Current Signal Transduction Therapy - Volume 11, Issue 1, 2016

The mechanism for the chemoresistance of cancer cells is quite complicated. Most of the anti-cancer drugs are known to induce apoptosis in cancer cells, as well as in normal cells, in part by the activation of the p53 pathway. p53 is often referred to as the 'guardian of the genome' and is one of the most investigated tumor suppressor genes. A majority of human tumors harbor p53 mutations which can influence the effect of chemotherapy. Thus pre-therapeutic evaluation of the p53 gene can be extremely informative for patients with diverse malignancies. In this mini review, we introduce a p53 functional analysis system in mammalian cells, which can identify different types of p53 abnormalities, such as loss of function, dominant negative function, or gain of oncogenic function. The kinetic analysis of mutated-p53 may help to determine the therapeutic strategy in the individual patients with several malignancies. Furthermore, detailed information on the mutated p53 gene in cancer cells might provide useful suggestions for developing new anti-cancer drugs.

Pancreatic cancer is one of the most lethal cancers and leading cause of cancer related death worldwide. Due to its nonspecific early symptoms, pancreatic cancer is difficult to diagnose before extensive local invasion and distant metastasis. The 5-year survival rate of patients diagnosed with pancreatic cancer is less than 5%. Their median survival time is less than 12 months. The molecular mechanisms of pancreatic tumor genesis are poorly understood. Mesothelin is a glycosylphosphatidylinositol (GPI) anchored cell surface protein, which has been found overexpressed in human pancreatic cancer. The function of mesothelin in tumor progression remains unclear. This review aims to outline the roles of mesothelin in pancreatic cancer cell proliferation, apoptosis and invasion, as well as its potential role in mesothelintargeted cancer therapy. Therefore, mesothelin is malignant factor for pancreatic cancer and could be exploited as an antigenic target of therapeutic cancer vaccine.

As a pathological product of bovine gallbladder, natural Calculus Bovis (CB) has a long history in Traditional Chinese Medicine to treat many diseases such as: stroke,coma, delirium, epilepsy, encephalitis B, etc. Experimental studies showed that natural CB had effects on central nervous system, cardiovascular system, inflammation, etc. Recent analyses confirmed that bilirubin composed the main proportion of all CB components. Preclinical researches demonstrated that bilirubin had ischemia protection, antiinflammation, anti-cancer, anti-virus, erythropoiesis, anti-pyretic, immune function protection, and cardiovascular effects. Mechanism investigations indicated bilirubin as a powerful antioxidant. Bilirubin also inhibited inflammatory factors and complement. Here, we suggest bilirubin may account for many effects of CB, and has potential therapeutic prospects.

Biliary and pancreatic lithiasis are rare complications in postpancreaticoduodenectomy (PD) patients, the possible risk factors and treatment strategies remain unclear. In this study, medical records of patients who underwent PD procedure from 2003 to 2013 in Qilu hospital, Shandong University in China were reviewed retrospectively. Clinical data were collected and statistically analyzed. We found that bile duct stone or pancreatic duct stone occurred in 1.23% patients (6/489), including 4 males and 2 females, with the mean age being 60.6±10.3 years old. The most common symptoms were shivering and fever (6/6, 100%), abdominal pain (4/6, 66.7%), jaundice (3/6, 50.0%) and vomiting (2/6, 33.3%) The mean internal time of onset of symptoms after Whipple procedure was 47.3±27.8 months (9-98). CT scan was the most effective diagnostic method. Reoperations were performed on these patients; anastomotic stricture was confirmed in 3 patients, and then stones removal, complete resection of stricture and reconstruction were performed. Based on our clinical findings, we concluded that lithiasis is still a rare complication after PD. Anastomotic stricture, infection and reflux might be important reasons. The aims of therapy are stone removal and dilation of the anastomotic stricture through non-surgical or surgical procedures. Effective prevention methods can decrease incidence of lithiasis after PD.

Background: Chitin and its derivatives participate and influence many important biological activities, such as antibiosis, modulating immunity, suppressing tumor growth, and promoting wound healing as well as promoting hemostasis. This study aimed at confirming the effects of water-soluble chitosan (ws-chitosan) on accelerating healing of induced fractures in New Zealand white rabbits. Materials and methods: Thirty-six selected New Zealand rabbits (each with a 3mm bone defect in the middle segment of radius) were randomly divided into two groups (control group, n=18 and experimental group, n=18). The two groups of rabbits were given normal saline (1.00mg/kg) and ws-chitosan (0.28g/kg) every day through gastric tubes, respectively. Three postoperative observation time points of 7 days, 14 days and 28 days were selected. X-ray was applied to examine the healing effect; immunohistochemistry was introduced for observing the bone morphogenetic protein-2 (BMP-2) expression, and the fracture healing related biochemical indexes (serum ALP and calcium concentration) were measured and recorded. Results: The X-ray results revealed that the fracture healing effect in experimental group was more remarkable than that in the control group on 7 days, 14 days and 28 days, postoperatively. The BMP-2 expression and the calcium concentration in experimental group on 7 and 14 days were clearly higher than those in the control group, while the serum ALP and calcium concentration in ws-chitosan group were distinctly higher than those in the control group on 7 and 14 days. No adverse events were observed in the study period. Conclusion: Results showed that ws-chitosan can enhance facture healing in rabbit model, for it could not only increase ALP and calcium concentrations in serum, but also promote the osteoblast differentiation and BMP-2 expression for accelerating the healing process.

Celiac disease is one of the most frequent diseases genetically determined, with vast and heterogeneous series of clinical manifestations, interests all ages of life. A gliadin peptide, P31-43, is being able to induce an immune response in patients with CD, mainly by means of IL15 and IL15Ralpha activation has been identified. Recently, 30 genes were identified in the small bowel which are able to control the epithelial cell differentiation and celiac disease pathogenesis. Two regions on the chromosome 2, ITG4/UBE2E3 (2q31.3) and CTLA4/ICOS/CD28 (2q33.2) are in contiguity with HOXD genes, located on chromosome 2q31-32. HOX genes or Class I homeobox genes, consist of 39 transcription factors involved in the regulation of embryonic and body plan development, they are related to the cell memory program through the interaction with noncoding-RNAs. LncRNA HOTAIR is a non-coding RNA located at chromosome 12q13.13 and transcribed from HOXC locus; the overexpression of the HOTAIR has been linked to several diseases, originally, it was found in colorectal, gastric cancer and hepatoma. In general, HOTAIR is crucial in Epithelial- Mesenchymal Transition (EMT). HOTAIR is epigenetically able to promote EMT mainly by means of silencing miRNA34a and interacting with Polycomb-Responsive-Element-2 (PRC2). The purpose of this report is to evaluate the capability of P31-43 toxic peptide of the gliadin, and to regulate the transcriptional control of the lncRNA HOTAIR, HOXC11 and HOXC12 genes.

The inhibition of scorpion extracts on esophageal cancer and lung adenocarcinoma cells has been reported by previous studies, but the specific anti-tumor efficacy and potential molecular mechanism have not been clarified. In this study, we first modified the optimal enzymolysis and inactivation technology by imitating gastric and intestinal enzyme, and then investigated the antitumor effect of scorpion extracts both in vitro and in vivo. Our results showed that scorpion alcohol extraction with or without enzymolysis and fermentation could inhibit the cell proliferation of esophageal cancer and lung adenocarcinoma, and tumor growth in S180 tumor burden mice. In addition, the SOD activity increased by scorpion extracts, but MDA content decreased. The scorpion alcohol extracts without fermentation and enzymolysis exert inhibitory effect on the growth of esophageal cancer cells, and unenzymolytic fermented extracts have strong inhibitory effect on the growth of lung cancer cells. The scorpion and its extracts may serve as a new therapeutic agent to suppress tumor growth probably by promoting the function of immune organs and enhancing the activity of the immune system.

Trypsin, chymotrypsin and elastase were combined to hydrolyze scorpion Buthus marstesii Karsch powders to prepare scorpion peptides (SP). Orthogonal design experiment L16 (44) was used to optimize variables of enzymolysis temperature, time, pH and enzyme concentration. Degree of hydrolysis (DH) and inhibition rate (IR) of A549 cells were selected as analysis indicators. The optimum enzymolysis conditions were determined as follows: enzymolysis temperature 40°C, time 3h, pH 8.5 and enzyme concentration of each 2000U. The anti-tumor activity of SP was determined on a panel of representative cell lines (A549, MCF7 and EC109) using MTT assay. In vitro, SP significantly inhibited the proliferation of A549, which was more obvious than MCF-7 and EC109. Further experiments on cell apoptosis and cell cycle analysis revealed that SP induce apoptosis and arrest cell cycle progression in S phase.

Background: Hyperglycemia is found to be a regulator of HIF-1α gene expression but the regulation of HIF-1α on glucose homeostasis is unclear. Objective: To determine whether chronic intermittent hypoxia (CIH) alters glucose regulation and such alterations can revert through treatments with either antioxidant (vitamin c) or calcium channel blocker (cilnidipine) in male albino rats. Methods: The rats were divided into six groups i.e. normoxia (21% oxygen), CIH (10% oxygen with cycle time 3:1.5; 8h/day), normoxia with vitamin c (50 mg /100g. b.wt, orally), CIH with vitamin c, normoxia with cilnidipine (1 mg/kg/day; ip) and CIH with cilnidipine. Serum MDA, HIF-1α, fasting plasma glucose, insulin, GTT, HOMA-IR and insulinogenic index were evaluated. Results: Serum HIF-1α and MDA concentration in rats exposed to CIH increased significantly whereas simultaneous CIH with vitamin c and CIH with cilnidipine treatment show reversion of both serum HIF- 1α and MDA concentrations towards normoxic status. CIH rats showed increased fasting glucose level with unchanged plasma insulin level but both vitamin c and cilnidipine treatment improved the status. Elevated HOMA-IR and insulinogenic index along with impaired GTT were found in CIH groups although vitamin c and cilnidipine improved the glucose homeostasis in CIH exposed rats. Conclusion: CIH induces over production of reactive oxygen species as well as hyper activities of sympathetic N-type Ca2+ channels possibly through HIF 1-α expression and influence on insulin signaling by causing hyperglycemia, glucose intolerance and insulin resistance in rats. Simultaneous treatment with vitamin c or cilnidipine improves glucose homeostasis in CIH exposed rats.

The concurrence of different types of brain tumors is extremely rare. We present a 29-yearold women with brainstem hemangioblastoma, posterior fossa meningiomas and a pituitary spaceoccupying lesion causing hyperprolactinemia.Despite multiple primary intracranial tumors,through systemic work-up, no other manifestation related to von Hippel-Lindau(VHL) disease was found. Complete resection of the brainstem hemangioblastoma and posterior fossa meningiomas was achieved in one single operation via a sub-occipital posterior combined with retrosigmoid approach. The patient was discharged without obvious postoperative complications. Gene copy number analysis based on quantitative PCR revealed partial deletion of Exon 1 in VHL gene in the peripheral blood, brainstem hemangioblastoma and meningiomas. The germline and somatic abnormality in VHL gene might be causally related to tumorigenesis in tumors other than hemangioblastoma,although the exact mechanism is unclear. A close follow-up is significant for such a patient with a de-novo deletion of VHL gene.