A review on the effect of prolyl isomerization on immune response aberration and hypersensitivity reactions: A unifying hypothesis.

Little is known about the causes and mechanisms of ectopic immune responses, including different types of hypersensitivity, superantigens, and cytokine storms. Two of the most questionable phenomena observed in immunology are why the intensity and extent of immune responses to different antigens are different, and why some self-antigens are attacked as foreign. The secondary structure of the peptides involved in the immune system, such as the epitope-paratope interfaces plays a pivotal role in the resulting immune responses. Prolyl cis/trans isomerization plays a fundamental role in the form of the secondary structure and the folding of proteins. This review covers some of the emerging evidence indicating the impact of prolyl isomerization on protein conformation, aberration of immune responses, and the development of hypersensitivity reactions.

A new shortened protocol to obtain islet-like cells from hESC-derived ductal cells.

Conventional methods for obtaining pancreatic ß cells are based on simulating the embryonic development phase of endocrine cells via hierarchical differentiation of pluripotent stem cells (PSCs). Accordingly, we attempted to modify the protocols for obtaining insulin-secreting cells (ISCs) by sequential differentiation of a human embryonic stem cell (hESC), using the HS181 cell line. Furthermore, we hypothesize that actual pancreatic endocrine cells may arise from trans-differentiation of mature ductal cells after the embryonic developmental stage and throughout the rest of life. According to the hypothesis, ductal cells are trans-differentiated into endocrine and exocrine cells, undergoing a partial epithelial to mesenchymal transition (EMT). To address this issue, we developed two new protocols based on hESC differentiation to obtain ductal cells and then induce EMT in cells to obtain hormone-secreting islet-like cells (HSCs). The ductal (pre-EMT exocrine) cells were then induced to undergo partial EMT by treating with Wnt3a and activin A, in hypoxia. The cell derived from the latter method significantly expressed the main endocrine cell-specific markers and also ß cells, in particular. These experiments not only support our hypothetical model but also offer a promising approach to develop new methods to compensate ß cell depletion in patients with type 1 diabetes mellitus (T1DM). Although this protocol of generating islet-like cells from ductal cells has a potential to treat T1DM, this strategy may be exploited to optimize the function of these cells in an animal model and future clinical applications.

A new hypothetical model for pancreatic development based on change in the cell division orientation.

Although lifelong renewal and additional compensatory growth in response to demand are undeniable facts, so far, no specific stem cells have been found for pancreatic cells. According to the consensus model, the development of pancreas results from the hierarchical differentiation of pluripotent stem cells towards the appearance of the first endocrine and exocrine cells at approximately 7.5 to 8th gestation week (GW) of human embryo. However, the primitive endocrine cells arising from the embryonic phase of development do not appear to be mature or fully functional. Asymmetric localization of cellular components, such as Numb, partition protein complexes (PAR), planar cell polarity components, and certain mRNAs on the apical and basal sides of epithelial cells, causes cellular polarization. According to our model, the equal distribution of cellular components during symmetric cell division yields similar daughter cells that are associated with duct expansion. In contrast, asymmetric cell division is associated with uneven distribution of cellular components among daughter cells, resulting in different fates. Asymmetric cell division leads to duct branching and the development of acinar and stellate cells by a daughter cell, as well as the development of islet progenitor cells through partial epithelial-to-mesenchymal transition (EMT) and delamination of another daughter cell. Recently, we have developed an efficient method to obtain insulin-secreting cells from the transdifferentiation of hESC-derived ductal cells inducing a partial EMT by treatment with Wnt3A and activin A in a hypoxic environment. Similar models can be offered for other tissues and organs such as mammary glands, lungs, prostate, liver, etc. This model may open a new horizon in the field of regenerative medicine and be useful in explaining the cause of certain abnormalities, such as the occurrence of certain cysts and tumors.

Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways.

Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.

Signaling pathways involved in colorectal cancer progression.

Colorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-ß (TGF-ß), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

A review on insulin trafficking and exocytosis.

Insulin is a peptide hormone responsible for stable glycemia, is entirely secreting from pancreatic ß cells at the core of glucose homeostatic regulation. Upon synthesis as preproinsulin on rough endoplasmic reticulum (rER), proinsulin is directed to trans Golgi apparatus. Subsequently, proinsulin packaging into secretory granules occurs in a dynamic and highly efficient process. During maturation stage of secretory granules, proinsulin undergoes cleavage and produces insulin and C-peptide upon acidification of the granules due to the activation of ATP-deriven proton pump. Fusion of the insulin containing secretory granules with the plasma membranes takes place after an increase in intracellular Ca2+. Finally, insulin is co-secreting with other components that are present in the secretory granules, including C-peptide, ATP, γ-aminobutyric acid (GABA), ghrelin and amylin. The other accompanying components of the insulin vesicles play important roles in the insulin secretion, insulin receptor activation and other homeostatic effects.. Responding to the glucose stimulation or increases in cytoplasmic Ca2+ levels, insulin secretion is immediately starts. Whereas, the second phase of insulin secretion is slow and continued, which reaches a plateau within 1-3 hours and lasts for longer period. In contrast to the first phase, the second phase of insulin secretion is independent of the extracellular glucose level. Finally, sequential or compound exocytosis of insulin is repressed to prevent sugar crash arising from excessive and sudden insulin secretion. In this paper we have reviewed the recent progress of molecular scenarios which are behind insulin biogenesis, intracellular sorting and exocytosis events.