Rapamycin is an immunosuppressant drug used to prevent organ rejection in transplant patients. In this study, we investigated the metabolic effects of rapamycin in an obese animal model, KK/HlJ mice. Mice were treated with a daily intraperitoneal injection of rapamycin at 2 mg/kg or vehicle for 42 days on a high-fat diet. Treated mice lost body weight and adiposity, reduced weight gain and retroperitoneal and epididymal fat pads/body weight, decreased serum leptin and plasma triglyceride levels and had lower liver fat concentration. However, treated mice had higher serum insulin levels and food intake. Dissection of rapamycin-treated mice revealed a marked reduction in fatty liver scores and fat cell size in retroperitoneal and epididymal adipocytes. Moreover, Western blot analysis revealed that rapamycin treatment resulted in decreasing adipophilin expression, as a marker of lipid accumulation, and reducing phosphorylation of mTOR downstream targets S6K1 compared to control group. Unfortunately, rapamycin-treated animals showed a marked decline in glucose tolerance as judged by the 180-min. area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species. These results suggest that continual rapamycin administration may help to prevent diet-induced obesity, while prolonged use of rapamycin may exacerbate glucose intolerance.The mammalian target of the rapamycin (mTOR) signalling pathway performs an important function in the regulation of cell growth, proliferation and nutrient signals [1,2]. Recent studies have demonstrated that mTOR is involved in specific pathological responses including obesity, diabetes, and cancer [2,3]. Consistent with the development of these diseases, the activation of the mTOR pathway is evident in insulin-resistant obese rats maintained on a high-fat diet [4].Rapamycin (also known as sirolimus), an anti-fungal macrolide, is a uniquely specific mTOR kinase inhibitor [5]. Rapamycin blocks mTOR Complex1 (mTORC1) function by forming a gain-of-function inhibitory complex with the immunophilin FK506 binding protein 1A (FKBP12) that inhibits progression through involvement in the G1 phase of the cell cycle [6]. Subsequently, rapamycin was shown to have potent immunosuppressive and antiproliferative effects [7]. As an immunosuppressant drug, it is used to prevent organ rejection following kidney, liver, and heart transplants [8,9]. In addition, because of its antiproliferative effects, rapamycin and its analogues have been shown to be effective and novel anticancer agents [10,11]. Moreover, rapamycin has recently been used to coat cardiac stents, preventing stenosis [12,13].However, despite evidence suggesting a role by mTOR in regulating metabolic syndromes [14,15], the extent of its role has not been fully explored. In this study, we aimed to clarify how rapamycin administration inhibition of the mTOR pathway affects the relationship between metabolic syndrome and diabetes. We planned to achieve this by examining the effect of ra...

Abstract. Rapamycin (RAPA), an immunosuprpressive drug used extensively to prevent graft rejection in transplant patients, has been reported to inhibit adipogenesis in vitro. In this study, we investigated the anti-obesity effects of RAPA in C57BL/6J mice on a high-fat diet (HFD). Mice treated with RAPA (2 mg/kg per week for 16 weeks) had reduced body weight and epididymal fat pads /body weight, reduced daily food efficiency, and lower serum leptin and insulin levels compared with the HFD control mice. However, RAPA-treated mice were hyperphagic, demonstrating an increase in food intake. Dissection of RAPA-treated mice revealed a marked reduction in fatty liver scores, average fat cell size, and percentage of large adipocytes of retroperitoneal and epididymal white adipose tissue (RWAT and EWAT), compared to the HFD control mice. These results suggest that RAPA prevented the effect of the high-fat diet on the rate of accretion in body weight via reducing lipid accumulation, despite greater food intake. It is likely that RAPA may serve as a potential strategy for body weight control and/or antiobesity therapy.[ Supplementary Tables: available only at http://dx

BACKGROUND AND PURPOSERapamycin, which is used clinically to treat graft rejection, has also been proposed to have an effect on metabolic syndrome; however, very little information is available on its effects in lean animals/humans. The purpose of this study was to characterize further the effects of the continuous use of rapamycin on glucose homeostasis in lean C57BL6/J mice. EXPERIMENTAL APPROACHMice were fed a high-protein diet (HPD) for 12 weeks to develop a lean model and then were treated daily with rapamycin for 5 weeks while remaining on a HPD. Metabolic parameters, endocrine profiles, glucose tolerance tests, insulin sensitivity index, the expression of the glucose transporter GLUT4 and chromium distribution were measured in vivo. KEY RESULTSLower body weight gain as well as a decreased caloric intake, fat pads, fatty liver scores, adipocyte size and glucose tolerance test values were observed in HPD-fed mice compared with mice fed a high-fat or standard diet. Despite these beneficial effects, rapamycin-treated lean mice showed greater glucose intolerance, reduced insulin sensitivity, lower muscle GLUT4 expression and changes in chromium levels in tissues even with high insulin levels. CONCLUSION AND IMPLICATIONSOur findings demonstrate that continuous rapamycin administration may lead to the development of diabetes syndrome, as it was found to induce hyperglycaemia and glucose intolerance in a lean animal model. AbbreviationsEWAT, epididymal white adipose tissue; HFD, high-fat diet; HPD, high-protein diet; IPGTT, i.p. glucose tolerance test; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; RWAT, retroperitoneal white adipose tissue; SD, standard diet BJP British Journal of Pharmacology

Naphthomycins (NATs) are 29-membered naphthalenic ansamacrolactam antibiotics with antimicrobial and antineoplastic activities. Their biosynthesis starts from 3-amino-5-hydroxy-benzoic acid (AHBA). By PCR amplification with primers for AHBA synthase and amino-dehydroquinate (aDHQ) synthase, a genomic region containing orthologs of these genes was identified in Streptomyces sp. CS. It was confirmed to be involved in naphthomycin biosynthesis by deletion of a large DNA fragment, resulting in abolishment of naphthomycin production. A 106 kb region was sequenced, and 32 complete ORFs were identified, including five polyketide synthase genes, eight genes for AHBA synthesis, and putative genes for modification, regulation, transport or resistance. Targeted inactivation and complementation experiments proved that the halogenase gene nat1 is responsible for the chlorination of C-30 of NATs. The nat1 mutant could also be complemented with asm12, the halogenase gene of ansamitocin biosynthesis. Likewise, an asm12 mutant could be complemented with nat1, suggesting a similar catalytic mechanism for both halogenases. A putative hydroxylase gene, nat2, was also inactivated, whereupon the biosynthesis of NATs was completely abolished with a tetraketide desacetyl-SY4b accumulated, indicating the participation of nat2 in the formation of the naphthalene ring. The information presented here expands our understanding of the biosynthesis of naphthalenic ansamycins, and may pave the way for engineering ansamacrolactams with improved pharmaceutical properties.

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Objective: To study the differences in clinical characteristics, risk factors, and complications across age-groups among the inpatients with the coronavirus disease 2019 (COVID-19).Methods: In this population-based retrospective study, we included all the positive hospitalized patients with COVID-19 at Wuhan City from December 29, 2019 to April 15, 2020, during the first pandemic wave. Multivariate logistic regression analyses were used to explore the risk factors for death from COVID-19. Canonical correlation analysis (CCA) was performed to study the associations between comorbidities and complications.Results: There are 36,358 patients in the final cohort, of whom 2,492 (6.85%) died. Greater age (odds ration [OR] = 1.061 [95% CI 1.057–1.065], p < 0.001), male gender (OR = 1.726 [95% CI 1.582–1.885], p < 0.001), alcohol consumption (OR = 1.558 [95% CI 1.355–1.786], p < 0.001), smoking (OR = 1.326 [95% CI 1.055–1.652], p = 0.014), hypertension (OR = 1.175 [95% CI 1.067–1.293], p = 0.001), diabetes (OR = 1.258 [95% CI 1.118–1.413], p < 0.001), cancer (OR = 1.86 [95% CI 1.507–2.279], p < 0.001), chronic kidney disease (CKD) (OR = 1.745 [95% CI 1.427–2.12], p < 0.001), and intracerebral hemorrhage (ICH) (OR = 1.96 [95% CI 1.323–2.846], p = 0.001) were independent risk factors for death from COVID-19. Patients aged 40–80 years make up the majority of the whole patients, and them had similar risk factors with the whole patients. For patients aged <40 years, only cancer (OR = 17.112 [95% CI 6.264–39.73], p < 0.001) and ICH (OR = 31.538 [95% CI 5.213–158.787], p < 0.001) were significantly associated with higher odds of death. For patients aged >80 years, only age (OR = 1.033 [95% CI 1.008–1.059], p = 0.01) and male gender (OR = 1.585 [95% CI 1.301–1.933], p < 0.001) were associated with higher odds of death. The incidence of most complications increases with age, but arrhythmias, gastrointestinal bleeding, and sepsis were more common in younger deceased patients with COVID-19, with only arrhythmia reaching statistical difference (p = 0.039). We found a relatively poor correlation between preexisting risk factors and complications.Conclusions: Coronavirus disease 2019 are disproportionally affected by age for its clinical manifestations, risk factors, complications, and outcomes. Prior complications have little effect on the incidence of extrapulmonary complications.

Background Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations. Objective We aimed to explore the potential causative gene for PKD. Methods A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing. Results Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups. Conclusions We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society

Background Deep vein thrombosis (DVT) of lower limb is one of the common complications after total hip arthroplasty(THA), we aimed to evaluate the potential risk factors of DVT of lower limb in patients with THA, to provide insights into the management of THA. Methods Patients who underwent THA in our hospital from January 1, 2017 to November 30, 2020 were included. The personal characteristics and clinical data of DVT and no-DVT patients were compared and analyzed. Logistic regression analyses were perfomed to identify the potential risk factors of DVT in patients with THA. Results A total of 182 THA patients were included, the incidence of DVT of lower limb in patients with THA was 19.78 %. There were significant differences in the age, BMI, diabetes, number of replacement, duration of surgery, type of prosthesis and duration of days in bed between DVT and no-DVT patients(all P < 0.05). And there were no significant differences in the gender, hypertension, hyperlipidemia, preoperative D-dimer, type of anesthesia and anticoagulant drugs use(all P > 0.05). Logistic regression analysis indicated that age > 70y(OR4.406, 95 %CI1.744 ~ 6.134), BMI ≥ 28(OR2.275, 95 %CI1.181 ~ 4.531), diabetes(OR3.949, 95 %CI1.284 ~ 5.279), bilateral joint replacements(OR2.272, 95 %CI1.402 ~ 4.423), duration of surgery ≥ 120 min(OR3.081, 95 %CI1.293 ~ 5.308), cemented prosthesis(OR2.435, 95 %CI1.104 ~ 4.315), and duration of days in bed > 3 days(OR1.566, 95 %CI1.182 ~ 1.994) were the risk factors of DVT of lower limb in patients with THA. Conclusions DVT in the lower limb after THA is common, and its onset is affected by many factors. In clinical work, attention should be paid to identify the risk factors for DVT and targeted interventions are highlighted to prevent the postoperative DVT.