A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations .

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. , FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease is not clear. Here we take a combined biochemical and modeling approach to define functional properties of tau driving neurotoxicity We express wild-type human tau and five FTDP-17 mutant forms of tau in using a site-directed insertion strategy to ensure equivalent levels of expression.

Failure of cell cleavage induces senescence in tetraploid primary cells.

Tetraploidy can arise from various mitotic or cleavage defects in mammalian cells, and inheritance of multiple centrosomes induces aneuploidy when tetraploid cells continue to cycle. Arrest of the tetraploid cell cycle is therefore potentially a critical cellular control. We report here that primary rat embryo fibroblasts (REF52) and human foreskin fibroblasts become senescent in tetraploid G1 after drug- or small interfering RNA (siRNA)-induced failure of cell cleavage.

TD-60 is required for interphase cell cycle progression.

We previously identified TD-60 (RCC2) as a mitotic centromere-associated protein that is necessary for proper completion of mitosis. We now report that TD-60 is an essential regulator of cell cycle progression during interphase. siRNA suppression blocks progression of mammalian G₁/S phase cells and progression of G₂ cells into mitosis.

Analysis of dynamic instability of steady-state microtubules in vitro by video-enhanced differential interference contrast microscopy with an appendix by Emin Oroudjev.

Microtubules are major constituents of the cytoskeleton which display dynamic properties. They exhibit dynamic instability which is defined as the stochastic switching between growing and shortening at microtubule ends. Dynamic instability plays an important role in diverse cellular functions including cell migration and mitosis.

The neuroprotective peptide NAP does not directly affect polymerization or dynamics of reconstituted neural microtubules.

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is a neuroprotective peptide that shows cognitive protection in patients with amnestic mild cognitive impairment, a precursor to Alzheimer's disease. NAP exhibits potent neuroprotective properties in several in vivo and cellular models of neural injury. While NAP has been found in many studies to affect microtubule assembly and/or stability in neuronal and glial cells at fM concentrations, it has remained unclear whether NAP acts directly or indirectly on tubulin or microtubules.

Carbendazim inhibits cancer cell proliferation by suppressing microtubule dynamics.

Carbendazim (methyl 2-benzimidazolecarbamate) is widely used as a systemic fungicide in human food production and appears to act on fungal tubulin. However, it also inhibits proliferation of human cancer cells, including drug- and multidrug-resistant and p53-deficient cell lines. Because of its promising preclinical anti-tumor activity, it has undergone phase I clinical trials and is under further clinical development.

Therapeutic efficacy of DL-alpha-lipoic acid on cyclosporine A induced renal alterations.

The present study was designed to evaluate the possible beneficial effect of lipoic acid in preventing the renal damage induced by cyclosporine A in rats. Male albino rats of Wistar strain were divided into four groups and treated as follows. Two groups received cyclosporine A by oral gavage (25 mg/kg/body weight) for 21 days to induce nephrotoxicity, one of which simultaneously received lipoic acid treatment (20 mg/kg body weight) for 21 days.

Lupeol and its ester inhibit alteration of myocardial permeability in cyclophosphamide administered rats.

Cyclophosphamide (CP), an alkylating agent widely used in cancer chemotherapy causes cardiac membrane damage. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate possess a wide range of medicinal properties. The effect of lupeol and its ester was evaluated in CP induced alterations in cardiac electrolytes in rats.

Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy.

Cyclophosphamide is a potent alkylating agent used in cancer chemotherapy and immunosuppression. The present study is aimed at evaluating the role of a potent antioxidant lipoic acid in cyclophosphamide induced hyperlipidemic cardiomyopathy. Adult male Wistar rats were divided into four treatment groups.

Lupeol and its ester exhibit protective role against cyclophosphamide-induced cardiac mitochondrial toxicity.

Cyclophosphamide (CP), an anti-cancer and immunosuppressant drug, causes fatal cardiotoxicity during high dose chemotherapy. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate, possess wide range of medicinal properties. The objective of this study was to establish the pharmacological efficacy of lupeol and its ester against CP-induced mitochondrial-cardiomyopathy.

Lupeol and its ester ameliorate the cyclophosphamide provoked cardiac lysosomal damage studied in rat.

Cyclophosphamide (CP), an alkylating agent widely used in cancer chemotherapy causes fatal cardiotoxicity. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate possess a wide range of medicinal properties. The effect of lupeol and its ester was evaluated in CP-induced myocardial toxicity in rats.

Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-alpha-lipoic acid.

The present study investigated the protective effect of DL-alpha-lipoic acid on the tissue peroxidative damage and abnormal antioxidant levels in cyclophosphamide (CP) induced hepatotoxicity. Male Wistar rats of 140 +/- 20 g were categorized into four groups. Two groups were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce hepatotoxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks; 24 h prior to the CP administration).

Beneficial effects of DL-alpha-lipoic acid on cyclophosphamide-induced oxidative stress in mitochondrial fractions of rat testis.

The present study investigated the protective efficacy of dl-alpha-lipoic acid on the peroxidative damage and abnormal antioxidant levels in the mitochondrial fraction of testis in cyclophosphamide (CP) administered rats. Male Wistar rats of 140+/-20 g were categorized into four groups. Two groups were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce testicular toxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks, 24 h prior to CP administration).

Protective effect of DL-alpha-lipoic acid in cyclophosphamide induced oxidative injury in rat testis.

The aim of the present study was to evaluate the protective effect of DL-alpha-lipoic acid on the biochemical changes, tissue peroxidative damage and abnormal antioxidant levels in the rat testis during cyclophosphamide (CP)-induced injury. Adult male Wistar rats were divided into four treatment groups: (I) control, (II) 15 mg/kg CP once a week for 10 weeks by gavage, (III) 35 mg/kg lipoic acid once a week for 10 weeks by intraperitoneal injection, and (IV) CP plus lipoic acid (24 h prior to CP administration). Testicular toxicity, assessed by decreased enzymatic activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase, was reversed with lipoic acid pretreatment.