Pre-pubertal exposure of cytarabine-induced testicular atrophy, impaired spermatogenesis and germ cell DNA damage in SD rats.

CONTEXT: Cytarabine (Ara-C) is an effective chemotherapeutic drug for the treatment of acute leukaemias. It inhibits the DNA synthesis and repair, thereby causes cytotoxicity in the proliferating cells. OBJECTIVE: This study was aimed to investigate the effects of pre-pubertal exposure of Ara-C on testesticular development in juvenile SD rats and their function at puberty. MATERIALS AND METHODS: Ara-C was injected at the doses of 50, 100 and 200 mg/kg/day from postnatal day (PND) 29-42 (14 days) by intraperitoneal (i.p.) route. Half of the animals were sacrificed on PND 43 and remaining on PND 70. End points of the evaluation included gross pathological examination, histomorphometric analysis, sperm count and sperm head morphology, cell proliferation and DNA damage as well as apoptosis analysis. RESULTS: Ara-C treatment significantly decreased food and water intake, weight gain, testes and epididymis weight and increased histological alterations in the seminiferous tubule. Furthermore, Ara-C treatment significantly decreased the PCNA-positive cells and sperm count in a dose-dependent manner. Ara-C treatment also increased the DNA damage and apoptosis in testes and sperm as evident from the comet and TUNEL assays results. DISCUSSION: The present study results clearly indicated that Ara-C treatment impaired spermatogenesis and adversely affects the testicular development and its function in rats by reducing the germ cell proliferation and the inducing DNA damage and apoptosis.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice.

It remains challenging to produce decisive vaccines against MUC1, a tumor-associated antigen widely expressed by pancreas, breast and other tumors. Employing clinically relevant mouse models, we ruled out such causes as irreversible T-cell tolerance, inadequate avidity, and failure of T-cells to recognize aberrantly glycosylated tumor MUC1. Instead, every tested MUC1 preparation, even non-glycosylated synthetic 9mer peptides, induced interferon gamma-producing CD4(+) and CD8(+) T-cells that recognized glycosylated variants including tumor-associated MUC1. Vaccination with synthetic peptides conferred protection as long as vaccination was repeated post tumor challenge. Failure to revaccinate post challenge was associated with down-regulated tumor MUC1 and MHC molecules. Surprisingly, direct admixture of MUC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC1 immunoediting, whereas ex vivo activation of the hyperimmune T-cells prior to tumor admixture rendered them curative. Therefore, surrogate T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, can overcome tumor escape.

A review of the use of melatonin in ulcerative colitis: experimental evidence and new approaches.

: Ulcerative colitis (UC), an inflammatory bowel disease, affects many people across the globe, and its prevalence is increasing steadily. Inflammation and oxidative stress play a vital role in the perpetuation of inflammatory process and the subsequent DNA damage associated with the development of UC. UC induces not only local but also systemic damage, which involves the perturbation of multiple molecular pathways. Furthermore, UC leads to an increased risk of colorectal cancer, the third most common malignancy in humans. Most of the drugs used for the treatment of UC are unsatisfactory because they are generally mono-targeted, relatively ineffective and unaffordable for many people. Thus, agents that can target multiple molecular pathways and are less expensive have enormous potential to treat UC. Melatonin has beneficial effects against UC in experimental and clinical studies because of its ability to modulate several molecular pathways of inflammation, oxidative stress, fibrosis, and cellular injury. However, many novel targets are yet to be explored on which melatonin may act to exert its favorable effects in UC. It is time to explore improved intervention strategies with melatonin in UC on the basis of studies investigating different molecular targets using proteomic and genomic approaches. This review identifies various molecular targets for melatonin with the intent of providing novel strategies for combating UC and the associated extraintestinal manifestations of this debilitating disease.