used chemotherapy agent in the treatment of various forms of carcinomas and sarcomas. Its effectiveness in delaying negative outcome in cancer patients has been amply documented, and attributed primarily to its ability to crosslink DNA purine bases, thus interfering with DNA repair mechanisms in cancer cells. Ultimately, this interference causes DNA damage and leads to cell apoptosis. However, the chemotherapy use of cisplatin and cisplatin-derivatives is hampered by the occurrence of major side effects in a significant percentage of cancer patients, thus limiting considerably its prolonged utilization. Acute kidney injury, gastrointestinal disorders, hemorrhage, and decreased immune response to infections are among the most common side-effects observed. On the other hand, synergistic utilization of cisplatin with other anti-cancer agents and especially its ability to induce immunomodulation in otherwise immune-depressed patients has gained significant therapeutic traction in recent times, validating the continuing clinical utilization of this agent and its derivatives. In this review, we will examine the basic physico-chemical properties of cisplatin and related derivatives, and discuss the main molecular mechanisms of actions that results in the therapeutic benefit of this class of anti-cancer agents but also in the development of major organ complications. Lastly, we will address the more recent conceptual utilization of cisplatin-induced anti-cancer immunomodulation in synergistic therapies that can also benefit of the traditional chemotherapy advantages of this class of anti-cancer agents.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

The Relationship between Obesity and Pre-Eclampsia: Incidental Risks and Identification of Potential Biomarkers for Pre-Eclampsia.

Obesity has been steadily increasing over the past decade in the US and worldwide. Since 1975, the prevalence of obesity has increased by 2% per decade, unabated despite new and more stringent guidelines set by WHO, CDC, and other public health organizations. Likewise, maternal obesity has also increased worldwide over the past several years. In the United States, pre-pregnancy rates have increased proportionally across all racial groups. Obesity during pregnancy has been directly linked to obstetric complications including gestational diabetes, HTN, hematomas, pre-eclampsia, and congenital defects. In the particular case of pre-eclampsia, the incidence rate across the globe is 2.16%, but the condition accounts for 30% of maternal deaths, and a robust body of evidence underscored the relationship between obesity and pre-eclampsia. More recently, attention has focused on the identification of reliable biomarkers predictive of an elevated risk for pre-eclampsia. The aim of this literature review is to elucidate the relationship between obesity and these predictive biomarkers for future prediction and prevention of pre-eclampsia condition in women at risk.

The controversy on the beneficial effect of phytoestrogens in diabetic treatment in postmenopausal women.

Phytoestrogens have been identified as a natural, plant-based alternative to synthetically derived estrogens, to supplement the absence of endogenous estrogens in post-menopausal women, and attenuate the progression of pathologies and side-effects associated with menopause. The increased availability of these plant's derived compounds as diet or nutritional supplements makes their ingestion and consumption easier and more accessible as compared to pharmacological alternatives. Further, phytoestrogen intake has shown beneficial effects as estrogens alternatives in attenuating severe complications in diseases such as type 2 diabetes, metabolic syndrome, NAFLD, and obesity. However, in many cases phytoestrogen effectiveness remains largely circumstantial or just anecdotal as significant uncertainties on the relative abundance of different phytoestrogens in a given diet, the need for conversion to an active principle through the gut microbiome, the possibility of an effect threshold, the synergistic effect of different phytoestrogens possible due to different modality of actions still persist. The present article aims at highlighting the main issues and concerns plaguing the field as well as some of the possible causes of inconsistencies observed in the various nutritional and clinical studies attempted so far.

Erratum to "Nonpharmacologic Interventions in Prevention and Treatment of Hypertension".

[This corrects the article DOI: 10.1155/2019/6709817.].

Progesterone and cAMP synergize to inhibit responsiveness of myometrial cells to pro-inflammatory/pro-labor stimuli.

Progesterone (P4) acting through the P4 receptor (PR) isoforms, PR-A and PR-B, promotes uterine quiescence for most of pregnancy, in part, by inhibiting the response of myometrial cells to pro-labor inflammatory stimuli. This anti-inflammatory effect is inhibited by phosphorylation of PR-A at serine-344 and -345 (pSer344/345-PRA). Activation of the cyclic adenosine monophosphate (cAMP) signaling pathway also promotes uterine quiescence and myometrial relaxation. This study examined the cross-talk between P4/PR and cAMP signaling to exert anti-inflammatory actions and control pSer344/345-PRA generation in myometrial cells. In the hTERT-HMA/B immortalized human myometrial cell line P4 inhibited responsiveness to interleukin (IL)-1ß and forskolin (increases cAMP) and 8-Br-cAMP increased this effect in a concentration-dependent and synergistic manner that was mediated by activation of protein kinase A (PKA). Forskolin also inhibited the generation of pSer344/345-PRA and expression of key contraction-associated genes. Generation of pSer344/345-PRA was catalyzed by stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Forskolin inhibited pSer344/345-PRA generation, in part, by increasing the expression of dual specificity protein phosphatase 1 (DUSP1), a phosphatase that inactivates mitogen-activated protein kinases (MAPKs) including SAPK/JNK. P4/PR and forskolin increased DUSP1 expression. The data suggest that P4/PR promotes uterine quiescence via cross-talk and synergy with cAMP/PKA signaling in myometrial cells that involves DUSP1-mediated inhibition of SAPK/JNK activation.

Beneficial Role of Mg2+ in Prevention and Treatment of Hypertension.

Hypertension constitutes one of the most widespread pathological conditions in developed and developing countries. Currently, more than 1 billion people worldwide are affected by the condition, either as frank hypertension or as prehypertension, raising the risk for major long-term complications and life-threatening pathologies. The costs in terms of health care services, medications for the treatment of hypertension and its complications, and associated loss in productivity represent a major economic burden for the various countries. The necessity of developing treatments that are economically more sustainable and with better compliance has been increasing alongside the incidence of the pathology. Along these lines, attention has been paid to the implementation of affordable but nutritious diets that deliver appropriate levels of macro- and micronutrients as integral part of the diets themselves or as supplements. In particular, experimental and clinical evidence suggests that an appropriate intake of dietary magnesium can be beneficial in controlling blood pressure. Additional advantages of a more diffuse therapeutic and/or preventive utilization of magnesium supplements are the virtual absence of side-effects and their affordable costs. The present review will attempt to frame our knowledge of how magnesium exerts its beneficial effects on blood pressure maintenance, which may lead to the development of more effective treatments of hypertension and its main complications.

The Metabolic Syndrome and the Relevance of Nutrients for its Onset.

BACKGROUND: Metabolic Syndrome is a pathological condition characterized by the copresence of various dysmetabolic and pathological processes including hypertension, dyslipidemia, type 2 diabetes mellitus, obesity, and cardiovascular complications. Because these conditions manifest themselves differently in a given patient, the ensuing pathophysiological state varies from patient to patient. Consequently, the order in which signs and symptoms manifest themselves can vary, making difficult to establish cause-effect relationship, and efficacious treatment and prevention options. Furthermore, the available therapeutic options do not necessarily apply in an effective manner to all patients due to the modality of the syndrome's onset and progression, and the fact that each patient presents different clinical manifestations. RESULTS: Where do the metabolic disturbances originate? Genetic predisposition, maternal health, age, and ethnicity are possible influential factors, which put individuals at higher risk for developing metabolic defects. More recently, dietary factors and deficiency in key macro- and micro-nutrients have been indicated as key players in the onset and progression of the disease. We revised all possible patents applying to this topic. Aside from pharmacological agents used to treat specific medical conditions, no patents were observed to be registered for specific dietary macro- and micro-nutrients. CONCLUSION: The present review attempts to provide a framework to help the reader understand the causes behind the development of the metabolic syndrome and its complication.

Effect of acute and prolonged alcohol administration on Mg(2+) homeostasis in cardiac cells.

Alcoholic cardiomyopathy represents a major clinical complication in chronic alcoholics. Previous studies from our laboratory indicate that acute and chronic exposure of liver cells to ethanol results in a major loss of cellular Mg(2+) as a result of alcohol oxidation. We investigated whether exposure to ethanol induces a similar Mg(2+) loss in cardiac cells. The results indicate that chronic exposure to a 6% ethanol-containing diet depleted cardiac myocytes of >25% of their cellular Mg(2+) content. Acute ethanol exposure, instead, induced a time- and dose-dependent manner of Mg(2+) extrusion from perfused hearts and collagenase-dispersed cardiac ventricular myocytes. Pretreatment with chlormethiazole prevented ethanol-induced Mg(2+) loss to a large extent, suggesting a role of ethanol oxidation via cyP4502E1 in the process. Magnesium extrusion across the sarcolemma occurred via the amiloride-inhibited Na(+)/Mg(2+) exchanger. Taken together, our data indicate that Mg(2+) extrusion also occurs in cardiac cells exposed to ethanol as a result of alcohol metabolism by cyP4502E1. The extrusion, which is mediated by the Na(+)/Mg(2+) exchanger, only occurs at doses of ethanol ≥0.1%, and depends on ethanol-induced decline in cellular ATP. The significance of Mg(2+) extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated.

The trigger-maintenance model of persistent mild to moderate hyperoxaluria induces oxalate accumulation in non-renal tissues.

Persistent mild to moderate hyperoxaluria (PMMH) is a common side effect of bariatric surgery. However, PMMH's role in the progression to calcium oxalate (CaOx) urolithiasis and its potential effects on non-renal tissues are unknown. To address these points, a trigger + maintenance (T + Mt) model of PMMH was developed in rats (Experiment 1). The trigger was an i.p. injection of PBS (TPBS) or 288 µmol sodium oxalate (T288). Maintenance (Mt) was given via minipumps dispensing PBS or 7.5-30 µmol potassium oxalate/day for 28 days. Urinary oxalate ranged from 7.7 ± 0.8 µmol/day for TPBS + MtPBS to 18.2 ± 1.5 µmol/day for T288 + Mt30 (p ≤ 0.0005). All rats receiving T288 developed CaOx nephrocalcinosis, and many developed 'stones'. This was also true for Mt doses that did not elevate urinary oxalate above that of TPBS + MtPBS (p > 0.1) and for rats that did not have a detectable surge in urinary oxalate post T288. When TPBS was administered, CaOx nephrocalcinosis did not develop regardless of the Mt dose even if urinary oxalate was elevated compared to TPBS + MtPBS (p ≤ 0.0005). One of the risks associated with PMMH is oxalate accumulation within tissues. Hence, in a second set of experiments (Experiment 2) different doses of oxalate (Mt0.05, Mt15, Mt30) labeled with (14)C-oxalate ((14)C-Ox) were administered by minipump for 13 days. Tissues were harvested and (14)C-Ox accumulation assessed by scintillation counting. (14)C-Ox accumulated in a dose dependent manner (p ≤ 0.004) in bone, kidney, muscle, liver, heart, kidney, lungs, spleen, and testis. All these tissues exhibited (14)C-Ox concentrations higher (p ≤ 0.05) than the plasma. Extrapolation of our results to patients suggests that PMMH patients should take extra care to avoid dietary-induced spikes in oxalate excretion to help prevent CaOx nephrocalcinosis or stone development. Monitoring for oxalate accumulation within tissues susceptible to damage by oxalate or CaOx crystals may also be required.

Magnesium homeostasis in Mammalian cells.

Magnesium, the second most abundant cation within the cell, plays an important role in numerous biological functions. Experimental evidence indicates that mammalian cells tightly regulate cellular magnesium ion content through specific mechanisms controlling Mg(2+) entry and efflux across the cell membrane and the membrane of various cellular organelles as well as intracellular Mg(2+) buffering under resting conditions and following hormonal and metabolic stimuli. This chapter will provide an assessment of the various mechanisms controlling cellular Mg(2+) homeostasis and transport, and the implications changes in cellular Mg(2+) content play under physiological and pathological conditions.

Magnesium in health and disease.

Mammalian cells tightly regulate cellular Mg(2+) content through a variety of transport and buffering mechanisms under the control of various hormones and cellular second messengers. The effect of these hormones and agents results in dynamic changes in the total content of Mg(2+) being transported across the cell membrane and redistributed within cellular compartments. The importance of maintaining proper cellular Mg(2+) content optimal for the activity of various cellular enzymes and metabolic cycles is underscored by the evidence that several diseases are characterized by a loss of Mg(2+) within specific tissues as a result of defective transport, hormonal stimulation, or metabolic impairment. This chapter will review the key mechanisms regulating cellular Mg(2+) homeostasis and their impairments under the most common diseases associated with Mg(2+) loss or deficiency.

Modulation of cellular Mg2+ content in cardiac cells by α1-adrenoceptor stimulation and anti-arrhythmic agents.

Magnesium (Mg(2+)) is used pharmacologically to sedate specific forms of arrhythmias. Administration of pharmacological doses of catecholamine or adrenergic receptor agonists often results in arrhythmias onset. Results from the present study indicate that stimulation of cardiac adrenergic receptors elicits an extrusion of cellular Mg(2+) into the extracellular space. This effect occurs in both perfused hearts and isolated cells within 5-6 min following either ß- or α1- adrenergic receptor stimulation, and is prevented by specific adrenergic receptors antagonists. Sequential stimulation of the two classes of adrenergic receptor results in a larger mobilization of cellular Mg(2+) provided that the two agonists are administered together or within 1-2 min from each other. A longer delay in administering the second stimulus results in the abolishment of Mg(2+) extrusion. Hence, these data suggest that the stimulation of ß- and α1-adrenergic receptors mobilizes Mg(2+) from two distinct cellular pools, and that Mg(2+) loss from either pool triggers a Mg(2+) redistribution within the cardiac myocyte. At the sarcolemmal level, Mg(2+) extrusion occurs through a Na(+)/Mg(2+) exchange mechanism phosphorylated by cAMP. Administration of quinidine, a patent anti-arrhythmic agent, blocks Na(+) transport in a non-specific manner and prevents Mg(2+) extrusion. Taken together, these data indicate that catecholamine administration induces dynamic changes in total and compartmentalized Mg(2+) pools within the cardiac myocytes, and suggest that prevention of Mg(2+) extrusion and redistribution may be an integral component of the effectiveness of quinidine and possibly other cardiac antiarrhythmic agents. Confirmation of this possibility by future experimental and clinical studies might result in new patents of these compounds as Mg(2+) preserving agents.

Cellular magnesium homeostasis.

Magnesium, the second most abundant cellular cation after potassium, is essential to regulate numerous cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways, as attested by more than 1000 entries in the literature. Despite significant recent progress, however, our understanding of how cells regulate Mg(2+) homeostasis and transport still remains incomplete. For example, the occurrence of major fluxes of Mg(2+) in either direction across the plasma membrane of mammalian cells following metabolic or hormonal stimuli has been extensively documented. Yet, the mechanisms ultimately responsible for magnesium extrusion across the cell membrane have not been cloned. Even less is known about the regulation in cellular organelles. The present review is aimed at providing the reader with a comprehensive and up-to-date understanding of the mechanisms enacted by eukaryotic cells to regulate cellular Mg(2+) homeostasis and how these mechanisms are altered under specific pathological conditions.

Oxalate in renal stone disease: the terminal metabolite that just won't go away.

The incidence of calcium oxalate nephrolithiasis in the US has been increasing throughout the past three decades. Biopsy studies show that both calcium oxalate nephrolithiasis and nephrocalcinosis probably occur by different mechanisms in different subsets of patients. Before more-effective medical therapies can be developed for these conditions, we must understand the mechanisms governing the transport and excretion of oxalate and the interactions of the ion in general and renal physiology. Blood oxalate derives from diet, degradation of ascorbate, and production by the liver and erythrocytes. In mammals, oxalate is a terminal metabolite that must be excreted or sequestered. The kidneys are the primary route of excretion and the site of oxalate's only known function. Oxalate stimulates the uptake of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. Fecal excretion of oxalate is stimulated by hyperoxalemia in rodents, but no similar phenomenon has been observed in humans. Studies in which rats were treated with (14)C-oxalate have shown that less than 2% of a chronic oxalate load accumulates in the internal organs, plasma, and skeleton. These studies have also demonstrated that there is interindividual variability in the accumulation of oxalate, especially by the kidney. This Review summarizes the transport and function of oxalate in mammalian physiology and the ion's potential roles in nephrolithiasis and nephrocalcinosis.

Magnesium homeostasis and alcohol consumption.

Clinical and experimental evidence indicates alcohol consumption as one of the major causes of magnesium loss from several tissues. As a result of this loss, serum magnesium tends to decrease while urinary magnesium excretion increases 2-3 fold. Experimental data confirm that chronic consumption of 6% ethanol in the Lieber De-Carli diet for 3 weeks results in a marked decrease in total tissue magnesium content in rats. This decrease affects brain, liver and all skeletal muscle, including heart, to a varying extent. While a full picture of the implications of magnesium loss in these tissues is still lacking, it is becoming progressively clear that magnesium loss affects energy production, protein synthesis, cell cycle, and specific functions in the various organs affected. In addition, as magnesium regulated cytokine production and secretion, especially in macrophages and leukocytes, a major role of magnesium deficiency in alcohol-induced inflammatory processes can be envisioned. Considering all these various aspects together, it becomes apparent that magnesium loss may represent a predisposing factor to the onset of alcohol-induced pathologies including brain stroke, sarcopenia, cardiomyopathy, steatohepatitis and cirrhosis. The present review will attempt to clarify some of the mechanisms by which ethanol impairs magnesium transport and homeostasis in brain, brain vasculature, skeletal muscle, heart and liver cells, as a first step towards more mechanistic studies aimed at relating magnesium loss with the incurrence of short- and long-term ethanol-induced complications in these organs.

Functional characterization of two distinct Mg(2+) extrusion mechanisms in cardiac sarcolemmal vesicles.

Cardiac ventricular myocytes extrude a sizeable amount of their total Mg(2+) content upon stimulation by beta-adrenergic agonists. This extrusion occurs within a few minutes from the application of the agonist, suggesting the operation of rapid and abundantly represented Mg(2+) transport mechanisms in the cardiac sarcolemma. The present study was aimed at characterizing the operation of these transport mechanisms under well defined conditions. Male Sprague-Dawley rats were used to purify a biochemical standardized preparation of sealed rat cardiac sarcolemmal vesicles. This experimental model has the advantage that trans-sarcolemmal cation transport can be studied under specific extra- and intra-vesicular ionic conditions, in the absence of intracellular organelles, and buffering or signaling components. Magnesium ion (Mg(2+)) transport was assessed by atomic absorbance spectrophotometry. The results reported here indicate that: (1) sarcolemma vesicles retained trapped intravesicular Mg(2+) in the absence of extravesicular counter-ions; (2) the addition of Na(+) or Ca(2+) induced a rapid and concentration-dependent Mg(2+) extrusion from the vesicles; (3) co-addition of maximal concentrations of Na(+) and Ca(2+) resulted in an additive Mg(2+) extrusion; (4) Mg(2+ )extrusion was blocked by addition of amiloride or imipramine; (5) pre-treatment of sarcolemma vesicles with alkaline phosphatase at the time of preparation completely abolished Na(+)- but not Ca(2+)-induced Mg(2+) extrusion; (6) Na(+)-dependent Mg(2+) transport could be restored by stimulating vesicles loaded with protein kinase A catalytic subunit and ATP with membrane-permeant cyclic-AMP analog; (7) extra-vesicular Mg(2+) could be accumulated in exchange for intravesicular Na(+) via a mechanism inhibited by amiloride or alkaline phosphatase treatment; (8) Mg(2+) accumulation could be restored via cAMP/protein kinase A protocol. Overall, these data provide compelling evidence for the operation of distinct Na(+)- and Ca(2+)-dependent Mg(2+) extrusion mechanisms in sarcolemma vesicles. The Na(+)-dependent mechanism appears to be specifically activated via protein kinase A/cAMP-dependent phosphorylation process, and can operate in either direction based upon the cation concentration gradient across the sarcolemma. The Ca(2+)-dependent mechanism, instead, only mediates Mg(2+) extrusion in a cAMP-independent manner.

Magnesium homeostasis in mammalian cells.

Mammalian cells tightly regulate cellular Mg2+ content despite undergoing a variety of hormonal and metabolic stimulatory conditions. Evidence from several laboratories indicates that stimulatory conditions that increase cellular cAMP level result in a major mobilization of Mg2+ from cells and tissues into the bloodstream. Conversely, hormones or agents that decrease cAMP level or activate protein kinase C signaling induce a major accumulation of Mg2+ into the tissues. These Mg2+ fluxes are quite large and fast suggesting the operation of powerful transport mechanisms. At front of the recent identification of several Mg2+ entry mechanisms, the Mg2+ extrusion pathway(s) still remain(s) poorly characterized. Similarly, it remains not completely elucidated the physiological significance of these Mg2+ fluxes in the various tissues in which they occur. In the present review, we will attempt to provide a comprehensive framework of the modalities by which cellular Mg2+ homeostasis and transport are regulated, as well as examples of cellular functions regulated by changes in cellular Mg2+ level.