TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma.

A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-ß) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, KrasG12D , culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-ß signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by KrasG12D /MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in KrasG12D ;Tgif1KO mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains KrasG12D -driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF-ß signaling might act to accelerate PDAC progression rather than to suppress its initiation.

High phosphate actively induces cytotoxicity by rewiring pro-survival and pro-apoptotic signaling networks in HEK293 and HeLa cells.

Inorganic phosphate (Pi) is an essential nutrient for human health. Due to the changes in our dietary pattern, dietary Pi overload engenders systemic phosphotoxicity, including excessive Pi-related vascular calcification and chronic tissue injury. The molecular mechanisms of the seemingly distinct phenotypes remain elusive. In this study, we investigated Pi-mediated cellular response in HEK293 and HeLa cells. We found that abnormally high Pi directly mediates diverse cellular toxicity in a dose-dependent manner. Up to 10 mM extracellular Pi promotes cell proliferation by activating AKT signaling cascades and augmenting cell cycle progression. By introducing additional Pi, higher than the concentration of 40 mM, we observed significant cell damage caused by the interwoven Pi-related biological processes. Elevated Pi activates mitogen-activated protein kinase (MAPK) signaling, encompassing extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and Jun amino-terminal kinase (JNK), which consequently potentiates Pi triggered lethal epithelial-mesenchymal transition (EMT). Synergistically, high Pi-caused endoplasmic reticulum (ER) stress also contributes to apparent apoptosis. To counteract, Pi-activated AKT signaling promotes cell survival by activating the mammalian target of rapamycin (mTOR) signaling and blocking ER stress. Pharmacologically or genetically abrogating Pi transport, the impact of high Pi-induced cytotoxicity could be reduced. Taken together, abnormally high extracellular Pi results in a broad spectrum of toxicity by rewiring complicated signaling networks that control cell growth, cell death, and homeostasis.

Phosphate Metabolism: From Physiology to Toxicity.

Systemic phosphate homeostasis is tightly controlled by the delicate cross-organ talk among intestine, kidney, bone, and parathyroid glands. The endocrine regulation of phosphate homeostasis is primarily mediated by fibroblast growth factor 23 (FGF23), vitamin D, and parathyroid hormone (PTH). Bone-derived FGF23 acts on the proximal tubular epithelial cells of the kidney to partly maintain the homeostatic balance of the phosphate. FGF23, through binding with its cell surface receptors in the presence of klotho, can activate downstream signaling kinases to reduce the functionality of the sodium-phosphate (NaPi) co-transporters of the kidney to influence the systemic phosphate homeostasis. Given the complexity of molecular regulation of phosphate homeostasis, providing information on all aspects of its homeostatic control in a single volume of a book is an overwhelming task. As the Editor, I have organized the chapters that I believe will provide necessary information on the physiologic regulation and pathologic dysregulation of phosphate in health and diseases. Readers will be able to use this volume as a quick reference for updated information on phosphate metabolism without prior acquaintance with the field.

Phosphate Burden and Inflammation.

Phosphate is an essential macromineral often introduced to the body through dietary intake. The mechanisms for maintaining phosphate levels are tightly controlled via hormonal interactions and excretion via the kidneys. However, western diets consist of high levels of inorganic phosphate, which can overwhelm the regulatory mechanisms in place for maintaining homeostasis. Recent studies have found that phosphate burden can lead to activation of inflammatory signaling in various parts of the body. In addition, individuals with impaired kidney function may also experience exacerbated symptoms of phosphate overload due to decreased filtration and elimination. Many disease states can arise as a result of phosphate burden and subsequent inflammatory signaling, including cardiovascular diseases, tumorigenesis, depression, and neuronal disorders. While the pathophysiological causes of these diseases have been elucidated, there remains a need to address the clinical impacts of excessive dietary phosphate intake and to clarify potential drug candidates that may help alleviate these conditions. This brief chapter looks to explain the overall connection between phosphate burden and inflammation in various diseases.

Extracellular Phosphate, Inflammation and Cytotoxicity.

Phosphorus is an essential nutrient that plays a crucial role in various biological processes, including cell membrane integrity, synthesis of nucleic acids, energy metabolism, intracellular signaling, and hard tissue mineralization. Therefore, the control of phosphorus balance is critical in all living organisms, and the fibroblast growth factor 23 (FGF23)-αKlotho system is central to maintain phosphate homeostasis in mammals. Although phosphate is indispensable for basic cellular functions, its excessive retention is toxic and can affect almost all organ systems' functionality. In human patients, hyperphosphatemia has been implicated in an increase in morbidity and mortality. Also, mouse models with hyperphosphatemia generated by disruption of the FGF23-αKlotho system exhibit extensive tissue damage, premature aging, and a short lifespan. Experimental studies using cell and animal models suggest that cytotoxic and inflammatory effects of elevated phosphate are partly mediated by abnormal cell signaling and oxidative stress. This review provides an overview of our current understanding regarding the toxicity of phosphate.

Common Dietary Sources of Natural and Artificial Phosphate in Food.

The Recommended Dietary Allowance (RDA) for phosphate in the U.S. is around 700 mg/day for adults. The majority of healthy adults consume almost double the amount of phosphate than the RDA. Lack of awareness, and easy access to phosphate-rich, inexpensive processed food may lead to dietary phosphate overload with adverse health effects, including cardiovascular diseases, kidney diseases and tumor formation. Nutritional education and better guidelines for reporting phosphate content on ingredient labels are necessary, so that consumers are able to make more informed choices about their diets and minimize phosphate consumption. Without regulatory measures, dietary phosphate toxicity is rapidly becoming a global health concern, and likely to put enormous physical and financial burden to the society.

Phosphate Dysregulation and Neurocognitive Sequelae.

The endocrine regulator proteins, fibroblast growth factor 23 (FGF23) and Klotho have been well studied as mediators of phosphate metabolism. FGF23 has been implicated in the renal excretion of phosphate by limiting the docking of sodium-dependent phosphate transporters, Npt2a and Npt2c, into the luminal side of renal proximal tubular epithelial cells. By limiting Npt2a/c activity in the renal tubular epithelial cells, phosphate is reabsorbed at lower rates and is excreted at higher rates. The action of Klotho is relatively less understood but has been implicated as an FGF23 cofactor in receptor binding. Klotho is mostly synthesized in the distal tubules of the nephron relative to FGF23's activity in proximal renal tubules. The neurological sequelae due to alterations in the FGF23-Klotho axis may be explained by the direct effects of these phosphate-regulating proteins on neuronal tissues or by the roles of these proteins in phosphate metabolism. Hyperphosphatemia has been associated with vascular wall stiffness that may alter blood flow and weakenvessels in the brain. In contrast, hypophosphatemia may alter ATP usage and metabolism in the central nervous system (CNS), leading to neurological compromise. Altered levels of FGF23 and Klotho have both been associated with neurocognitive decline, clinical dementia, memory loss, and poor executive function in humans. Furthermore, FGF23 and Klotho dysregulation has been linked to structural and functional changes of the cardiovascular system with an increased risk of stroke. Subsequent research should focus on characterizing the neuropathology associated with alterations in the FGF23-Klotho system and dysregulated phosphate metabolism.

Vitamin D and Phosphate Interactions in Health and Disease.

Vitamin D plays an essential role in calcium and inorganic phosphate (Pi) homeostasis, maintaining their optimal levels to assure adequate bone mineralization. Vitamin D, as calcitriol (1,25(OH)2D), not only increases intestinal calcium and phosphate absorption but also facilitates their renal reabsorption, leading to elevated serum calcium and phosphate levels. The interaction of 1,25(OH)2D with its receptor (VDR) increases the efficiency of intestinal absorption of calcium to 30-40% and phosphate to nearly 80%. Serum phosphate levels can also influence 1,25(OH)2D and fibroblast growth factor 23 (FGF23) levels, i.e., higher phosphate concentrations suppress vitamin D activation and stimulate parathyroid hormone (PTH) release, while a high FGF23 serum level leads to reduced vitamin D synthesis. In the vitamin D-deficient state, the intestinal calcium absorption decreases and the secretion of PTH increases, which in turn causes the stimulation of 1,25(OH)2D production, resulting in excessive urinary phosphate loss. Maintenance of phosphate homeostasis is essential as hyperphosphatemia is a risk factor of cardiovascular calcification, chronic kidney diseases (CKD), and premature aging, while hypophosphatemia is usually associated with rickets and osteomalacia. This chapter elaborates on the possible interactions between vitamin D and phosphate in health and disease.

Fibroblast Growth Factor 23 as Regulator of Vitamin D Metabolism.

Fibroblast growth factor 23 (FGF23) is a hormone produced by osteocytes in bone that acts on the kidneys to regulate phosphate and vitamin D metabolism.FGF23 levels were shown to be increased in the early stage of chronic kidney disease (CKD), with a slight decline in estimated glomerular filtration rate (eGFR) even when the range was restricted to above 60 mL/min/1.73 m2, indicating that subtle phosphate load is a stimulator of FGF23 in serum. FGF23 is also known to inhibit vitamin D activation from 25-hydroxyvitamin D (25-OH-D) to 1,25-dihydroxyvitamin D [1,25(OH)2D], while it stimulates its degradation from 25-OH-D to 24,25-dihydroxyvitamin D [24,25(OH)2D]. Previously, we demonstrated a significant and negative association of serum FGF23 with serum 1,25(OH)2D and 1,25(OH)2D/25-OH-D ratio, a putative parameter for CYP27B1, and confirmed the physiological effects of FGF23 on phosphate and vitamin D metabolism in non-CKD subjects. Elevated FGF23 by itself is reported to be associated with various adverse outcomes, including left ventricular hypertrophy, endothelial dysfunction, and activation of the renin-angiotensin-aldosterone system, leading to increased mortality even in non-CKD individuals. On the other hand, our previous study showed that the impaired incremental response of serum FGF23 in response to oral phosphate load in diabetic patients can help to significantly increase serum phosphate (Yoda et al., J Clin Endocrinol Metab 97:E2036-43, 2012) and thus may contribute to progression of vascular calcification in those patients (personal observation). It is suggested that increased serum FGF23 might be an important indicator of adverse outcomes in non-CKD as well as CKD patients.

Phosphate Toxicity and Epithelial to Mesenchymal Transition.

The underlying role of inadequate or excess intake of phosphate is evident in disease states, including metabolic, skeletal, cardiac, kidney and various cancers. Elevated phosphate levels can induce epithelial to mesenchymal transition (EMT) and cell death. EMT and associated lethal, metastatic or fibrinogenic responses are known to be underlying disease processes in fibrotic diseases and various solid tumors. Studies have shown EMT is regulated by induction of different signaling pathways, including TGF-ß, RTK, SRC, Wnt and Notch signal transduction. However, cross-talk amongst these signaling pathways is less understood. We have shown that elevated phosphate levels enhanced EMT partially through activating ERK1/2 pathway, resulting in massive cell death. We thus proposed excess phosphate-mediated lethal EMT as one of the underlying mechanisms of phosphate-induced cytotoxicity, which could explain high phosphate-associated renal fibrosis and cancer metastasis in preclinical and clinical studies. This chapter provides the overview of EMT with the highlights of its regulation by various signaling pathways induced by phosphate toxicity. We further put lately reported lethal EMT in the context of phosphate toxicity with the intent to explain it to excessive phosphate-associated pathologies.

Phosphate toxicity and tumorigenesis.

In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.

COVID-19 Pandemic: Can Maintaining Optimal Zinc Balance Enhance Host Resistance?

The novel coronavirus disease 2019 (COVID-19) is now officially declared as a pandemic by the World Health Organization (WHO), and most parts of the world are taking drastic measures to restrict human movements to contain the infection. Millions around the world are wondering, if there is anything that could be done, other than maintaining high personal hygiene, and be vigilant of the symptoms, to reduce the spread of the disease and chances of getting infected, or at least to lessen the burden of the disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The National and International health agencies, including the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the WHO have provided clear guidelines for both preventive and treatment suggestions. In this article, I will briefly discuss, why keeping adequate zinc balance might enhance the host response and be protective of viral infections.

Dietary phosphate toxicity: an emerging global health concern.

Phosphate is a common ingredient in many healthy foods but, it is also present in foods containing additives and preservatives. When found in foods, phosphate is absorbed in the intestines and filtered from the blood by the kidneys. Generally, any excess is excreted in the urine. In renal pathologies, however, such as chronic kidney disease, a reduced renal ability to excrete phosphate can result in excess accumulation in the body. This accumulation can be a catalyst for widespread damage to the cellular components, bones, and cardiovascular structures. This in turn can reduce mortality. Because of an incomplete understanding of the mechanism for phosphate homeostasis, and the multiple organ systems that can modulate it, treatment strategies designed to minimize phosphate burden are limited. The Recommended Dietary Allowance (RDA) for phosphorous is around 700 mg/day for adults, but the majority of healthy adult individuals consume far more phosphate (almost double) than the RDA. Studies suggest that low-income populations are particularly at risk for dietary phosphate overload because of the higher amounts of phosphate found in inexpensive, processed foods. Education in nutrition, as well as access to inexpensive healthy food options may reduce risks for excess consumption as well as a wide-range of disorders, ranging from cardiovascular diseases to kidney diseases to tumor formation. Pre-clinical and clinical studies suggest that dietary phosphate overload has toxic and prolonged adverse health effects. Improved regulations for reporting of phosphate concentrations on food labels are necessary so that people can make more informed choices about their diets and phosphate consumption. This is especially the case given the lack of treatments available to mitigate the short and long-term effects of dietary phosphate overload-related toxicity. Phosphate toxicity is quickly becoming a global health concern. Without measures in place to reduce dietary phosphate intake, the conditions associated with phosphate toxicity will likely to cause untold damage to the wellbeing of individuals around the world.

TGIF function in oncogenic Wnt signaling.

Transforming growth-interacting factor (TGIF) has been implicated in the pathogenesis of many types of human cancer, but the underlying mechanisms remained mostly enigmatic. Our recent study has revealed that TGIF functions as a mediator of oncogenic Wnt/ß-catenin signaling. We found that TGIF can interact with and sequesters Axin1 and Axin2 into the nucleus, thereby culminating in disassembly of the ß-catenin-destruction complex and attendant accumulation of ß-catenin in the nucleus, where it activates expression of Wnt target genes, including TGIF itself. We have provided proof-of-concept evidences that high levels of TGIF expression correlate with poor prognosis in patients with triple negative breast cancer (TNBC), and that TGIF empowers Wnt-driven mammary tumorigenesis in vivo. Here, we will briefly summarize how TGIF influences Wnt signaling to promote tumorigenesis.

Vitamin D, phosphate, and vasculotoxicity.

Vascular calcification is a complex process that results in the ectopic deposition of calcium-phosphate hydroxyapatite. Medial and intimal vascular calcification is frequently present in patients with diabetes mellitus and chronic kidney disease (CKD), and markedly increases the morbidity and mortality of these patients. Increased serum levels of calcium and phosphate, along with the use of active vitamin D metabolites, are commonly implicated in the evolvement of vascular wall mineralization in CKD patients. Because CKD patients have lower serum levels of vitamin D, they are routinely prescribed vitamin D supplements that exert a dualistic role that is both healthful and harmful in these patients, perhaps protecting bone health, but at the expense of promoting vascular pathology. This review briefly explains how reducing the phosphate burden in CKD patients could minimize vitamin-D-associated vascular wall calcification.

Molecular interactions of FGF23 and PTH in phosphate regulation.

Bone-derived fibroblast growth factor-23 (FGF23) plays an important role in systemic phosphate turnover. Increased FGF23 activity results in hypophosphatemic disorders, while reduced activity is linked to hyperphosphatemic disorders. FGF23, together with klotho as co-factor, can activate FGF receptors in its target tissues to exert its functions. However, the molecular regulation of FGF23 synthesis is not clearly defined, and recent studies have found that parathyroid hormone (PTH) can activate the nuclear receptor-associated protein-1 (Nurr1) to induce FGF23 transcription in bone cells.

Can adverse cardiac events of the COVID-19 vaccine exacerbate preexisting diseases?

INTRODUCTION: SARS-CoV-2 infection and COVID-19 vaccination can both lead to serious cardiac conditions such as myocarditis, arrhythmia, acute myocardial infarction, and coagulopathy. Further studies are needed to better understand the risks and benefits of COVID-19 vaccination, and to determine the best course of action for individuals with preexisting heart conditions. AREAS COVERED: The current knowledge and challenges in understanding vaccine-associated heart issues concerning the COVID-19 pandemic are briefly summarized, highlighting similar cardiac conditions caused by either SARS-CoV-2 infection or COVID-19 vaccination and the potential clinical impacts. EXPERT OPINION: The short-term risks of severe cardiovascular side effects following COVID-19 vaccination are relatively low. However, further studies are needed to determine whether adverse vaccination events outweigh the long-term benefits in specific groups of individuals. Since cardiac inflammation, blood pressure dysregulation, coagulopathy, acute myocardial infarction, or arrhythmia could be the consequences of either SARS-CoV-2 infection or COVID-19 vaccination, clinical questions should be asked whether the COVID-19 vaccine worsens the condition in persons with preexisting heart diseases. It is important to carefully assess the potential risks and benefits of COVID-19 vaccination, especially for individuals with preexisting heart conditions, and to continue monitoring and studying the long-term effects of vaccination on cardiovascular health.

Zinc and Diabetes: A Connection between Micronutrient and Metabolism.

Diabetes mellitus is a global health problem and a major contributor to mortality and morbidity. The management of this condition typically involves using oral antidiabetic medication, insulin, and appropriate dietary modifications, with a focus on macronutrient intake. However, several human studies have indicated that a deficiency in micronutrients, such as zinc, can be associated with insulin resistance as well as greater glucose intolerance. Zinc serves as a chemical messenger, acts as a cofactor to increase enzyme activity, and is involved in insulin formation, release, and storage. These diverse functions make zinc an important trace element for the regulation of blood glucose levels. Adequate zinc levels have also been shown to reduce the risk of developing diabetic complications. This review article explains the role of zinc in glucose metabolism and the effects of its inadequacy on the development, progression, and complications of diabetes mellitus. Furthermore, it describes the impact of zinc supplementation on preventing diabetes mellitus. The available information suggests that zinc has beneficial effects on the management of diabetic patients. Although additional large-scale randomized clinical trials are needed to establish zinc's clinical utility further, efforts should be made to increase awareness of its potential benefits on human health and disease.

The role of magnesium in pancreatic beta-cell function and homeostasis.

Magnesium plays an essential role in glucose utilization and insulin signaling. Recent advances have revealed a greater prevalence of hypomagnesemia in general, and low intracellular magnesium levels in individuals with diabetes contribute to ß-cell dysfunction and insulin resistance. This article describes the documented effects of magnesium on various aspects of ß-cells and glucose homeostasis. Studies have demonstrated that magnesium deficiency is associated with reduced pancreatic ß-cell activity and increased insulin resistance in patients with type 2 diabetes. Additionally, magnesium is involved in many cellular events, including energy homeostasis, protein synthesis, and DNA stability. Furthermore, magnesium is critical for proper glucose utilization and insulin signaling, and magnesium deficiency can lead to the dysregulation of ATP-sensitive potassium (KATP) channels in pancreatic ß-cells, impairing insulin secretion. Therefore, maintaining adequate magnesium levels is crucial for maintaining overall health and preventing of metabolic disorders such as type 2 diabetes.

Potential Impact of COVID-19 on Medical Career Aspirations of Prospective Students.

This article describes the evolving landscape of medical education in the wake of the COVID-19 pandemic, emphasizing the renewed importance of public health, mental well-being, and career choices among medical students. The pandemic has prompted a significant shift in medical student's career aspirations, highlighting the need for mental health support mechanisms within the medical education framework. Medical students' career choices are influenced directly and indirectly by the challenges and experiences of the pandemic era, which are discussed in this article under four key themes: traditional values, global health interests and disparities, developing trends, and digital healthcare. There is an urgent need to adjust medical training to the new reality and share the future directions of the medical education landscape by embracing diverse career paths in medicine, integrating technology into medical training, adapting to the changing context of medicine, and strengthening collaboration and communication. The pandemic underscores the importance of evidence-based patient care, necessitating the preparation of tomorrow's doctors to address the emerging healthcare challenges with resilience, adaptability, and a comprehensive understanding of both local and global health challenges.