Many diseases, especially cancers, result from aberrant or overexpression of pathogenic proteins. Specific inhibitors against these proteins have shown remarkable therapeutic effects, but these are ...limited mainly to enzymes. An alternative approach that may have utility in drug development relies on selective degradation of pathogenic proteins via small chimeric molecules linking an E3 ubiquitin ligase to the targeted protein for proteasomal degradation. To this end, we recently developed a protein knockdown system based on hybrid small molecule SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers) that recruit inhibitor of the apoptosis protein (IAP) ubiquitin ligases to specifically degrade targeted proteins. Here, we extend our previous study to show a proof of concept of the SNIPER technology in vivo. By incorporating a high affinity IAP ligand, we developed a novel SNIPER against estrogen receptor α (ERα), SNIPER(ER)-87, that has a potent protein knockdown activity. The SNIPER(ER) reduced ERα levels in tumor xenografts and suppressed the growth of ERα-positive breast tumors in mice. Mechanistically, it preferentially recruits X-linked IAP (XIAP) rather than cellular IAP1, to degrade ERα via the ubiquitin-proteasome pathway. With this IAP ligand, potent SNIPERs against other pathogenic proteins, BCR-ABL, bromodomain-containing protein 4 (BRD4), and phosphodiesterase-4 (PDE4) could also be developed. These results indicate that forced ubiquitylation by SNIPERs is a useful method to achieve efficient protein knockdown with potential therapeutic activities and could also be applied to study the role of ubiquitylation in many cellular processes.
Reports on the health of the people of ancient Egypt, one of the four great civilizations of the world, are of considerable interest to many. This paper addresses the paleohealth of people from Qau ...in ancient Egypt based on samples housed at the University of Cambridge. This skeletal series extends from the Protodynastic Period to the 30th Dynasty, with the largest number being from the 6th to 8th Dynasties. The remains are divided into four groups (male, female, early middle age, and late middle age) and physical anthropology methods were used to investigate dental caries, periodontal disease, antemortem tooth loss, dental wear, alveolar bone recession, enamel hypoplasia, and cribra orbitalia. The study was limited in that resource materials from multiple dynasties were combined, and no postcranial skeletal examinations were possible. However, the following matters were found regarding the paleohealth of the ancient Egyptian Qau people: (i) the rate of dental caries was low; (ii) periodontal disease was present and progressed with age; (iii) even so, tooth loss was low; (iv) dental wear was pronounced; and (v) there were no age-related stress markers, and few individuals with serious disease. Overall, based on the Qau people in this data, it can be assumed that the health status was poor, the death rate of newborns, infants, and young children was high, and individuals exhibiting severe stress markers died before reaching adulthood. Ancient Egyptians have long been the subject of much anthropological and archaeological study, and this paper introduces several interesting topics for further investigation concerning the paleoenvironment and paleohealth of these ancient people.
Over the decades, mummy studies have expanded to reconstruct a multifaceted knowledge about the ancient populations’ living conditions, pathologies, and possible cause of death in different ...spatiotemporal contexts. Mainly due to linguistic barriers, however, the international knowledge of East Asian mummies has remained sketchy until recently. We thus analyse and summarize the outcomes of the studies so far performed in Korea and China in order to provide mummy experts with little-known data on East Asian mummies. In this report, similarities and differences in the mummification processes and funerary rituals in Korea and China are highlighted. Although the historical periods, the region of excavation, and the structures of the graves differ, the cultural aspects, the mechanisms of mummification, and biological evidence appear to be essentially similar to each other. Independently from the way they are called locally, the Korean and Chinese mummies belong to the same group with a shared cultural background.
Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been ...established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical function. Together, these findings suggest that SARM-2f might represent an effective treatment for sarcopenia and cachexia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
doi: 10.1111/j.1741‐2358.2011.00511.x
The number of missing teeth in people of the Edo period in Japan in the 17th to 19th centuries
Objective: The aims of this study were to examine the number of ...missing teeth in the people of the Edo period (or number of remaining teeth) and to contribute to the 8020 movement proposed in Japan to help people retain 20 or more of their own teeth until the age of 80.
Background: The study of dentition in ancient skeletal remains of our ancestors from multiple perspectives can yield information that can contribute to the study of physical anthropology and the leading edge of modern dental research.
Materials and methods: The materials were 82 excavated individuals (52 males and 30 females) from 1603 to 1868 whose maxillas and mandibles were both examinable. The age and sex were estimated by anthropological methods, and the individuals were divided into five groups. The status of missing teeth was compared between groups, and a chi‐square test was used to test significant differences between groups. The rates of tooth loss were examined in the maxillas and mandibles.
Results: In the people of the Edo period, many teeth remained in good condition until early to late middle age. There were more remaining teeth in these individuals than in modern‐day individuals. However, the Edo people clearly showed increased tooth loss with age. There were no differences in tooth loss by sex. The tooth type with a high rate of tooth loss was posterior teeth, but incisor loss also occurred with ageing. Mandibular canines were most likely to be remaining.
Conclusion: The Edo people had more remaining teeth than modern‐day society. This finding was unexpected. The notion that “people of long past ages lost more teeth more quickly” does not seem to apply to people in the Edo period in Japan.
Background and Purpose
Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both ...responsible for the NmU‐mediated anti‐obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor‐selective agonists.
Experimental Approach
Efficacy and safety were assessed in mice with diet‐induced obesity (DIO) and those with leptin‐deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU‐6102) and NMU2 (NMU‐2084), along with non‐selective NMU1/2 agonists (NMU‐0002 and NMU‐6014). We also performed immunohistochemistry for c‐Fos protein expression in the brain to probe their mechanisms of action.
Key Results
Although both non‐selective NMU1/2 agonists and the NMU2‐selective agonist had high efficacy compared with the NMU1‐selective agonist, only the NMU2‐selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the non‐selective NMU1/2 agonist and the NMU1‐selective agonist, but not the NMU2‐selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2‐selective agonists preferentially activate pro‐opiomelanocortin neurons in the hypothalamic arcuate nucleus but not in the paraventricular nucleus.
Conclusions and Implications
These results suggest that an NMU2 receptor‐selective agonist may be a well‐balanced drug for the treatment of obesity and that an NMU1 receptor‐selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.
Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment ...option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.
Notwithstanding the significant anthropological advancements that have taken place over the past several decades, the health and disease statuses of ancient people have yet to be fully elucidated. To ...this end, paleopathology - the pathological study of tissues remnant in ancient biological specimens - has been established by many pioneering researchers around the world. The field includes various sub-disciplines such as the diagnosis of specific diseases seen in archaeological specimens, the tracing of secular changes in health and disease patterns of human populations, and the biological reconstruction of pathogenic evolution by molecular techniques. The information obtained inspires ever-greater achievements, thereby contributing to the comprehensive understanding of the reciprocal interaction between human beings and disease throughout history. Anthropological Science (AS) is an authoritative academic journal with a long publishing history, some issues of which have already included paleopathology-related articles.
If all the conceptual devices involved in what Bergson calls “the planes of consciousness,” from the persistence of pure memory to perception and action, concern the relation between two different ...realms of existence, mind-memory and body-matter, Matter and Memory is then a work that attempts to rethink the problem of imagination and schematism. This is why we can legitimately claim that Heidegger’s challenge in his Kant and the Problem of Metaphysics to read transcendental imagination as primordial temporality can be interpreted as being on the way to a Bergsonian philosophy of immanence that sees the transcendental as the folds and folding of experience. In other words, corresponding to Bergson’s theory of image, Heidegger’s challenge does not reach at pure memory and its power of idleness im-plicated under the form of the inverted cone diagram of consciousness. It is Kant in the Critique of Judgment who comes to the rescue of Heidegger, who has stopped in the middle of his path. Why is the sublime important? Because it exposes, within experience, the limits of the transcendental imagination, of the transcendental schematism, and thus of the Heideggerian interpretation. And it is Bergson in his analysis of the panoramic vision that reveals, through the difference between the tension of attention to life and the tension of conversion, an imagination backlit by the movement of what overflows from the system of memory and perception represented in the diagram of the inverted cone. Especially, his third analysis of panoramic memory is so valuable that, in contrast to the other two analyses, it suggests, through the philosophical gesture of looking-back, that time is not external to experience, as in the sublime, but time is itself a re-living of the past.
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We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles ...and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR.
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