Bone morphogenetic protein 6 (BMP6) antagonises experimental proliferative vitreoretinopathy established by TGF-ß2 stimulation in retinal pigment epithelial cells through modulation of the p38 and JNK MAPK pathways.

The formation of the epiretinal fibrotic membrane by retinal pigment epithelial (RPE) cells is a primary pathological change for proliferative vitreoretinopathy (PVR). Bone morphogenetic protein 6 (BMP6) is an antifibrogenic factor in various cells. To date, it is still unknown whether BMP6 can interfere with the fibrogenesis of RPE cells during the progression of PVR. This work aimed to address the relationship between BMP6 and transforming growth factor-ß2 (TGF-ß2)-elicited fibrogenesis of RPE cells, an experimental model for studying PVR in vitro. The BMP6 level was down-regulated, while the TGF-ß2 level was up-regulated in the vitreous humor of PVR patients. The BMP6 level was down-regulated in human RPE cells challenged with TGF-ß2. The treatment of RPE cells with TGF-ß2 resulted in significant increases in proliferation, migration, epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodelling. These effects were found to be inhibited by the overexpression of BMP6 or exacerbated by the knockdown of BMP6. BMP6 overexpression reduced the phosphorylation of p38 and JNK in TGF-ß2-stimulated RPE cells, while BMP6 knockdown showed the opposite effects. The inhibition of p38 or JNK partially reversed the BMP6-silencing-induced promoting effects on TGF-ß2-elicited fibrogenesis in RPE cells. Taken together, BMP6 demonstrates the ability to counteract the proliferation, migration, EMT, and ECM remodelling of RPE cells induced by TGF-ß2. This is achieved through the regulation of the p38 and JNK MAPK pathways. These findings imply a potential connection between BMP6 and PVR, and highlight the potential application of BMP6 in therapeutic interventions for PVR.

Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-ß2.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism. METHODS: Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-ß2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST. RESULTS: Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-ß2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance. CONCLUSIONS: Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy.

Cytokines Associated With Onset of a Hypertensive Phase and Surgical Failure After Ahmed Glaucoma Valve Implantation.

PURPOSE: To investigate the relationship between cytokines of the aqueous humor or Tenon capsule, the onset of a hypertensive phase, and surgical failure in patients undergoing Ahmed Glaucoma Valve (AGV) implantation DESIGN: Prospective clinical cohort study. METHODS: A total of 36 patients who underwent AGV implantation were included. Samples of aqueous humor and Tenon tissue were collected at the time of surgery. Multiple cytokines were evaluated in the samples using a bead-based multiplex cytokine assay. As for surgical outcomes, a hypertensive phase was defined as an intraocular pressure (IOP) of greater than 21 mm Hg within 3 months after surgery, whereas surgical failure was defined as an IOP greater than 21 mm Hg with maximum tolerable glaucoma medications during 2 consecutive visits. RESULTS: Patients who entered a hypertensive phase showed higher transforming growth factor-ß2 (TGF-ß2) levels in the aqueous humor (P = .012). A longer axial length and higher TGF-ß2 concentration of the aqueous humor were associated with higher maximum IOP values during 3 months after surgery per multiple regression analysis (P = .028 and P = .034). In the multiple logistic regression analysis, higher monocyte chemoattractant protein-1 (MCP-1) concentrations in the aqueous humor and higher interleukin-4 concentrations in Tenon tissue were related to surgical failure (P = .022 and P = .040). CONCLUSIONS: Greater concentrations of TGF-ß2 and MCP-1 were related to surgical outcome after glaucoma drainage device implantation. Further studies are needed to confirm that down-regulation of these cytokines could be helpful in improving surgical outcomes.

How Can a Polymeric Formula Induce Remission in Crohn's Disease Patients?

Crohn's disease is an inflammatory bowel disease whose prevalence is increasing worldwide. Among medical strategies, dietary therapy with exclusive enteral nutrition is recommended as a first-line option, at least for children, because it induces clinical remission and mucosal healing. Modulen®, a polymeric TGF-ß2 enriched formula, has good palatability and is widely used. For the first time in the literature, this review outlines and discusses the clinical outcomes obtained with this therapy, as well as the potential mechanisms of action of its compounds. It can be explained by its TGF-ß2 content, but also by its protein and lipid composition. Further well-designed studies are required to improve our knowledge and to optimize therapeutic strategies.

Preoperative oral polymeric diet enriched with transforming growth factor-beta 2 (Modulen) could decrease postoperative morbidity after surgery for complicated ileocolonic Crohn's disease.

OBJECTIVE: Exclusive polymeric diet enriched with transforming growth factor-beta 2 (ANS-TGF-ß2) has been used for remission induction and maintenance in pediatric Crohn's disease (CD). Its use in the preoperative setting has never been evaluated. The aim of this study was to evaluate preoperative ANS-TGF-ß2 to decrease postoperative complications after surgery for complicated ileocolonic CD. METHODS: From 2011 to 2015, data of all consecutive patients who underwent elective surgery for ileocolonic CD were collected prospectively. Preoperative, exclusive ANS-TGF-ß2 was administered in high-risk patients with complicated CD. Complicated CD was defined by the presence of obstructive symptoms, and/or steroid treatment, and/or preoperative weight loss >10% and/or perforating CD. Outcomes of high-risk patients receiving preoperative ANS-TGF-ß2 were compared to those of low-risk patients with no complicated CD who underwent upfront surgery. RESULTS: Fifty-six patients underwent surgery for ileocolonic CD. Among them, 35 high-risk patients received preoperative ANS-TGF-ß2 and 21 low-risk patients underwent upfront surgery. Preoperative full-dose ANS-TGF-ß2 was feasible in 34/35 high-risk patients. Discontinuation of steroids during preoperative ANS-TGF-ß2 could be achieved in 10/16 patients (62.5%). Postoperative complications rates were 8/35 (23.8%) and 5/21 (22.9%) in high-risk and low-risk patients, respectively (p = 1). Temporary ileocolostomy rates in high-risk patients and in low-risk patients were 4/35 (11%) and 0/21, respectively (p = 0.286) Conclusion: Preoperative ANS-TGF-ß2 is feasible in most high-risk patients with complicated ileocolonic CD and could limit the deleterious effects of risk factors of postoperative morbidity. These results need to be confirmed in a large randomized controlled trial.

Evaluation of transforming growth factor-ß2 for radiation-induced diarrhea after pelvic radiotherapy.

AIMS AND BACKGROUND: Radiotherapy (RT) plays a central role in the management of cancers located in the abdomen and pelvis. However, radiation-induced toxicity remains a major concern for patients receiving RT to the abdominopelvic region. In this context, our study aims to evaluate the use of transforming growth factor (TGF)-ß2-enriched formula for amelioration of radiation-induced diarrhea for patients undergoing pelvic RT. METHODS AND STUDY DESIGN: Between September 2013 and September 2014, 86 malnourished patients undergoing RT for pelvic cancers who received oral nutritional supplementation with or without TGF-ß2-enriched formula were assessed retrospectively in 3 groups. Oral diphenoxylate-atropine tablets were used at onset of diarrhea in all groups. Kruskal-Wallis and chi-square tests were used in the comparison of continuous and categorical variables, respectively. RESULTS: Patients receiving nutritional supplemention with TGF-ß2-enriched formula (groups I and II) experienced a significantly lower median number of diarrhea episodes compared to patients receiving nutritional supplementation with other products (group III), which was statistically significant (p<0.05). Also, number of patients experiencing grade 2 and grade 3 diarrhea was significantly lower in groups I and II compared to group III (p<0.05). CONCLUSIONS: Nutritional supplemention with TGF-ß2-enriched formula offers amelioration of radiation-induced diarrhea for patients receiving pelvic RT. Since this is the first study assessing the use of nutritional supplementation with TGF-ß2-enriched formula for patients undergoing pelvic RT, future prospective studies are needed to confirm the results.

Transforming growth factor-ß gene silencing using adenovirus expressing TGF-ß1 or TGF-ß2 shRNA.

Tumor cells secrete a variety of cytokines to outgrow and evade host immune surveillance. In this context, transforming growth factor-ß1 (TGF-ß1) is an extremely interesting cytokine because it has biphasic effects in cancer cells and normal cells. TGF-ß1 acts as a growth inhibitor in normal cells, whereas it promotes tumor growth and progression in tumor cells. Overexpression of TGF-ß1 in tumor cells also provides additional oncogenic activities by circumventing the host immune surveillance. Therefore, this study ultimately aimed to test the hypothesis that suppression of TGF-ß1 in tumor cells by RNA interference can have antitumorigenic effects. However, we demonstrated here that the interrelation between TGF-ß isotypes should be carefully considered for the antitumor effect in addition to the selection of target sequences with highest efficacy. The target sequences were proven to be highly specific and effective for suppressing both TGF-ß1 mRNA and protein expression in cells after infection with an adenovirus expressing TGF-ß1 short hairpin RNA (shRNA). A single base pair change in the shRNA sequence completely abrogated the suppressive effect on TGF-ß1. Surprisingly, the suppression of TGF-ß1 induced TGF-ß3 upregulation, and the suppression of TGF-ß2 induced another unexpected downregulation of both TGF-ß1 and TGF-ß3. Taken together, this information may prove useful when considering the design for a novel cancer immunogene therapy.

Inflammatory bowel disease: role of diet, microbiota, life style.

Inflammatory bowel disease (IBD) encompassed several chronic inflammatory disorders leading to damage of the gastrointestinal tract (GI). The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn disease (CD). Bacteria are involved in the etiology of IBD, and the genetic susceptibility, environmental factors, and lifestyle factors can affect the individual's predisposition to IBD. The review discusses the potential role of environmental factors such as diet and microbiota as well as genetics in the etiology of IBD. It is suggested that microbial ecosystem in the human bowel colonizing the gut in many different microhabitats can be influence by diet, leading to formation of metabolic processes that are essential form the bowel metabolism.

Induction of bone formation by transforming growth factor-beta2 in the non-human primate Papio ursinus and its modulation by skeletal muscle responding stem cells.

OBJECTIVES: Four adult non-human primates Papio ursinus were used to study induction of bone formation by recombinant human transforming growth factor-beta(2) (hTGF-beta(2)) together with muscle-derived stem cells. MATERIALS AND METHODS: The hTGF-beta(2) was implanted in rectus abdominis muscles and in calvarial defects with and without addition of morcellized fragments of striated muscle, harvested from the rectus abdominis or temporalis muscles. Expression of osteogenic markers including osteogenic protein-1, bone morphogenetic protein-3 and type IV collagen mRNAs from generated specimens was examined by Northern blot analysis. RESULTS: Heterotopic intramuscular implantation of 5 and 25 microg hTGF-beta(2) combined with 100 mg of insoluble collagenous bone matrix yielded large corticalized mineralized ossicles by day 30 with remodelling and induction of haematopoietic marrow by day 90. Addition of morcellized rectus abdominis muscle to calvarial implants enhanced induction of bone formation significantly by day 90. CONCLUSIONS: In Papio ursinus, in marked contrast to rodents and lagomorphs, hTGF-beta(2) induced large corticalized and vascularized ossicles by day 30 after implantation into the rectus abdominis muscle. This striated muscle contains responding stem cells that enhance the bone induction cascade of hTGF-beta(2). Induction of bone formation by hTGF-beta(2) in the non-human primate Papio ursinus may occur as a result of expression of bone morphogenetic proteins on heterotopic implantation of hTGF-beta(2); the bone induction cascade initiated by mammalian TGF-beta proteins in Papio ursinus needs to be re-evaluated for novel molecular therapeutics for induction of bone formation in clinical contexts.

TGF-beta as a promising option in the treatment of multiple sclerosis.

Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. Among T cells, CD4+CD25+FOXP3+ T regs contain the main source of TGF-beta that suppresses immune responses in inflammatory sites. Defects in TGF-beta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. Thus, understanding the function and regulation of TGF-beta during immune responses offers therapeutic promise for the control of autoimmune diseases such as multiple sclerosis. However, the main mechanism by which TGF-beta exerts its protective effects on the experimental model of multiple sclerosis remains to be elucidated. Paradoxically, TGF-beta1 also acts as a pro-inflammatory cytokine and induces interleukin 17-producing pathogenic T helper cells (Th IL-17 cells) synergistically during an inflammatory response in which interleukin 6 is produced. In this review, we will describe the regulatory and therapeutic effects of TGF-beta in multiple sclerosis.

Nutritional supplementation with polymeric diet enriched with transforming growth factor-beta 2 for children with Crohn's disease.

BACKGROUND: A polymeric diet rich in transforming growth factor-beta 2 used as a single nutrient has been shown to induce remission in 79% of children with Crohn's disease. OBJECTIVES: To summarize the experience of several pediatric gastroenterology units in Israel using a TGFbeta2-enriched polymeric diet (Modulen IBD) supplementation in children and adolescents with Crohn's disease. METHODS: In a retrospective study we reviewed the charts of 28 children with Crohn's disease (10 girls, 18 boys) who received, in addition to conventional treatment, Modulen IBD as a supplement to their regular nutrition. These children were compared with 18 children supplemented with standard polymeric formula (Ensure Plus) and 18 children without formula supplementation. We recorded clinical manifestations, growth, and the Pediatric Crohn's Disease Activity Index before and after initiation of the polymeric diet. RESULTS: The Modulen-treated children showed a significant decrease in PCDAI from 34.3 to 15.7 (P< 0.0001). A significant decrease in PCDAI was recorded also in the Ensure Plus group, from 35 to 22 (P= 0.02) but not in the non-supplemented group. Significant improvements in body mass index (P = 0.01) and erythrocyte sedimentation rate (P= 0.03) were recorded at follow-up (median 3.4 months) only in the Modulen IBD group. CONCLUSIONS: In this cohort of children with Crohn's disease, supplementation of the diet with Modulen IBD as well as supplementation with Ensure Plus was associated with a decrease in PCDAI. The children supplemented with Modulen IBD also showed improvement in BMI, suggesting an additional advantage of nutritional therapy in children with this disease.