In silico models for the screening of human transthyretin disruptors.

The use of New Approach Methodologies (NAMs), such as Quantitative Structure-Activity Relationship (QSAR) models, is highly recommended by international regulations to speed up hazard and risk assessment of Endocrine Disruptors, which are known to be linked to a wide spectrum of severe diseases on humans and wildlife. A very sensitive target for these chemicals is the thyroid hormone system, which plays a key role in regulating metabolic and cognitive functions. Several chemicals have been demonstrated to compete with the thyroid hormone thyroxine (T4) for binding to human thyroid hormone distributor protein transthyretin (hTTR).

BECLIN1 is essential for intestinal homeostasis involving autophagy-independent mechanisms through its function in endocytic trafficking.

Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance.

Induction of endoplasmic reticulum stress is associated with the anti-tumor activity of monepantel across cancer types.

Background: Monepantel is an anti-helminthic drug that also has anti-cancer properties. Despite several studies over the years, the molecular target of monepantel in mammalian cells is still unknown, and its mechanism-of-action is not fully understood, though effects on cell cycle, mTOR signalling and autophagy have been implicated.

Methods: Viability assays were performed on >20 solid cancer cell cells, and apoptosis assays were performed on a subset of these, including 3D cultures.

A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples.

Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders.

Bisphosphonates are the first-choice treatment of osteoporosis and Paget's disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins.

Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.

Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis.

BCL-XL is an actionable target for treatment of malignant pleural mesothelioma.

Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway.

Diversity in the intrinsic apoptosis pathway of nematodes.

Early studies of the free-living nematode C. elegans informed us how BCL-2-regulated apoptosis in humans is regulated. However, subsequent studies showed C.

Increased Prevalence of Nephrolithiasis and Hyperoxaluria in Paget Disease of Bone.

Context: Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget disease of bone (PDB), but recent data regarding their prevalence in PDB patients are lacking.

Objectives: Study 1: To compare the prevalence of primary HPTH and NL in 708 patients with PDB and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 patients with PDB and NL, 219 PDB patients without NL, 364 NL patients without PDB, and 219 controls, all of them without HPTH.

Osteoporosis is a Predictive Factor for Nephrolithiasis in an Adult Free-Living Caucasian Population From Southern Italy: A Longitudinal Retrospective Study Based on a General Practice Database.

Osteoporosis and nephrolithiasis are common multifactorial disorders with high incidence and prevalence in the adult population worldwide. Both are associated with high morbidity and mortality if not correctly diagnosed and accurately treated. Nephrolithiasis is considered a risk factor for reduced bone mineral density.

BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival.

Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required.

Characterisation of the conformational preference and dynamics of the intrinsically disordered N-terminal region of Beclin 1 by NMR spectroscopy.

Beclin 1 is a 450 amino acid protein that plays critical roles in the early stages of autophagosome formation. We recently reported the successful expression, purification and structural characterisation of the entire N-terminal region of Beclin 1 (residues 1-150), including its backbone NMR chemical shift assignments. Based on assigned backbone NMR chemical shifts, it has been established that the N-terminal region of Beclin 1 (1-150), including the BH3 domain (112-123), is intrinsically disordered in the absence of its interaction partners.

Physiological restraint of Bak by Bcl-xL is essential for cell survival.

Due to the myriad interactions between prosurvival and proapoptotic members of the Bcl-2 family of proteins, establishing the mechanisms that regulate the intrinsic apoptotic pathway has proven challenging. Mechanistic insights have primarily been gleaned from in vitro studies because genetic approaches in mammals that produce unambiguous data are difficult to design. Here we describe a mutation in mouse and human Bak that specifically disrupts its interaction with the prosurvival protein Bcl-xL Substitution of Glu75 in mBak (hBAK Q77) for leucine does not affect the three-dimensional structure of Bak or killing activity but reduces its affinity for Bcl-xL via loss of a single hydrogen bond.

The BECN1 N-terminal domain is intrinsically disordered.

BECN1/Beclin 1 has a critical role in the early stages of autophagosome formation. Recently, structures of its central and C-terminal domains were reported, however, little structural information is available on the N-terminal domain, comprising a third of the protein. This lack of structural information largely stems from the inability to produce this region in a purified form.

α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.

Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-amino acids) suffer from significant limitations in vivo.

The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains.

Bcl-2 homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members, although their primary function is believed to be associated with induction of cell death. Here, we identify critical features of the BH3 domains of pro-survival proteins that distinguish them functionally from their pro-apoptotic counterparts.

Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1.

Human term placental cells: phenotype, properties and new avenues in regenerative medicine.

The human placenta has long been the subject of scientific interest due to the important roles which it performs during pregnancy in sustaining the fetus and maintaining fetomaternal tolerance. More recently, however, researchers have begun to investigate the possibility that the placenta's utility may extend beyond fetal development to act as a source of cells with clinically relevant properties. Indeed, several groups have reported the isolation of cells from different placental regions which display both multilineage differentiation potential and immunomodulatory properties in vitro.

Crystal structure of a BCL-W domain-swapped dimer: implications for the function of BCL-2 family proteins.

The prosurvival and proapoptotic proteins of the BCL-2 family share a similar three-dimensional fold despite their opposing functions. However, many biochemical studies highlight the requirement for conformational changes for the functioning of both types of proteins, although structural data to support such changes remain elusive. Here, we describe the X-ray structure of dimeric BCL-W that reveals a major conformational change involving helices α3 and α4 hinging away from the core of the protein.

Structural basis of Bcl-xL recognition by a BH3-mimetic α/β-peptide generated by sequence-based design.

The crystal structure of a complex between the prosurvival protein Bcl-x(L) and an α/β-peptide 21-mer is described. The α/β-peptide contains six β-amino acid residues distributed periodically throughout the sequence and adopts an α-helix-like conformation that mimics the bioactive shape of the Puma BH3 domain. The α/β-peptide forms all of the noncovalent contacts that have previously been identified as necessary for recognition of the prosurvival protein by an authentic BH3 domain.

Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni.

Toward cell therapy using placenta-derived cells: disease mechanisms, cell biology, preclinical studies, and regulatory aspects at the round table.

Among the many cell types that may prove useful to regenerative medicine, mounting evidence suggests that human term placenta-derived cells will join the list of significant contributors. In making new cell therapy-based strategies a clinical reality, it is fundamental that no a priori claims are made regarding which cell source is preferable for a particular therapeutic application. Rather, ongoing comparisons of the potentiality and characteristics of cells from different sources should be made to promote constant improvement in cell therapies, and such comparisons will likely show that individually tailored cells can address disease-specific clinical needs.