The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors

Phthalate diesters, widely used in flexible plastics and consumer products, have become prevalent contaminants in the environment. Human exposure is ubiquitous and higher phthalate metabolite concentrations documented in patients using medications with phthalate-containing slow release capsules raises concerns for potential health effects. Furthermore, animal studies suggest that phthalate exposure can modulate circulating hormone concentrations and thus may be able to adversely affect reproductive physiology and the development of estrogen sensitive target tissues. Therefore, we conducted a systematic review of the epidemiological and experimental animal literature examining the relationship between phthalate exposure and adverse female reproductive health outcomes. The epidemiological literature is sparse for most outcomes studied and plagued by small sample size, methodological weaknesses, and thus fails to support a conclusion of an adverse effect of phthalate exposure. Despite a paucity of experimental animal studies for several phthalates, we conclude that there is sufficient evidence to suggest that phthalates are reproductive toxicants. However, we note that the concentrations needed to induce adverse health effects are high compared to the concentrations measured in contemporary human biomonitoring studies. We propose that the current patchwork of studies, potential for additive effects and evidence of adverse effects of phthalate exposure in subsequent generations and at lower concentrations than in the parental generation support the need for further study.

/pdf/reproductive-and-developmental-effects-of-phthalate-diesters-390sd5mtmg.pdf

Reproductive and developmental effects of phthalate diesters in females.

The mTOR Complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs lifespan in model organisms A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin as well as to nutrient and growth factor starvation within cells Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals

mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin

The adverse health effects of bisphenol A and related toxicity mechanisms.

// Brock Humphries 1, 2 , Chengfeng Yang 1, 2, 3 1 Department of Physiology, Michigan State University, East Lansing, MI 48824, USA 2 Cellular and Molecular Biology Graduate Program, Michigan State University, East Lansing, MI 48824, USA 3 Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA Correspondence to: Chengfeng Yang, e-mail: yangcf@msu.edu Keywords: microRNA, miR-200, cancer initiation, cancer metastasis, cancer therapeutic target Received: November 14, 2014      Accepted: January 06, 2015      Published: January 30, 2015 ABSTRACT MicroRNAs (miRNAs) are a large family of small non-coding RNAs that negatively regulate protein-coding gene expression post-transcriptionally via base pairing between the 5′ seed region of a miRNA and the 3′ untranslated region (3′UTR) of a messenger RNA (mRNA). Recent evidence has supported the critical role that miRNAs play in many diseases including cancer. The miR-200 family consisting of 5 members (miR-200a, -200b, -200c, -141, -429) is an emerging miRNA family that has been shown to play crucial roles in cancer initiation and metastasis, and potentially be important for the diagnosis and treatment of cancer. While miR-200s were found to be critically involved in the metastatic colonization to the lungs in mouse mammary xenograft tumor models, a large number of studies demonstrated their strong suppressive effects on cell transformation, cancer cell proliferation, migration, invasion, tumor growth and metastasis. This review aims to discuss research findings about the role of the miR-200 family in cancer initiation, each step of cancer metastatic cascade, cancer diagnosis and treatment. A comprehensive summary of currently validated miR-200 targets is also presented. It is concluded that miR-200 family may serve as novel targets for the therapy of multiple types of cancer.

/pdf/the-microrna-200-family-small-molecules-with-novel-roles-in-2h53kopop0.pdf

The microRNA-200 family: small molecules with novel roles in cancer development, progression and therapy

Background 
Hyperlipidemia-induced apoptosis mediated by fatty acid translocase CD36 is associated with increased uptake of ox-LDL or fatty acid in macrophages, hepatocytes and proximal tubular epithelial cells, leading to atherosclerosis, liver damage and fibrosis in obese patients, and diabetic nephropathy (DN), respectively. However, the specific role of CD36 in podocyte apoptosis in DN with hyperlipidemia remains poorly investigated.


Methods 
The expression of CD36 was measured in paraffin-embedded kidney tissue samples (Ctr = 18, DN = 20) by immunohistochemistry and immunofluorescence staining. We cultured conditionally immortalized mouse podocytes (MPC5) and treated cells with palmitic acid, and measured CD36 expression by real-time PCR, Western blot analysis and immunofluorescence; lipid uptake by Oil red O staining and BODIPY staining; apoptosis by flow cytometry assay, TUNEL assay and Western blot analysis; and ROS production by DCFH-DA fluorescence staining. All statistical analyses were performed using SPSS 21.0 statistical software.


Results 
CD36 expression was increased in kidney tissue from DN patients with hyperlipidemia. Palmitic acid upregulated CD36 expression and promoted its translocation from cytoplasm to plasma membrane in podocytes. Furthermore, palmitic acid increased lipid uptake, ROS production and apoptosis in podocytes, Sulfo-N-succinimidyloleate (SSO), the specific inhibitor of the fatty acid binding site on CD36, decreased palmitic acid-induced fatty acid accumulation, ROS production, and apoptosis in podocytes. Antioxidant 4-hydroxy-2,2,6,6- tetramethylpiperidine -1-oxyl (tempol) inhibited the overproduction of ROS and apoptosis in podocytes induced by palmitic acid.


Conclusions 
CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress might participate in the process of DN.

/pdf/cd36-mediated-fatty-acid-induced-podocyte-apoptosis-via-3s0mi0f96o.pdf

CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress.

The combined toxicity of dibutyl phthalate and benzo(a)pyrene on the reproductive system of male Sprague Dawley rats in vivo.

DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms

Effects of sodium fluoride on reproductive function in female rats.

Spermatogenesis is a critical process for maintaining male fertility. Sustained spermatogonial stem cell self-renewal and differentiation ensures constant spermatogenesis, and several signalling pathways regulate this process. An increasing number of studies have suggested that the mammalian target of rapamycin (mTOR) signalling pathway plays an important role in spermatogenesis; however, the mechanism remains unknown. Our study showed that mTOR was positively related with spermatogenesis by detecting mTOR expression and the expression of its target p70s6k, rps6 and 4e-bp1 at different developmental stages. Phosphorylated p70s6k, rps6 and 4ebp1 levels were independently and gradually down-regulated with age. Subsequently, we showed in vivo and in vitro that, upon mTOR inactivation by rapamycin, the number of sperm significantly decreased (P < 0.05) and spermatogonia proliferation was blocked. Phosphorylated p70s6k and rps6 levels were down-regulated, but the levels of phosphorylated 4e-bp1 did not change. Spermatogonia were treated with the specific PI3K inhibitor LY294002, and p70s6k, rps6 and 4ebp1 phosphorylation overtly decreased. Therefore, we suggest that mTOR plays an important role in spermatogenesis by regulating p70s6k activation and that 4e-bp1 is either directly or indirectly regulated by PI3K.

Xuemei Chen

Papers

CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress.

The combined toxicity of dibutyl phthalate and benzo(a)pyrene on the reproductive system of male Sprague Dawley rats in vivo.

DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms

Effects of sodium fluoride on reproductive function in female rats.

mTOR/P70S6K promotes spermatogonia proliferation and spermatogenesis in Sprague Dawley rats.