Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

/pdf/pathogenesis-of-osteoporosis-concepts-conflicts-and-1qvwtxb15u.pdf

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

/pdf/mammalian-abc-transporters-in-health-and-disease-4l5ns15q3r.pdf

Mammalian ABC Transporters in Health and Disease

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro‐survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.

https://www.embopress.org/doi/pdf/10.15252/embr.201642195

The integrated stress response.

5. Cyanine-Based pHi Indicators 2717 5.1. Design of pH-Sensitive Cyanine Dyes 2717 5.2. Near-Neutral Cyanine-Based pH Indicators 2718 5.3. Acidic Cyanine-Based pH Indicators 2719 6. Miscellaneous Small Molecule pHi Indicators 2719 6.1. Various Indicators for Near-Neutral pH Values 2719 6.1.1. Europium Complex 2719 6.1.2. Fluorene Derivative 2719 6.1.3. 1,4-Dihydroxyphthalonitrile (1,4-DHPN) 2720 6.1.4. 8-Hydroxypyrene-1,3,6-trisulfonic acid (HPTS) 2720

Fluorescent indicators for intracellular pH.

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

https://www.mdpi.com/2072-6694/3/1/1351/pdf

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-1930.pdf

Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy

To evaluate whether mutations in the human multidrug resistance (MDR)-1 gene correlate with placental P-glycoprotein (PGP) expression, we sequenced the MDR-1 cDNA and measured PGP expression by Western blotting in 100 placentas obtained from Japanese women. Nine single nucleotide polymorphisms (SNPs) were observed with an allelic frequency of 0.005 to 0.420. Of these SNPs, G2677A (allelic frequency = 0.18) and G2677T (0.39) in exon 21 were associated with an amino acid conversion from Ala to Thr and to Ser, respectively. Sixty-one of 65 samples (93.8%), which had a C3435T allele, also had a mutant G2677(A,T) allele, suggesting an association between the two SNPs. Correlations of mutations with expression levels were observed; individuals having the G2677(A,T) and/or T-129C (p < 0.05) allele had less placental PGP. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based genotyping tests were developed for the detection of these SNPs. The PCR, in which genomic DNAs obtained from healthy subjects (n = 48) are used as samples, was successful. The frequency of mutations in placental cDNA was identical with that in genomic DNA. When genotype results were compared between Caucasians and Japanese, ethnic differences in the frequency of polymorphism in the MDR-1 gene were suspected. Although it remains to be determined whether these SNPs influence the pharmacokinetic and dynamic properties of clinically useful drugs that are substrates of PGP, the polymorphism of the MDR-1 gene presented here may provide useful information in in vivo study of these issues.

Expression of P-glycoprotein in human placenta : relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene

Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts

Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects.

Background Tacrolimus is a substrate of P-glycoprotein (PGP) encoded by the multidrug resistant (MDR)1 gene (ABCB1). PGP, a multidrug efflux pump, restricts the distribution of tacrolimus in the brain. In this study, we investigate the correlation of ABCB1 gene polymorphism with tacrolimus-induced neurotoxicity in patients after liver transplantation. Methods. The genotype of 6 patients with neurotoxic events and 11 patients without neurotoxic events was analyzed by polymerase chain reaction (PCR), and 8 mutations were detected. In addition to laboratory findings and patient characteristics, the contribution of mutations in the ABCB1 gene was evaluated with stepwise discriminant function analysis. Results. High tacrolimus concentration, liver dysfunction, and mutation at position 2677 in exon 21 were demonstrated as positive predictors of tacrolimus-induced neurotoxicity. Conclusion. It is indicated that blood concentrations, liver function, graft weight, and polymorphism in the ABCB1 gene are important factors in tacrolimus-induced neurotoxicity.

Mizuho Tanabe

Papers

Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy

Expression of P-glycoprotein in human placenta : relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene

Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts

Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects.

Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene.