Endocrinology

The Matrix Reloaded: CCN, Tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities

2016-01-01T00:00:00Z

The Matrix Reloaded: CCN, Tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities Thakur, Ravi; Mishra, D P Matricellular proteins (MCPs) are the non-structural extracellular matrix (ECM) proteins with various regulatory functions. MCPs are critical regulators of ECM homeostasis and are often found dysregulated in various malignancies. They interact with various ECM structural proteins like integrins, growth factor receptors and growth factors to modulate their availability and activity. Cancer supporting MCPs are known to induce proliferation, migration and invasion of cancer cells. MCPs also support cancer stem (like) cell growth and induce a drug resistant state. Apart from their direct effects on cancer cells, they play key roles in angiogenesis, immunomodulation, stromal cell infiltration, stromal proliferation and matrix remodeling. High expression of various MCPs belonging to the tenascin, CCN, and SIBLING families is often associated with aggressive tumors and poor patient prognosis. Due to their differential expression and distinct functional role, these MCPs are perceived as attractive therapeutic targets in cancer. Studies on preclinical models have indicated that targeting tumor supportive MCPs could be a potent avenue for developing anti-cancer therapies. The MCP receptors, like integrins and some associated growth factor receptors are already being targeted using pharmacological inhibitors and neutralizing antibodies. Neutralizing antibodies against CCNs, Tenascins and SIBLINGs have shown promising results in preclinical cancer models, suggesting an opportunity to develop anti-MCP therapies to target cancer. Peptides derived from anti-cancer MCPs could also serve as therapeutic entities. In the present review, in continuation with the expanding horizon of MCP functions and disease association, we focus on - i) their unique domain arrangement, ii) their association with cancer hallmarks and iii) available and possible therapeutic interventions.

The dose-dependent effects of Asparagus adscendens roots (AARR) extract on the anabolic, reproductive and sexual behavioral activity in rats

2015-01-01T00:00:00Z

The dose-dependent effects of Asparagus adscendens roots (AARR) extract on the anabolic, reproductive and sexual behavioral activity in rats Bansode, F W; Arya, K R; Singh, R K; Narender, T Context: Asparagus adscendens Roxb (Liliaceae) has a promising role in modulation of various disorders such as leucorrhea, diarrhea, dysentery, diabetes, senile pruritus, asthma, fatigue antifilarial, antifungal, spermatorrhea, and sexual debility/seminal weakness. Objective: To investigate dose-dependent effects of AARR extract on anabolic, reproductive, and sexual behavioral activities with a view to emphasize pharmacological basis. Materials and methods: Rats were divided into five groups: Gr. I (Control), Gr. II- IV (AARR- treated, 100, 200 and 300 mg/kg body weight, respectively, orally for 30 days) and Gr. V (Standard Control- treated with sildenafil citrate, 5 mg/kg body weight). On day 31, copulatory and potency tests were carried out and autopsy was done to study reproductive function viz. organ weights, spermatogenesis, daily sperm production rate (DSP) and epididymal sperm count (ESC). Results: AARR extract (200 and 300 mg/kg doses) caused significant increase in body (p<0.02 and p<0.001) and testes (p<0.01 and p<0.001, Control vs. treated) weights. Reproductive activity showed significant increase in testicular tubular diameter (p<0.005-0.001), number of round/elongated spermatids (p<0.02-0.001), DSP and ESC (p<0.05-0.001). The sexual behavioral parameters including mounting/intromission frequency (13.0±0.32/11.8±0.37 and 18.2±2.12/14.8±1.15 vs. 11.2±0.66/8.2±1.16), ejaculation latency (187.4±1.91 and 191.4±1.72 vs. 180.0±3.47) and penile erections (13.5±0.3 and 14.5±0.5 vs. 8.5±0.2) showed significant increase at 200 and 300 mg/kg doses (ED50 300 mg/kg), but less than Standard control. In contrast, 100 mg/kg dose caused increase (p<0.005) in mounting latency only. Conclusion: Results indicate increased anabolic, reproductive and sexual activities by AARR-treatment. Thus, provides scientific rationale for its traditional use as aphrodisiac/for sexual disorders.

Enhanced immunoprotective effects by anti-IL17 antibody translates to improved skeletal parameters under estrogen deficiency compared to anti- RANKL and anti-TNFα antibodies

2014-01-01T00:00:00Z

Enhanced immunoprotective effects by anti-IL17 antibody translates to improved skeletal parameters under estrogen deficiency compared to anti- RANKL and anti-TNFα antibodies Tyagi, A M; Mansoori, M N; Srivastava, Kamini; Khan, M P; Kureel, Jyoti; Dixit, Manisha; Shukla, Priyanka; Trivedi, Ritu; Chattopadhyay, Naibedya; Singh, Divya Activated T cell has a key role in the interaction between bone and immune system. T cells produce pro-inflammatory cytokines including, RANKL, TNF-α and IL-17, all of which augment osteoclastogenesis. RANKL and TNF- are targeted by inhibitors like denosumab, a human monoclonal RANKL anti¬body and infliximab, which neutralizes TNF-α. IL-17 is also an important mediator of bone loss and an antibody against IL-17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, however the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti-TNF, anti-RANKL or anti-IL17 antibody administration to estrogen deficient mice on CD4+T cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti-RANKL/-TNF/-IL17 subcutaneously, twice a week, post-ovariectomy (Ovx) for four weeks. Animals were then autopsied; bone marrow cells collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that while anti-RANKL and anti-TNF therapies had no effect on Ovx-induced CD4+T cell proliferation and B lymphopoesis; anti-IL17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti-IL17 antibody reduced pro-inflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however cortical bone parameters, bone biomechanical properties and histomorphometry were best preserved by anti-IL17 antibody likely due to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti-IL17 which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL-17 for treatment of post-menopausal osteoporosis.

Genetically engineered flavonol enriched tomato fruit modulates chondrogenesis to increase bone length in growing animals

2016-01-01T00:00:00Z

Genetically engineered flavonol enriched tomato fruit modulates chondrogenesis to increase bone length in growing animals Choudhary, Dharmendra; Pandey, Ashutosh; Adhikary, Sulekha; Ahmad, Naseer; Bhatia, Chitra; Bhambhani, Sweta; Trivedi, P K; Trivedi, Ritu Externally visible body and longitudinal bone growth is a result of proliferation of chondrocytes. In growth disorder, there is delay in the age associated increase in height. The present study evaluates the effect of extract from transgenic tomato fruit expressing AtMYB12 transcription factor on bone health including longitudinal growth. Constitutive expression of AtMYB12 in tomato led to a significantly enhanced biosynthesis of flavonoids in general and the flavonol biosynthesis in particular. Pre-pubertal ovary intact BALB/c mice received daily oral administration of vehicle and ethanolic extract of wild type (WT-TOM) and transgenic AtMYB12-tomato (MYB12-TOM) fruits for six weeks. Animal fed with MYB12-TOM showed no inflammation in hepatic tissues and normal sinusoidal Kupffer cell morphology. MYB12-TOM extract significantly increased tibial and femoral growth and subsequently improved the bone length as compared to vehicle and WT-TOM. Histomorphometry exhibited significantly wider distal femoral and proximal tibial growth plate, increased number and size of hypertrophic chondrocytes in MYB12-TOM which corroborated with micro-CT and expression of BMP-2 and COL-10, marker genes for hypertrophic cells. We conclude that metabolic reprogramming of tomato by AtMYB12 has the potential to improve longitudinal bone growth thus helping in achievement of greater peak bone mass during adolescence.