A Conserved Mechanism of Cardiac Hypertrophy Regression through FoxO1.

The heart is a highly plastic organ that responds to diverse stimuli to modify form and function. The molecular mechanisms of adaptive physiological cardiac hypertrophy are well-established; however, the regulation of hypertrophy regression is poorly understood. To identify molecular features of regression, we studied Burmese pythons which experience reversible cardiac hypertrophy following large, infrequent meals. Using multi-omics screens followed by targeted analyses, we found forkhead box protein O1 (FoxO1) transcription factor signaling, and downstream autophagy activity, were downregulated during hypertrophy, but re-activated with regression. To determine whether these events were mechanistically related to regression, we established an in vitro platform of cardiomyocyte hypertrophy and regression from treatment with fed python plasma. FoxO1 inhibition prevented regression in this system, while FoxO1 activation reversed fed python plasma-induced hypertrophy in an autophagy-dependent manner. We next examined whether FoxO1 was implicated in mammalian models of reversible hypertrophy from exercise and pregnancy and found that in both cases FoxO1 was activated during regression. In these models, as in pythons, activation of FoxO1 was associated with increased expression FoxO1 target genes involved in autophagy. Taken together, our findings suggest FoxO1-dependent autophagy is a conserved mechanism for regression of physiological cardiac hypertrophy across species.

Utility of the burmese Python as a model for studying plasticity of extreme physiological systems.

Non-traditional animal models present an opportunity to discover novel biology that has evolved to allow such animals to survive in extreme environments. One striking example is the Burmese python (Python molurus bivittatus), which exhibits extreme physiological adaptation in various metabolic organs after consuming a large meal following long periods of fasting. The response to such a large meal in pythons involves a dramatic surge in metabolic rate, lipid overload in plasma, and massive but reversible organ growth through the course of digestion. Multiple studies have reported the physiological responses in post-prandial pythons, while the specific molecular control of these processes is less well-studied. Investigating the mechanisms that coordinate organ growth and adaptive responses offers the opportunity to gain novel insight that may be able to treat various pathologies in humans. Here, we summarize past research on the post-prandial physiological changes in the Burmese python with a focus on the gastrointestinal tract, heart, and liver. Specifically, we address our recent molecular discoveries in the post-prandial python liver which demonstrate transient adaptations that may reveal new therapeutic targets. Lastly, we explore new biology of the aquaporin 7 gene that is potently upregulated in mammalian cardiac myocytes by circulating factors in post-prandial python plasma.

Effects of Diets With Different Protein Levels on Lipid Metabolism and Gut Microbes in the Host of Different Genders.

The purpose of this experiment was to investigate the effects of different protein levels on lipid metabolism and gut microbes in mice of different genders. A total of 60 mice (30 female and 30 male) were randomly assigned to six groups and fed female mice with low protein diet (FLP), basal protein diet (FBD), and high protein diet (FHP). Similarly, the male mice fed with low protein diet (MLP), basal protein diet (MBD), and high protein diet (MHP). The low protein diet contained 14% CP, the basal diet contained 20% CP, and the high protein diet contained 26% CP. The results of the study showed that both basal and high protein diets significantly reduced the perirenal adipose tissues (PEAT) index in male mice compared to low protein diet (p < 0.05). For the gut, the FHP significantly increased the relative gut weight compared to the FBD and FLP (p < 0.05). At the same time, the FHP also significantly increased the relative gut length compared with the FBD and FLP (p < 0.05). The MHP significantly increased TC concentration compared with the MLP (p < 0.05), and the MBD tended to increase TC concentration compared with the MLP in serum (p = 0.084). The histomorphology result of the jejunum and ileum showed that a low protein diet was beneficial to the digestion and absorption of nutrients in the small intestine of mice. While different protein levels had no effect on the total number of fecal microbial species in mice, different protein levels had a significant effect on certain fecal microbes in mice, the absolute abundance of Verrucomicrobia in the feces of male mice was significantly higher in both high and basal protein diets than in the low protein diet (p < 0.05). The high protein diet significantly reduced the absolute abundance of Patescibacteria in the feces of female mice compared to both the basal and low protein diets (p < 0.05). The absolute abundance of Patescibacteria in male feces was not affected by dietary protein levels (p > 0.05). Taken together, our results suggest that a low protein diet can alter fat deposition and lipid metabolism in mice, and that it benefited small intestinal epithelial structure and microbes.

Spread and Molecular Characteristics of Enterobacteriaceae Carrying fosA-Like Genes from Farms in China.

In this study, we aimed to investigate the occurrence and molecular characteristics of fosfomycin-resistant Enterobacteriaceae isolates from pig, chicken and pigeon farms in Guangxi Province of China. A total of 200 fosfomycin-resistant strains were obtained from food animals and their surrounding environments, with the fosA, fosA3, and fosA7.5 genes being detected in 26% (52/200), 10% (20/200), and 5% (10/200), respectively. Surprisingly, three fosA7.5-producing E. coli isolates were found to be concomitant with fosA3. Most of the fosA-like-gene-positive isolates were multidrug-resistant strains and consistently possessed blaCTX-M-1/CTX-M-9, floR, and blaTEM genes. Only fosA3 was successfully transferred to the recipient strains, and the 29 fosA3-carrying transconjugants exhibited high-level resistance to fosfomycin (MIC ≥ 512 µg/mL). Multilocus sequence typing (MLST) combined with enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) analyses indicated that fosA3 or fosA7.5 genes were spread by horizontal transfer as well as via clonal transmission between E. coli. We used the PCR mapping method to explore the genetic contexts of fosA-like genes, and two representative strains (fEc.1 and fEcg99-1) were fully sequenced. Six different genetic structures surrounding fosA3 were detected and one infrequent context was discovered among the conjugable fosA3-positive E. coli isolates. The five genetic environments of fosA were identified and found to be highly similar to the partial sequence of transposon Tn2921. Furthermore, whole-genome sequencing (WGS) results showed that fosA7.5 was colocalized with mcr-3, blaCMY-63, sul3, tet(A), dfrA, and a number of virulence-related factors on the same chromosomes of strains, and various insertion sequences (IS3/ISL3) were detected upstream or downstream of fosA7.5. The phylogenetic analysis revealed that both fosA7.5- and fosA3-carrying E. coli ST602 and fosA7.5-carrying E. coli ST2599 were closely related to E. coli isolates from humans, which may indicate that they pose a threat to human health. IMPORTANCE Here, we report the widespread and complex genetic environments of fosA-like genes in animal-derived strains in China. The fosA7.5 gene was identified in this study and was found to confer resistance to fosfomycin. The high prevalence of fosA-like genes in farms indicates that food animals serve as a potential reservoir for the resistance genes. This study also discovered that fosfomycin resistance genes were always associated with mobile elements, which would accelerate the transmission of fosA-like genes in strains. Importantly, E. coli ST602 and ST2599 carrying fosA3 or fosA7.5 from food animals had high similarity to E. coli isolates from humans, suggesting that fosA-like genes can be transmitted to humans through the food chain, thus posing a serious threat to public health. Therefore, the prevalence of fosA-like genes isolated from animals should be further monitored.

Burmese pythons exhibit a transient adaptation to nutrient overload that prevents liver damage.

As an opportunistic predator, the Burmese python (Python molurus bivittatus) consumes large and infrequent meals, fasting for up to a year. Upon consuming a large meal, the Burmese python exhibits extreme metabolic responses. To define the pathways that regulate these postprandial metabolic responses, we performed a comprehensive profile of plasma metabolites throughout the digestive process. Following ingestion of a meal equivalent to 25% of its body mass, plasma lipoproteins and metabolites, such as chylomicra and bile acids, reach levels observed only in mammalian models of extreme dyslipidemia. Here, we provide evidence for an adaptive response to postprandial nutrient overload by the python liver, a critical site of metabolic homeostasis. The python liver undergoes a substantial increase in mass through proliferative processes, exhibits hepatic steatosis, hyperlipidemia-induced insulin resistance indicated by PEPCK activation and pAKT deactivation, and de novo fatty acid synthesis via FASN activation. This postprandial state is completely reversible. We posit that Burmese pythons evade the permanent hepatic damage associated with these metabolic states in mammals using evolved protective measures to inactivate these pathways. These include a transient activation of hepatic nuclear receptors induced by fatty acids and bile acids, including PPAR and FXR, respectively. The stress-induced p38 MAPK pathway is also transiently activated during the early stages of digestion. Taken together, these data identify a reversible metabolic response to hyperlipidemia by the python liver, only achieved in mammals by pharmacologic intervention. The factors involved in these processes may be relevant to or leveraged for remediating human hepatic pathology.