scholarly journals An Oligomeric Sulfated Hyaluronan and Silk-Elastinlike Polymer Combination Protects against Murine Radiation Induced Proctitis

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 175
Author(s):  
Douglas Steinhauff ◽  
Mark Martin Jensen ◽  
Ethan Griswold ◽  
Jolanta Jedrzkiewicz ◽  
Joseph Cappello ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Inflammatory Diseases ◽  
Mucosal Barrier ◽  
T Cell Signaling ◽  
Term Survival ◽  
Abdominal Radiotherapy ◽  
Radiation Induced ◽  
Pain Responses

Semisynthetic glycosaminoglycan ethers (SAGEs) are short, sulfated hyaluronans which combine the natural properties of hyaluronan with chemical sulfation. In a murine model, SAGEs provide protection against radiation induced proctitis (RIP), a side effect of lower abdominal radiotherapy for cancer. The anti-inflammatory effects of SAGE have been studied in inflammatory diseases at mucosal barrier sites; however, few mechanisms have been uncovered necessitating high throughput methods. SAGEs were combined with silk-elastinlike polymers (SELPs) to enhance rectal accumulation in mice. After high radiation exposure to the lower abdominal area, mice were followed for 3 days or until they met humane endpoints, before evaluation of behavioral pain responses and histological assessment of rectal inflammation. RNA sequencing was conducted on tissues from the 3-day cohort to determine molecular mechanisms of SAGE–SELP. After 3 days, mice receiving the SAGE–SELP combination yielded significantly lowered pain responses and amelioration of radiation-induced rectal inflammation. Mice receiving the drug–polymer combination survived 60% longer than other irradiated mice, with a fraction exhibiting long term survival. Sequencing reveals varied regulation of toll like receptors, antioxidant activities, T-cell signaling, and pathways associated with pain. This investigation elucidates several molecular mechanisms of SAGEs and exhibits promising measures for prevention of RIP.

scholarly journals Dissociated Steroids

2007 ◽  
Vol 7 ◽  
pp. 421-430 ◽  
Author(s):  
Matthew C. Catley
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Index ◽  
Clinical Use ◽  
Response Elements ◽  
Activation Of Transcription

Glucocorticoids (GCs) are some of the most important drugs in clinical use today. They are mainly used to suppress disease-related inflammation and are widely used for the treatment of many inflammatory diseases including asthma and arthritis. However, GCs are also associated with debilitating side effects that place limitations on the long-term use of these drugs. The development of a GC with reduced side effects would allow more effective treatments for patients who require long-term suppression of inflammation. GCs exert their effects by binding and activating the GC receptor (GR). The activated receptor then binds GC response elements (GREs) in the promoter of genes, and activates transcription (transactivation) or interferes with the activation of transcription by inhibiting the transactivating function of other transcription factors, such as AP-1 and NF-ĸB (transrepression). Transrepression is believed to be responsible for the majority of the beneficial anti-inflammatory effects of GCs, whereas transactivation is believed to play a bigger role in the unwanted side effects of GCs. Compounds that can dissociate the transactivation function of GCs from the transrepression function may, therefore, have an improved therapeutic index. A number of these dissociated corticosteroids have been developed.In vitroassays using these compounds appear to show good dissociation. However,in vivo, the dissociation appears to be lost and these compounds still produce many of the side effects associated with conventional GCs. A better understanding of the molecular mechanisms behind GC-induced effects would allow the design of novel selective GR modulators with an improved therapeutic index.

Towards new therapeutic approaches for malignant melanoma

2011 ◽  
Vol 13 ◽  
Author(s):  
Ivan Pacheco ◽  
Cristina Buzea ◽  
Victor Tron
Keyword(s):  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Therapeutic Approaches ◽  
Term Survival ◽  
Therapeutic Modalities ◽  
New Therapeutic Approaches ◽  
Mirna Genes ◽  
Molecular Therapeutics ◽  
Multistep Process

Recent progress in understanding the molecular mechanisms of the initiation and progression of melanoma has created new opportunities for developing novel therapeutic modalities to manage this potentially lethal disease. Although at first glance, melanoma carcinogenesis appears to be a chaotic system, it is indeed, arguably, a deterministic multistep process involving sequential alterations of proto-oncogenes, tumour suppressors and miRNA genes. The scope of this article is to discuss the most recent and significant advances in melanoma molecular therapeutics. It is apparent that using single agents targeting solely individual melanoma pathways might be insufficient for long-term survival. However, the outstanding results on melanoma survival observed with novel selective inhibitors of B-RAF, such as PLX4032 give hope that melanoma can be cured. The fact that melanoma develops acquired resistance to PLX4032 emphasises the importance of simultaneously targeting several pathways. Because the most striking feature of melanoma is its unsurpassed ability to metastasise, it is important to implement newer systems for drug delivery adapted from research on stem cells and nanotechnology.

scholarly journals Tackling Chronic Kidney Transplant Rejection: Challenges and Promises

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingqiang Lai ◽  
Xin Zheng ◽  
James M. Mathew ◽  
Lorenzo Gallon ◽  
Joseph R. Leventhal ◽  
...  
Keyword(s):  
Early Detection ◽  
Kidney Transplant ◽  
Molecular Mechanisms ◽  
Rapid Development ◽  
Transplant Rejection ◽  
Great Promise ◽  
Term Survival ◽  
Antibody Mediated Rejection ◽  
Novel Therapeutic

Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.

scholarly journals A Growing Microcolony can Survive and Support Persistent Propagation of Virulent Phages

2017 ◽  
Author(s):  
Rasmus Skytte Eriksen ◽  
Sine Lo Svenningsen ◽  
Kim Sneppen ◽  
Namiko Mitarai
Keyword(s):  
Defense Mechanisms ◽  
Extracellular Polymeric Substances ◽  
Molecular Mechanisms ◽  
Term Survival ◽  
Virulent Phage ◽  
Spatial Composition ◽  
The Individual ◽  
The Impact ◽  
Spherical Growth

Bacteria form colonies and secrete extracellular polymeric substances that surround the individual cells. These spatial structures are often associated with collaboration and quorum sensing between the bacteria. Here we investigate the mutual protection provided by spherical growth of a monoclonal colony during exposure to phages that proliferate on its surface. As a proof of concept we exposed growing colonies ofEscherichia colito a virulent mutant of phage P1. When the colony consists of less than ~ 50000 members it is eliminated, while larger initial colonies allow long-term survival because the growth of bacteria throughout the spherical colony exceeds the killing of bacteria on the surface. A mathematical model pinpoints how this critical colony size depends on key parameters in the phage infection cycle. Surprisingly, we predict that a higher phage adsorption rate would allow substantially smaller colonies to survive a virulent phage.Significance StatementBacteria are repeatedly exposed to an excess of phages, and carry evidence of this in terms of multiple defense mechanisms encoded in their genome. In addition to molecular mechanisms, bacteria may exploit the defense of spatial refuges. Here we demonstrate how bacteria can limit the impact of a virulent phage attack by growing as a colony which only exposes its surface to phages. We identify a critical size of the initial colony, below which the phages entirely eliminates the colony, and above which the colony continues to grow despite the presence of phages. Our study suggests that coexistence of phages and bacteria is strongly influenced by the spatial composition of microcolonies of susceptible bacteria.

scholarly journals Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

2011 ◽  
Vol 55 (1) ◽  
pp. 72-77 ◽  
Author(s):  
Lorena de Oliveira Lima ◽  
Antonio Marcondes Lerario ◽  
Guilherme Asmar Alencar ◽  
Luciana Pinto Brito ◽  
Madson Queiroz Almeida ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
P53 Mutation ◽  
Adrenocortical Tumor ◽  
Term Survival ◽  
Long Term Survival ◽  
Over Expression ◽  
Molecular Aspects ◽  
The Right ◽  
Igf1r Expression

The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient.

Clinical prevalence and associated intraoperative surgical complications of reproductive tract lesions in pot-bellied pigs undergoing ovariohysterectomy: 298 cases (2006–2016)

2017 ◽  
Vol 181 (25) ◽  
pp. 685-685 ◽  
Author(s):  
Elizabeth Cypher ◽  
Ricardo Videla ◽  
Rebecca Pierce ◽  
Robert T Snowden ◽  
Jennifer Ann Sexton ◽  
...  
Keyword(s):  
Hospital Discharge ◽  
Reproductive Tract ◽  
Inflammatory Diseases ◽  
Intraoperative Complications ◽  
Term Survival ◽  
Intraoperative Complication ◽  
Long Term Survival ◽  
Short And Long Term ◽  
Short Term Survival

To address the current dearth of clinically relevant publications regarding ovariohysterectomy (OVH) in the domestic pot-bellied pig (PBP), the present study aims to report prevalence of uterine lesions, intraoperative complications, and short and long-term survival in this species (n=298). Prevalence of lesions included uterine neoplasia 11.4 per cent (34/298), pyometra 1.6 per cent (5/298) and cystic endometrial hyperplasia 5 per cent (15/298). Pigs at least six years of age were statistically more likely to have a uterine lesion (less than P=0.001). Smooth muscle tumours represented the most frequent neoplasm. Haemorrhage was the most common intraoperative complication in 23 per cent (8/34) of pigs with neoplasia. Pigs without reproductive tract lesions were statistically more likely to survive to hospital discharge than those with lesions (P=0.001). Short-term survival, defined as survival to hospital discharge, of pigs with reproductive tract lesions was 89 per cent (48/54). Pigs with pyometra were least likely to survive to discharge 60 per cent (3/5). Long-term survival (≥1 year) was 93 per cent (14/15) for pigs with neoplasia. Practitioners should be aware of significantly higher rate of neoplastic and inflammatory diseases in PBP at least six years of age. To minimise morbidity and mortality in PBP undergoing OVH, the present study suggests the procedure should be performed prior to six years of age.

Whole-abdomen, single-dose consolidation radiotherapy in patients with pathologically confirmed complete remission of advanced ovarian epithelial carcinoma: a long-term survival analysis

2004 ◽  
Vol 14 (5) ◽  
pp. 794-798 ◽  
Author(s):  
A. Debby ◽  
T. Levy ◽  
H. Hayat ◽  
Y. Brenner ◽  
M. Glezerman ◽  
...  
Keyword(s):  
Single Dose ◽  
Complete Remission ◽  
Ovarian Carcinoma ◽  
Epithelial Ovarian Carcinoma ◽  
Consolidation Therapy ◽  
Term Survival ◽  
Long Term Survival ◽  
Second Look ◽  
Abdominal Radiotherapy

The value of consolidation therapy in advanced epithelial ovarian carcinoma patients is controversial. The aim of the present study was to assess the long-term survival of patients with a pathologically confirmed complete remission who had consolidation by single-dose, whole-abdominopelvic radiotherapy. Of 96 histologically confirmed stage II–IV epithelial ovarian carcinoma patients who underwent cytoreductive surgery followed by high-dose, platin-based chemotherapy, 57 were in complete clinical remission at the end of therapy and 50 underwent a second-look laparotomy. The study group comprises 32 consecutive patients who had no pathological evidence of disease and who received 800 cGy single-dose, whole-abdominal radiotherapy by an 8 MEV linear accelerator in a single fraction. The absolute 5-year survival and the actuarial 10-year survival were 78.7 and 63.3%, respectively. The survival was significantly better in patients who had ≤2 cm residual disease at the completion of the original operation. No severe postradiation complications were encountered. Mild complications were seen in three (9.4%) patients. Our data indicate a favorable long-term survival of patients with a negative second-look laparotomy who had consolidation with single-dose, whole-abdominal radiotherapy. These results seem to suggest that a collaborative, prospective, randomized multiarm study is indicated to solve the controversial issue of consolidation therapy.

scholarly journals Melatonin-induced cold and drought tolerance requires brassinosteroids and hydrogen peroxide signaling in perennial ryegrass

2021 ◽  
Author(s):  
Juanjuan Fu ◽  
Shentong Zhang ◽  
Huina Jiang ◽  
Xinfei Zhang ◽  
Hao Gao ◽  
...  
Keyword(s):  
Drought Tolerance ◽  
Perennial Ryegrass ◽  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Short Term ◽  
Brassinosteroid Signaling ◽  
Receptor Mutant ◽  
Glutathione Cycle

Abstract Aims The interplay between melatonin and brassinosteroids in enhancing tolerance to cold and drought and the underlying molecular mechanisms of this relationship still remain unknown. Methods Combined physiological and transcriptomic analyses were used to clarify the crosstalk of melatonin and brassinosteroids in perennial ryegrass. Brassinosteroids biosynthesis inhibitor propiconazole, Arabidopsis brassinosteroids-receptor mutant bri1-9, bak1, and H2O2 deficient rbohC and rbohF mutants were used to analyzed the role of H2O2 in melatonin and brassinosteroids-mediated tolerance to the stress. Results Melatonin-enhanced cold and drought tolerance of perennial ryegrass depends on the duration of dose and stress that were applied. Melatonin activates the expression of NADPH oxidase-related genes to promote H2O2 production when exposed to short-term cold/drought stresses but reduced accumulation of H2O2 under long-term stress. This was associated with an increase in enzymatic and non-enzymatic antioxidant activities by regulation of their gene expression and modulation of the ascorbate-glutathione cycle. Moreover, exogenous melatonin increased the biosynthesis of melatonin and brassinosteroids or the expression of signaling-related genes. However, the effects of melatonin on the expression of BR biosynthesis and signaling-related genes were inhibited in the rbohC and rbohF mutants. Chemical scavenging of H2O2 attenuated melatonin-mediated growth in the Arabidopsis wild-type, but the bak1 and bri1.9 mutants were relatively insensitive. Consistently, Inhibition of H2O2 production impaired the effect of melatonin and brassinosteroids on seed germination and the root growth of perennial ryegrass. Conclusions This research reveals a novel regulatory mechanism of the crosstalk of H2O2 and brassinosteroid signaling in melatonin-induced cold/drought tolerance in perennial ryegrass.

scholarly journals Estivation-responsive microRNAs in a hypometabolic terrestrial snail

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6515 ◽  
Author(s):  
Myriam P. Hoyeck ◽  
Hanane Hadj-Moussa ◽  
Kenneth B. Storey
Keyword(s):  
Cell Cycle ◽  
Metabolic Rate ◽  
Molecular Mechanisms ◽  
Metabolic Rate Depression ◽  
Strong Reduction ◽  
Term Survival ◽  
Cell Functions ◽  
Cycle Arrest ◽  
Hypometabolic State

When faced with extreme environmental conditions, the milk snail (Otala lactea) enters a state of dormancy known as estivation. This is characterized by a strong reduction in metabolic rate to <30% of normal resting rate that is facilitated by various behavioural, physiological, and molecular mechanisms. Herein, we investigated the regulation of microRNA in the induction of estivation. Changes in the expression levels of 75 highly conserved microRNAs were analysed in snail foot muscle, of which 26 were significantly upregulated during estivation compared with controls. These estivation-responsive microRNAs were linked to cell functions that are crucial for long-term survival in a hypometabolic state including anti-apoptosis, cell-cycle arrest, and maintenance of muscle functionality. Several of the microRNA responses by snail foot muscle also characterize hypometabolism in other species and support the existence of a conserved suite of miRNA responses that regulate environmental stress responsive metabolic rate depression across phylogeny.

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