Vactosertib potently improves anti-tumor properties of 5-FU for colon cancer.

BACKGROUND: Several studies have shown that the TGF-ß signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-ß receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models. METHODS: Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-ß inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples. RESULTS: Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity. CONCLUSION: This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients.

Evaluation of interleukin-32 and cyclooxygenase-2 expression in HAM/TSP patients and HTLV-1 asymptomatic carriers.

OBJECTIVES: HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disorder associated with HTLV-1. Cytokines and inflammatory mediators have a major role in forming inflammation in HAM/TSP patients. This study aimed to measure the levels of IL-32, a proinflammatory cytokine associated with autoinflammatory disorders, and also cyclooxygenase -2 (COX-2) as a key mediator of inflammatory pathways in HAM/TSP patients and HTLV-1 asymptomatic carriers (ACs). MATERIALS AND METHODS: Peripheral blood monocyte cells (PBMCs) were isolated from HAM/TSP patients, ACs, and healthy controls (HCs), and DNA and RNA were extracted to evaluate HTLV-1 proviral load (PVL) and expression of IL-32 and COX-2, using real-time PCR. Serum levels of IL-32 were determined by using an ELISA assay. RESULTS: The expression level of IL-32 was significantly higher in ACs compared with HAM/TSP patients and HCs (P<0.0001 and P>0.05, respectively). There were no statistically significant differences in the expression levels of Cox-2 and protein levels of IL-32 between the study groups. HTLV-1 PVL was higher in HAM/TSP patients compared with ACs. CONCLUSION: Results showed increased mRNA levels of IL-32 in ACs. Since HTLV-1 PVL in ACs is lower than in HAM/TSP patients, it could be concluded that IL-32 might be an HTLV-1 inhibitor that seems to control virus replication. Despite the difference in IL-32 mRNA levels between study groups, no statistically significant differences were observed in IL-32 serum levels. Also, there were no significant differences in COX-2 expression.

Metformin inhibits polyphosphate-induced hyper-permeability and inflammation.

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.

Therapeutic potential of active components of saffron in post-surgical adhesion band formation.

BACKGROUND: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease. PURPOSE: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model. MATERIAL METHOD: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment. RESULT: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups. CONCLUSION: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials. TAXONOMY: Abdominal surgeries/post-surgical adhesions.

Intraperitoneal Administration of Telmisartan Prevents Postsurgical Adhesion Band Formation.

BACKGROUND: Angiotensin II receptor blockers (ARBs) have a potential role in reducing inflammation and fibrosis. We have integrated systems and molecular biology approaches to investigate the therapeutic potential of ARBs in preventing postsurgical adhesion band formation. MATERIAL AND METHODS: we have followed the ARRIVE guidelines point by point during experimental studies. Telmisartan (1 and 9 mg/kg), valsartan (1 and 9 mg/kg), and losartan (1 and 10 mg/kg) were administered intraperitoneally in different groups of male albino Wistar rat. After 7 d of treatment, macroscopic evidence and score of fibrotic bands based on scaling methods was performed. Moreover, the anti-inflammatory and antifibrosis effects of telmisartan on reduction of fibrotic bands were investigated by using histopathology, ELISA, and real-time polymerase chain reaction methods. RESULTS: Telmisartan, but not losartan or valsartan, prevented the frequency as well as the stability of adhesion bands. Telmisartan appears to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that telmisartan prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic genes expression at the peritoneum adhesion tissues. CONCLUSIONS: These results support the potential application of telmisartan in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in postsurgery patients.

Novel oral transforming growth factor-ß signaling inhibitor potently inhibits postsurgical adhesion band formation.

Here, we have investigated the therapeutic potency of EW-7197, a transforming growth factor-ß type I receptor kinase inhibitor, against postsurgical adhesion band formation. Our results showed that this pharmacological inhibitor prevented the frequency and the stability of adhesion bands in mice model. We have also shown that downregulation of proinflammatory cytokines, reduce submucosal edema, attenuation of proinflammatory cell infiltration, inhibition of oxidative stress, decrease in excessive collagen deposition, and suppression of profibrotic genes at the site of surgery are some of the mechanisms by which EW-7197 elicits its protective responses against adhesion band formation. These results clearly suggest that EW-7197 has novel therapeutic properties against postsurgical adhesion band formation with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in postsurgery patients.

Thromboangiitis obliterans episode: autoimmune flare-up or reinfection?

BACKGROUND: The possible role of infectious pathogens in the development of thromboangiitis obliterans (TAO) was considered soon after the disease was first described. However, it is not yet known whether infectious pathogens induce thrombotic vasculitis or if they cause a type of autoimmune disease. To investigate whether TAO relapses are more likely due to reinfection or autoimmune flare, the serum levels of toll-like receptor (sTLR) 4, sTLR2, C-reactive protein (CRP), and neopterin were evaluated in TAO patients during both the acute and quiescent phases of the disease as well as in a gender-, age-, and smoking habit-matched control group. METHODS: Following a cross-sectional study design, 28 patients in the acute phase of TAO and 23 patients in the quiescent phase participated in this study. In addition, 31 matched controls were enrolled. RESULTS: Toll-like receptor (TLR) 4 was significantly higher in patients in the acute phase of the disease than in patients in the quiescent phase (P=0.012). Also, TLR4 was significantly higher in the patients with CRP >7 µm/mL than in the patients with lower CRP (P=0.031). Notably, TLR4 in the patients in the quiescent phase of TAO was significantly lower than in the controls (P=0.006). No significant difference in the level of TLR2 was found among the groups (P>0.05). Neopterin was significantly higher in the acute phase of TAO in comparison to the quiescent phase (P=0.003) and the controls (P=0.005). CONCLUSION: These findings indicate that the trigger of TAO might be Gram-negative bacteria, which can be hidden or immunologically suppressed in the quiescent phase of TAO, leading to a lower level of TLR4 accompanying the normal level of neopterin. However, relapses might develop according to toxic or hypoxic cell injuries. Hence, TLR4 shedding will increase, and therefore, sTLR4 could become closer to the level demonstrated in the controls.