phenanthrenes and Weight-Loss

Salvia miltiorrhiza bunge (Danshen) has been extensively used to treat a wide variety of diseases including cancers. Cryptotanshinone is a major lipophilic compound extracted from the root of Danshen and has been reported to exert various pharmacological effects, however, its anti-cachectic remains unknown.. The present study aims to investigate the anti-cachectic efficacy of cryptotanshinone and elucidate the underlying mechanism.. Prevention of muscle wasting by cryptotanshinone in colon adenocarcinoma CT26-induced cachexia and CT26 conditioned medium (TCM)-induced myotubes were investigated. Main features of cancer cachexia were determined after cryptotanshinone administration. The therapeutic effect of cryptotanshinone on myotube atrophy was assessed by morphological observation and myotube fiber width determination. E3 ubiquitin ligases muscle RING-finger containing protein 1 (MuRF1) and muscle atrophy Fbox protein (MAFbx/Atrogin-1) expression and STAT3 activation were examined using western blot, real-time qPCR and dual-luciferase reporter gene assays both in vitro and in vivo. The myotubes were infected with lentiviruses expressing STAT3 or GFP.. In CT26 tumor-bearing mice, cryptotanshinone (20 and 60 mg/kg) administration drastically prevented systemic cancer cachexia from whole body weight loss and wasting of multiple tissues including heart, fat and skeletal muscle, with a negligible effect on cancer growth at dose of 20 mg/kg cryptotanshinone administration prevented the induction of MuRF1 and MAFbx/Atrogin-1 in cachectic muscles. Moreover, cryptotanshinone (2.5-10 μM) dose-dependently reduced the elevated expression of MuRF1 and MAFbx/Atrogin-1 in C2C12 myotubes, and improved myotube atrophy. We showed that cryptotanshinone significantly suppressed the hyper-activated STAT3 in cachectic muscles and C2C12 myotubes and inhibited STAT3 transcriptional activity, but it did not repress the activation of STAT1. The inhibitory effect of cryptotanshinone on TCM-induced myotube atrophy was blocked by STAT3 overexpression.. These data suggest that cryptotanshinone prevents muscle wasting in cancer cachexia through STAT3 inhibition, and it may be a promising candidate drug for the treatment of cancer cachexia.

Topics: Adenocarcinoma; Animals; Cachexia; Colonic Neoplasms; HEK293 Cells; HeLa Cells; Humans; Male; Mice, Inbred BALB C; Muscle Fibers, Skeletal; Muscle Proteins; Muscular Atrophy; Phenanthrenes; Phosphorylation; Signal Transduction; SKP Cullin F-Box Protein Ligases; STAT3 Transcription Factor; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Loss

Heat stroke is a life-threatening illness characterized by an increased core body temperature as a result of exposure to high ambient temperature. Despite advances in supportive care, heat stroke is often fatal, and no specific and effective therapies exist. The pathophysiological responses to heat stroke involve a systemic inflammatory response and a disseminated intravascular coagulation in the host, which lead to a multiorgan dysfunction syndrome. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether inhibition of PARP activity might affect the heat stroke-induced injury.. Controlled animal study.. Research laboratory of an academic institution.. PARP-1-deficient mice (Parp-1(-/-)) and wild-type mice (C57BL/6J).. Wild-type mice untreated or treated with either PJ34 or 3-AB, two generic PARP inhibitors, and Parp-1(-/-) mice were subjected to heat exposure as a model to study heat stroke.. We measured rectal temperature, serum interleukin-1beta and interleukin-6, liver histology, and heat shock proteins expression. We found that the heat stroke-induced injury was attenuated in mice lacking PARP-1 and was markedly reduced in wild-type mice treated with PARP inhibitors. Interestingly, heat-induced expression of heat shock proteins 27 and 70 was boosted after PARP inhibition. Indeed, PARP inhibition increased expression of heat shock proteins 27 and 70 even in the absence of heat exposure. Accordingly, PARP inhibition increased thermal tolerance that may contribute to attenuate the clinical effects of heat stroke, resulting in increased survival.. Our results find a new protective function of PARP inhibitors and support their potential therapeutic application in the treatment of heat stroke.

Topics: Animals; Cytokines; Heat Stroke; Heat-Shock Proteins; Hematocrit; Liver Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Weight Loss

Topics: Analgesics; Animals; Aristolochic Acids; Balkan Nephropathy; Carcinogens; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Humans; Kidney Neoplasms; Phenacetin; Phenanthrenes; Weight Loss