Functional vertical connectivity of microbial communities in the ocean.

Sinking particles are a critical conduit for the transport of surface microbes to the ocean's interior. Vertical connectivity of phylogenetic composition has been shown; however, the functional vertical connectivity of microbial communities has not yet been explored in detail. We investigated protein and taxa profiles of both free-living and particle-attached microbial communities from the surface to 3000 m depth using a combined metaproteomic and 16S rRNA amplicon sequencing approach. A clear compositional and functional vertical connectivity of microbial communities was observed throughout the water column with Oceanospirillales, Alteromonadales, and Rhodobacterales as key taxa. The surface-derived particle-associated microbes increased the expression of proteins involved in basic metabolism, organic matter processing, and environmental stress response in deep waters. This study highlights the functional vertical connectivity between surface and deep-sea microbial communities via sinking particles and reveals that a considerable proportion of the deep-sea microbes might originate from surface waters and have a major impact on the biogeochemical cycles in the deep sea.

Examining graph neural networks for crystal structures: Limitations and opportunities for capturing periodicity.

Graph neural networks (GNNs) have recently been used to learn the representations of crystal structures through an end-to-end data-driven approach. However, a systematic top-down approach to evaluate and understand the limitations of GNNs in accurately capturing crystal structures has yet to be established. In this study, we introduce an approach using human-designed descriptors as a compendium of human knowledge to investigate the extent to which GNNs can comprehend crystal structures. Our findings reveal that current state-of-the-art GNNs fall short in accurately capturing the periodicity of crystal structures. We analyze this failure by exploring three aspects: local expressive power, long-range information processing, and readout function. To address these identified limitations, we propose a straightforward and general solution: the hybridization of descriptors with GNNs, which directly supplements the missing information to GNNs. The hybridization enhances the predictive accuracy of GNNs for specific material properties, most notably phonon internal energy and heat capacity, which heavily rely on the periodicity of materials.

Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on the Heart.

Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, ß-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of ß-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that ß-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

The Comparable Microenvironment Shared by Colorectal Adenoma and Carcinoma: An Evidence of Stromal Proteomics.

Tumor microenvironment (TME) is a key factor involved in cancer development and metastasis. In the TME of colorectal cancer (CRC), the gene expression status of stromal tissues could influence the CRC process from normal to adenoma then carcinoma; however, the expression status at the protein level has not yet been well evaluated. A total of 22 CRC patients were recruited for this study, and the tissue regions corresponding with adjacent, adenoma, and carcinoma were carefully excised by laser capture microdissection (LCM), including a patient with adenoma and carcinoma. The individual proteomes of this cohort were implemented by high-resolution mass spectrometer under data-independent acquisition (DIA) mode. A series of informatic analysis was employed to statistically seek the proteomic characteristics related with the stroma at different stages of CRC. The identified proteins in the colorectal stromal tissues were much less than and almost overlapped with that in the corresponding epithelial tissues; however, the patterns of protein abundance in the stroma were very distinct from those in the epithelium. Although qualitative and quantitative analysis delineated the epithelial proteins specifically typified in the adjacent, adenoma, and carcinoma, the informatics in the stroma led to another deduction that such proteomes were only divided into two patterns, adjacent- and adenoma/carcinoma-dependent. The comparable proteomes of colorectal adenoma and carcinoma were further confirmed by the bulk preparation- or individual LCM-proteomics. The biochemical features of the tumor stromal proteomes were characterized as enrichment of CD4+ and CD8+ T cells, upregulated pathways of antigen presentation, and enhancement of immune signal interactions. Finally, the features of lymphoid lineages in tumor stroma were verified by tissue microarray (TMA). Based on the proteomic evidence, a hypothesis was raised that in the colorectal tissue, the TME of adenoma and carcinoma were comparable, whereas the key elements driving an epithelium from benign to malignant were likely decided by the changes of genomic mutations or/and expression within it.

Evaluation of Spike Protein Epitopes by Assessing the Dynamics of Humoral Immune Responses in Moderate COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike protein (S) of SARS-CoV-2 is a major target for diagnosis and vaccine development because of its essential role in viral infection and host immunity. Currently, time-dependent responses of humoral immune system against various S protein epitopes are poorly understood. In this study, enzyme-linked immunosorbent assay (ELISA), peptide microarray, and antibody binding epitope mapping (AbMap) techniques were used to systematically analyze the dynamic changes of humoral immune responses against the S protein in a small cohort of moderate COVID-19 patients who were hospitalized for approximately two months after symptom onset. Recombinant truncated S proteins, target S peptides, and random peptides were used as antigens in the analyses. The assays demonstrated the dynamic IgM- and IgG recognition and reactivity against various S protein epitopes with patient-dependent patterns. Comprehensive analysis of epitope distribution along the spike gene sequence and spatial structure of the homotrimer S protein demonstrated that most IgM- and IgG-reactive peptides were clustered into similar genomic regions and were located at accessible domains. Seven S peptides were generally recognized by IgG antibodies derived from serum samples of all COVID-19 patients. The dynamic immune recognition signals from these seven S peptides were comparable to those of the entire S protein or truncated S1 protein. This suggested that the humoral immune system recognized few conserved S protein epitopes in most COVID-19 patients during the entire duration of humoral immune response after symptom onset. Furthermore, in this cohort, individual patients demonstrated stable immune recognition to certain S protein epitopes throughout their hospitalization period. Therefore, the dynamic characteristics of humoral immune responses to S protein have provided valuable information for accurate diagnosis and immunotherapy of COVID-19 patients.

SETD8 stabilized by USP17 epigenetically activates SREBP1 pathway to drive lipogenesis and oncogenesis of ccRCC.

Recently, epigenetic modifications, including DNA methylation, histone modification and noncoding RNA (ncRNA)-associated gene silencing, have received increasing attention from the scientific community. Many studies have demonstrated that epigenetic regulation can render dynamic alterations in the transcriptional potential of a cell, which then affects the cell's biological function. The initiation and development of clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell cancer (RCC), is also closely related to genomic alterations by epigenetic modification. For ccRCC, lipid accumulation is one of the most typical characteristics. In other words, dysregulation of lipid uptake and synthesis occurs in ccRCC, which inversely promotes cancer proliferation and progression. However, the link among epigenetic alterations, lipid biosynthesis and renal cancer progression remains unclear. SETD8 is a histone methyltransferase and plays pivotal roles in cell cycle regulation and oncogenesis of various cancers, but its role in RCC is not well understood. In this study, we discovered that SETD8 was significantly overexpressed in RCC tumors, which was positively related to lipid storage and correlated with advanced tumor grade and stage and poor patient prognosis. Depletion of SETD8 by siRNAs or inhibitor UNC0379 diminished fatty acid (FA) de novo synthesis, cell proliferation and metastasis in ccRCC cells. Mechanistically, SETD8, which was posttranslationally stabilized by USP17, could transcriptionally modulate sterol regulatory element-binding protein 1 (SREBP1), a key transcription factor in fatty acid biosynthesis and lipogenesis, by monomethylating the 20th lysine of the H4 histone, elevating lipid biosynthesis and accumulation in RCC and further promoting cancer progression and metastasis. Taken together, the USP17/SETD8/SREBP1 signaling pathway plays a pivotal role in promoting RCC progression. SETD8 might be a novel biomarker and potential therapeutic target for treating RCC.

Berberine enhances gemcitabine­induced cytotoxicity in bladder cancer by downregulating Rad51 expression through inactivating the PI3K/Akt pathway.

Although gemcitabine (GEM) has been used to treat bladder cancer (BC) for a number of years, severe adverse events or drug resistance frequently develops. A series of drugs have been proved to sensitize patients to GEM and reduce the side effects. The aim of the present study was to evaluate the potential effects of berberine (BER) on GEM­induced cytotoxicity in BC and to explore the possible underlying mechanisms. T24 and 5637 human BC cell lines were treated with GEM and/or BER before cell proliferation, apoptosis and migration were studied. Oncomine databases and Gene Expression Profiling Interactive Analysis (GEPIA) were used to retrieve RAD51 recombinase (Rad51) mRNA expression. Overexpression plasmid or specific Rad51 small interfering RNA were used to examine the role of Rad51 in drug­treated BC cells. BC model mice were administered with GEM and/or BER before changes in tumor volume, size and Ki67 expression were assessed. BER enhanced GEM­induced cytotoxicity, apoptosis and inhibition of migration, whilst attenuating the GEM­induced upregulation of phosphorylated Akt and Rad51 expression. According to Oncomine and GEPIA analyses, Rad51 was found to be significantly upregulated in BC tissues compared with that in normal tissues, where there was a weak positive correlation between Rad51 and Akt1 expression. Knockdown of Rad51 enhanced GEM­induced cytotoxicity, whilst overexpression of Rad51 reversed the suppressed cell viability induced by BER and GEM. Inactivation of the PI3K/Akt pathway by LY294002 or BER enhanced GEM­induced cytotoxicity and downregulated Rad51 expression, whilst overexpression of constitutively active Akt restored Rad51 expression and cell viability that was previously decreased by BER and GEM. BER additively inhibited tumor growth and Ki67 expression when combined with GEM in vivo. These results suggest that BER can enhance GEM­induced cytotoxicity in BC by downregulating Rad51 expression through inactivating the PI3K/Akt pathway, which may represent a novel therapeutic target for BC treatment.

Metabolic tuning of a stable microbial community in the surface oligotrophic Indian Ocean revealed by integrated meta-omics.

Understanding the mechanisms, structuring microbial communities in oligotrophic ocean surface waters remains a major ecological endeavor. Functional redundancy and metabolic tuning are two mechanisms that have been proposed to shape microbial response to environmental forcing. However, little is known about their roles in the oligotrophic surface ocean due to less integrative characterization of community taxonomy and function. Here, we applied an integrated meta-omics-based approach, from genes to proteins, to investigate the microbial community of the oligotrophic northern Indian Ocean. Insignificant spatial variabilities of both genomic and proteomic compositions indicated a stable microbial community that was dominated by Prochlorococcus, Synechococcus, and SAR11. However, fine tuning of some metabolic functions that are mainly driven by salinity and temperature was observed. Intriguingly, a tuning divergence occurred between metabolic potential and activity in response to different environmental perturbations. Our results indicate that metabolic tuning is an important mechanism for sustaining the stability of microbial communities in oligotrophic oceans. In addition, integrated meta-omics provides a powerful tool to comprehensively understand microbial behavior and function in the ocean. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-021-00119-6.

Discovery of Missing Proteins from an Aneuploidy Cell Line Using a Proteogenomic Approach.

With the steadfast development of proteomic technology, the number of missing proteins (MPs) has been continuously shrinking, with approximately 1470 MPs that have not been explored yet. Due to this phenomenon, the discovery of MPs has been increasingly more difficult and elusive. In order to face this challenge, we have hypothesized that a stable aneuploid cell line with increased chromosomes serves as a useful material for assisting MP exploration. Ker-CT cell line with trisomy at chromosome 5 and 20 was selected for this purpose. With a combination strategy of RNA-Seq and LC-MS/MS, a total of 22 178 transcripts and 8846 proteins were identified in Ker-CT. Although the transcripts corresponding to 15 and 15 MP genes located at chromosome 5 and 20 were detected, none of the MPs were found in Ker-CT. Surprisingly, 3 MPs containing at least two unique non-nest peptides of length ≥9 amino acids were identified in Ker-CT, whose genes are located on chromosome 3 and 10, respectively. Furthermore, the 3 MPs were verified using the method of parallel reaction monitoring (PRM). These results suggest that the abnormal status of chromosomes may not only impact the expression of the corresponding genes in trisomy chromosomes, but also influence that of other chromosomes, which benefits MP discovery. The data obtained in this study are available via ProteomeXchange (PXD028647) and PeptideAtlas (PASS01700), respectively.

FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner.

The aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpression promoted bladder cancer cell proliferation, whereas FTO knockdown inhibited bladder cancer cell proliferation. We also demonstrated that FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways. Taken together, our work revealed that FTO plays a critical role in bladder cancer and could be a potential diagnostic or prognostic biomarker for this disease.

An increase of phosphatidylcholines in follicular fluid implies attenuation of embryo quality on day 3 post-fertilization.

BACKGROUND: Although oocyte quality is the dominant factor determining embryo quality, few studies have been conducted to evaluate embryo quality based on the metabolites related to the oocyte. With quantification of the follicular fluid (FF) metabolites, in assisted reproductive technology (ART), this study sought to evaluate the embryo or oocyte quality through an informative approach. RESULTS: An evaluation model consisting of 17 features was generated to distinguish the embryo quality on day 3 post-fertilization, and phosphatidylcholines (PCs) were the key contributors to the evaluation. The model was extended to the patients under different ages and hyperstimulations, and the features were further enriched to facilitate the evaluation of the embryo quality. The metabolites were clustered through pathway analysis, leading to a hypothesis that accumulation of arachidonic acid induced by PCs might weaken embryo quality on day 3 post-fertilization. CONCLUSIONS: A discriminating model with metabolic features elicited from follicular fluid was established, which enabled the evaluation of the embryo or oocyte quality even under certain clinical conditions, and the increase of PCs in follicular fluid implies the attenuation of embryo quality on day 3 post-fertilization.

Illuminating Key Microbial Players and Metabolic Processes Involved in the Remineralization of Particulate Organic Carbon in the Ocean's Twilight Zone by Metaproteomics.

The twilight zone (from the base of the euphotic zone to the depth of 1,000 m) is the major area of particulate organic carbon (POC) remineralization in the ocean, and heterotrophic microbes contribute to more than 70% of the estimated remineralization. However, little is known about the microbial community and metabolic activity directly associated with POC remineralization in this chronically understudied realm. Here, we characterized the microbial community proteomes of POC samples collected from the twilight zone of three contrasting sites in the Northwest Pacific Ocean using a metaproteomic approach. The particle-attached bacteria from Alteromonadales, Rhodobacterales, and Enterobacterales were the primary POC remineralizers. Hydrolytic enzymes, including proteases and hydrolases, that degrade proteinaceous components and polysaccharides, the main constituents of POC, were abundant and taxonomically associated with these bacterial groups. Furthermore, identification of diverse species-specific transporters and metabolic enzymes implied niche specialization for nutrient acquisition among these bacterial groups. Temperature was the main environmental factor driving the active bacterial groups and metabolic processes, and Enterobacterales replaced Alteromonadales as the predominant group under low temperature. This study provides insight into the key bacteria and metabolic processes involved in POC remineralization, and niche complementarity and species substitution among bacterial groups are critical for efficient POC remineralization in the twilight zone. IMPORTANCE The ocean's twilight zone is a critical zone where more than 70% of the sinking particulate organic carbon (POC) is remineralized. Therefore, the twilight zone determines the size of biological carbon storage in the ocean and regulates the global climate. Prokaryotes are major players that govern remineralization of POC in this region. However, knowledge of microbial community structure and metabolic activity is still lacking. This study unveiled microbial communities and metabolic activities of POC samples collected from the twilight zone of three contrasting environments in the Northwest Pacific Ocean using a metaproteomic approach. Alteromonadales, Rhodobacterales, and Enterobacterales were the major remineralizers of POC. They excreted diverse species-specific hydrolytic enzymes to split POC into solubilized POC or dissolved organic carbon. Temperature played a crucial role in regulating the community composition and metabolism. Furthermore, niche complementarity or species substitution among bacterial groups guaranteed the efficient remineralization of POC in the twilight zone.

Metaproteomics Reveals Similar Vertical Distribution of Microbial Transport Proteins in Particulate Organic Matter Throughout the Water Column in the Northwest Pacific Ocean.

Solubilized particulate organic matter (POM) rather than dissolved organic matter (DOM) has been speculated to be the major carbon and energy sources for heterotrophic prokaryotes in the ocean. However, the direct evidence is still lack. Here we characterized microbial transport proteins of POM collected from both euphotic (75 m, deep chlorophyll maximum DCM, and 100 m) and upper-twilight (200 m and 500 m) zones in three contrasting environments in the northwest Pacific Ocean using a metaproteomic approach. The proportion of transport proteins was relatively high at the bottom of the euphotic zone (200 m), indicating that this layer was the most active area of microbe-driven POM remineralization in the water column. In the upper-twilight zone, the predicted substrates of the identified transporters indicated that amino acids, carbohydrates, taurine, inorganic nutrients, urea, biopolymers, and cobalamin were essential substrates for the microbial community. SAR11, Rhodobacterales, Alteromonadales, and Enterobacteriales were the key contributors with the highest expression of transporters. Interestingly, both the taxonomy and function of the microbial communities varied among water layers and sites with different environments; however, the distribution of transporter types and their relevant organic substrates were similar among samples, suggesting that microbial communities took up similar compounds and were functionally redundant in organic matter utilization throughout the water column. The similar vertical distribution of transport proteins from the euphotic zone to the upper twilight zone among the contrasting environments indicated that solubilized POM rather than DOM was the preferable carbon and energy sources for the microbial communities.

Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway.

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

Integral Analysis of the RNA Binding Protein-associated Prognostic Model for Renal Cell Carcinoma.

RNA binding protein (RBPs) dysregulation has been reported in various malignant tumors and plays a pivotal role in tumor carcinogenesis and progression. However, the underlying mechanisms in renal cell carcinoma (RCC) are still unknown. In the present study, we performed a bioinformatics analysis using data from TCGA database to explore the expression and prognostic value of RBPs. We identified 125 differently expressed RBPs between tumor and normal tissue in RCC patients, including 87 upregulated and 38 downregulated RBPs. Eight RBPs (RPL22L1, RNASE2, RNASE3, EZH2, DDX25, DQX1, EXOSC5, DDX47) were selected as prognosis-related RBPs and used to construct a risk score model. In the risk score model, the high-risk subgroup had a poorer overall survival (OS) than the low-risk subgroup, and we divided the 539 RCC patients into two groups and conducted a time-dependent receiver operating characteristic (ROC) analysis to further test the prognostic ability of the eight hub RBPs. The area under the curve (AUC) of the ROC curve was 0.728 in train-group and 0.688 in test-group, indicating a good prognostic model. More importantly, we established a nomogram based on the selected eight RBPs. The eight selected RBPS have predictive value for RCC patients, with potential applications in clinical decision-making and individualized treatment.

Metaproteomics reveals the molecular mechanism underlying bloom maintenance of a marine dinoflagellate under low ambient CO2 and inorganic nutrients.

Dinoflagellate blooming periods are paradoxically characterized by high biomass growth rate and low ambient dissolved CO2 and inorganic nutrients, however, the underlying mechanisms linking cell growth and nutrient acquisition are poorly understood. Here, we compared metaproteomes of non-bloom, mid-blooming and late-blooming cells of a marine dinoflagellate Prorocentrum donghaiense. Cell division, metabolism of carbon, nitrogen, phosphorus, lipid, porphyrin and chlorophyll were more active in blooming cells than in non-bloom cells. Up-regulation of carbonic anhydrase, ribulose-1,5-bisphosphate carboxylase/oxygenase II, and C4-cycle proteins enhanced CO2 assimilation of P. donghaiense. Proteins participating in external organic nutrient acquisition and conversion, such as transporters for fatty acids, peptides and amino acids, external- and internal-phosphomonoester hydrolase, and diverse peptidases and amino acid transaminases, exhibited higher expression in blooming cells relative to non-bloom cells. Interestingly, dissolved organic nitrogen (DON) such as urea and aspartate significantly down-regulated expression and activity of carbon assimilation proteins except for RuBisCO form II, suggesting that DON provided sufficient carbon source which reduced the need to concentrate internal CO2. This study demonstrates that coupling of efficient CO2 assimilation with DON utilization are essential for bloom maintenance of P. donghaiense, and future efforts should be devoted to dissolved organic nutrients for prevention and management of dinoflagelllate blooms.

Giant Paraganglioma Complicated With Catecholamine Crisis and Catecholamine Cardiomyopathy: A Case Report and Review of the Literature.

Background: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors which overproduce catecholamines. Heart failure and myocardial infarction caused by paraganglioma complicated with catecholamine crisis are the most common causes of death in PPGL patients before surgery. When giant paraganglioma is complicated with catecholamine crisis, treatment brooks no delay. Case Summary: A 49-year-old man had episodic sweating, tachycardia with irregular pulse, and headaches 5 days before, and then showed up with chest pain and wheezing for 1 day. Meanwhile, he developed symptoms of recurrent severe abdominal pain and loss of consciousness, and his blood pressure was severely unstable (from 70/40 to 300/200 mmHg). First, the electrocardiogram showed ventricular tachycardia, and then we noticed the waves of ST-segment elevation, but we did not find significant abnormalities in coronary angiography. Abdominal CT and MRI revealed a giant lesion with bleeding or infection in the retroperitoneal adrenal area. These imaging findings were confirmed during surgery, and there was vascular adhesion between the retroperitoneal tumor and the inferior vena cava and left and right renal vein. After the successful resection of the tumor, postoperative pathology confirmed paraganglioma, and the patient pulled through and was discharged quickly. Discussion: This is a rare case of giant paraganglioma complicated with catecholamine crisis and catecholamine cardiomyopathy. We can diagnosis this disease greatly by elevated norepinephrine, and it is a gold biochemical standard at present. Standard treatment is surgical resection, which is effective in treating this rare neuroendocrine tumor.

Pathway attenuation of fatty acid beta-oxidation in the skeletal muscle of a type 2 diabetic mouse model.

RATIONALE: Whether catabolic abnormalities of fatty acids exist in the skeletal muscle of type 2 diabetes mellitus (T2DM) has not been determined. In this study, we postulated that a systematic evaluation of the protein abundance and metabolic activity related to fatty acids in the skeletal muscle tissues of a T2DM mouse model was feasible to address this question. METHODS: Mitochondria were extracted from wild-type (WT) and db/db mice followed by quantitative analysis of the proteins involved in mitochondrial fatty acid oxidation (mFAO). The pathway activity of mFAO in skeletal muscle tissues was monitored in vitro using mass spectrometry, and tissue lipidomic analysis was conducted in profiling and target mode to distinguish the levels of long-chain acylcarnitines between WT and db/db mice. RESULTS: Two proteins related to the mFAO pathway were significantly downregulated in the skeletal muscle mitochondria of db/db mice. The measurement of mFAO pathway activity in vitro revealed that the abundance of long-chain acylcarnitines (C14 to C18) in db/db mice was lower than that in WT mice, and the determination of acylcarnitines in skeletal muscle tissues in vivo revealed that most long-chain acylcarnitines were decreased in db/db mice. CONCLUSIONS: The findings of lower abundance of ACAD9 and CPT1B, reduced activity of the mFAO pathway in vitro and decreased acylcarnitines in vivo firmly support that the mFAO pathway in the skeletal muscle of diabetic mice is attenuated, possibly resulting in cell/tissue dysfunction in diabetes.