Evidence for a partially folded intermediate in alpha-synuclein fibril formation.

Contraction of smooth muscle is regulated by the cytosolic Ca2+ level ([Ca2+]i)b, and the sensitivity to Ca2+ of the contractile elements in response to changes in the environment surrounding the cell. The first sequence of events in regulation includes the binding of endogenous substances, such as

/pdf/calcium-movements-distribution-and-functions-in-smooth-3zozpe9uj6.pdf

Calcium Movements, Distribution, and Functions in Smooth Muscle

Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the “hallmarks of cancer”. This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.

/pdf/tumor-glycolysis-as-a-target-for-cancer-therapy-progress-and-2b8jy98sx7.pdf

Tumor glycolysis as a target for cancer therapy: progress and prospects.

Carnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule.

Physiology and Pathophysiology of Carnosine

In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.

Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum.

Anti-crosslinking properties of carnosine: Significance of histidine

The GAPDH gene is highly conserved with a promoter that contains several types of regulatory elements, perhaps even in a distal intron Curiously, the transcription start site shows some ambiguity and there are codon-sharing exons at alternate exon junctions While there is only one functional gene for GAPDH in humans, the genome is littered with pseudogenes, representing a trove of researchable content Tissue-specific expression speaks to the glycolytic function of GAPDH; thus, it’s not surprising to see expression increased in cancer cells Modulation of protein levels becomes an opportunity for intervention The abundance of GAPDH in the cell provides the rationale (albeit, tenuous) for its use as a loading control The single paralogous GAPDHS, which is the spermatogenic form of the protein, provides a curious study in cell-type specificity and perhaps intervention (ie contraception) And it is no wonder that great biochemists were kept busy for decades unveiling the nuances of GAPDH enzymology While the active site of the enzyme is well-characterized and the catalytic mechanism is well-described, the role of inter-subunit interactions in catalysis still offers some mysteries, particularly with regards to other emerging enzymatic properties The GAPDH protein exhibits an intrinsic asymmetry of the subunits, which also may speak to its functional diversity

Norbert W. Seidler

Papers

Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum.

Anti-crosslinking properties of carnosine: Significance of histidine

Basic Biology of GAPDH

Carnosine disaggregates glycated alpha-crystallin: an in vitro study.

Exercise causes oxidative damage to rat skeletal muscle microsomes while increasing cellular sulfhydryls