Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC.

Insights into copper sensing and tolerance in species.

Introduction: species are pathogenic fungi known to cause pneumonia in immunocompromised mammals. They are obligate to their host, replicate extracellularly in lung alveoli and thrive in the copper-enriched environment of mammalian lungs. In this study, we investigated the proteome of , a model organism that infects mice, in the context of its copper sensing and tolerance.

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC.

Utilization of a zinc reporter reveals the complexities of fungal sensing of metal deprivation.

is a dimorphic fungal pathogen acquired via inhalation of soil-resident spores. Upon exposure to mammalian body temperatures, these fungal elements transform into yeasts that reside primarily within phagocytes. Macrophages (MΦ) provide a permissive environment for fungal replication until T cell-dependent immunity is engaged.

Utilization of a zinc reporter reveals the complexities of fungal sensing of metal deprivation.

Unlabelled: is a dimorphic fungal pathogen acquired via inhalation of soil-resident spores. Upon exposure to mammalian body temperatures, these fungal elements transform into yeasts that reside primarily within phagocytes. Macrophages (MΦ) provide a permissive environment for fungal replication until T cell-dependent immunity is engaged.

A miniaturized sample preparation method for routine elemental determination in whole blood using volumetric absorptive micro-sampling by ICP-QQQ.

Volumetric absorptive micro-sampling (VAMS) has emerged as a simple and safe tool for collecting and storing blood samples in clinical and bioanalytical fields. This study presents a novel method for determining essential and non-essential trace elements (As, Be, Cd, Cs, Cu, Fe, Mg, P, Pb, S, Sb, Se, Tl, V, U) in VAMS-collected blood samples using microwave-assisted digestion with diluted acid as sample preparation method and an inductively coupled plasma triple quadrupole mass spectrometry (ICP-QQQ) as determination technique. While certain elements posed challenges due to VAMS tip background issues (Al, Ti, Cr, Mn, Co, Ni, Sn, Mo, Ba), the method demonstrated high precision and accuracy for the targeted analytes.

Microtubule-associated protein MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells.

Microtubule-associated protein 1 light chain 3 gamma (MAP1LC3C or LC3C) is a member of the microtubule-associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor-suppressing activity, and its expression is dependent on kidney cancer tumor suppressors, such as von Hippel-Lindau protein and folliculin. Recently, we demonstrated that LC3C autophagy is regulated by noncanonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cell stemness.

Feasibility study for mercury remediation by selenium competition in Pleurotus mushrooms.

Mushrooms may incorporate significant levels of Hg making its consumption harmful to human health. Mercury remediation induced by Se competition in edible mushrooms represents a valuable alternative since Se plays effective roles against Hg uptake, accumulation, and toxicity. In this way, Pleurotus ostreatus and Pleurotus djamor were cultivated on Hg-contaminated substrate simultaneously supplemented with Se(IV) or Se(VI) under different dosages in this study.

An evaluation of M interference correction approaches associated with As and Se in ICP-MS using a multi-day dataset along with ICP-MS/MS/HR-ICP-MS based analysis and hierarchical modeling as a means of assessing bias in fortified drinking waters and single component matrices.

Three mass oriented rare earth element (REE) M correction approaches (fixed factor, a dual internal standard, and an in-sample) are evaluated for use in an ICP-MS environmental method update. The multi-variant-based evaluation includes analyzing the same 19 REE-fortified matrices on eight different days over a two-month period using two instrument tunes. These REE-fortified matrices were also analyzed using HR-ICP-MS and ICP-MS/MS to estimate the reference value for use in the principal component analysis (PCA) and hierarchical modeling evaluation.

Effects of Se(IV) or Se(VI) enrichment on proteins and protein-bound Se distribution and Se bioaccessibility in oyster mushrooms.

A successful mushroom enrichment process must produce foods that have compounds potentially absorbed by the human body. In this study, Pleurotus ostreatus and Pleurotus djamor mushrooms were grown on organic substrate supplemented with different Se(IV) and Se(VI) concentrations, and evaluated in the following features: Fruiting bodies morphology; Se uptake and accumulation; Distribution of proteins and protein-bound Se; Se species identification on enzymatic extracts; Se bioaccessibility; and Distribution of bioaccessible protein-bound Se. Pleurotus djamor grown on Se(IV)-supplemented substrate showed the greatest potential to uptake and accumulate Se.

Pirfenidone as a potential antifibrotic injectable for Dupuytren's disease.

Dupuytren's disease is a progressive fibrotic condition of the hand that causes contracture of fingers in later stages. Our previous studies suggest that the transformation of fibroblasts to myofibroblasts induced by transforming growth factor-beta can be inhibited by the addition of the antifibrotic drug, pirfenidone (PFD). We hypothesize that the local delivery of PFD directly to nodules can potentially prevent the progression to cords and, furthermore, that injection of PFD after the resection of cords can limit the recurrence of the disease.

The protective role of selenium against uptake and accumulation of cadmium and lead in white oyster () and pink oyster () mushrooms.

Mushrooms are bioaccumulators and have been used to produce Se-enriched foods. However, these fungi can also bioaccumulate potentially toxic metals, producing food dangerous to human health. It is known that co-exposure to Se plays a protective role against metal accumulation and toxicity in some organisms due to its antioxidant properties.

Metallothionein 3-Zinc Axis Suppresses Caspase-11 Inflammasome Activation and Impairs Antibacterial Immunity.

Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn) regulating protein, metallothionein 3 (MT3).

A metabolic inhibitor arms macrophages to kill intracellular fungal pathogens by manipulating zinc homeostasis.

Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource-poor environment by marshaling mechanisms to harvest nutrients.

Metabolic subtypes of clear cell renal cell carcinoma defined by tobacco smoking.

Tobacco smoking (TS) results in reprogramming of major metabolic pathways, including glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and metabolism of aspartate, glutamate and glutamine in clear cell renal cell carcinoma (ccRCC). TS alters the distribution and activities of cadmium, arsenic and copper in a manner mechanistically supporting metabolic remodeling. Alterations in metabolism and metal distribution identify new actionable targets for treatment of ccRCC.

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma.

The promise of personalized medicine is a therapeutic advance where tumor signatures obtained from different omics platforms, such as genomics, transcriptomics, proteomics, and metabolomics, in addition to environmental factors including metals and metalloids, are used to guide the treatments. Clear cell renal carcinoma (ccRCC), the most common type of kidney cancer, can be sporadic (frequently) or genetic (rare), both characterized by loss of the von Hippel-Lindau (VHL) gene that controls hypoxia inducible factors. Recently, several genomic subtypes were identified with different prognoses.

Dual-purpose isocyanides produced by contribute to cellular copper sufficiency and exhibit antimicrobial activity.

The maintenance of sufficient but nontoxic pools of metal micronutrients is accomplished through diverse homeostasis mechanisms in fungi. Siderophores play a well established role for iron homeostasis; however, no copper-binding analogs have been found in fungi. Here we demonstrate that, in , xanthocillin and other isocyanides derived from the biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties.

Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming.

Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages.

Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function.

The TRPP2-dependent channel of renal primary cilia also requires TRPM3.

Primary cilia of renal epithelial cells express several members of the transient receptor potential (TRP) class of cation-conducting channel, including TRPC1, TRPM3, TRPM4, TRPP2, and TRPV4. Some cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by defects in TRPP2 (also called polycystin-2, PC2, or PKD2). A large-conductance, TRPP2-dependent channel in renal cilia has been well described, but it is not known whether this channel includes any other protein subunits.

K⁺ and Rb⁺ Affinities of the Na,K-ATPase α₁ and α₂ Isozymes: An Application of ICP-MS for Quantification of Na⁺ Pump Kinetics in Myofibers.

The potassium affinities of Na,K-ATPase isozymes are important determinants of their physiological roles in skeletal muscle. This study measured the apparent K⁺ and Rb⁺ affinities of the Na,K-ATPase α₁ and α₂ isozymes in intact, dissociated myofibers obtained from WT and genetically altered mice (α₁α₂ and skα₂). It also validates a new method to quantify cations in intact, dissociated myofibers, using inductively coupled plasma mass spectrometry (ICP-MS).

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus.

The ubiquitous fungus Aspergillus flavus is notorious for contaminating many important crops and food-stuffs with the carcinogenic mycotoxin, aflatoxin. This fungus is also the second most frequent Aspergillus pathogen after A. fumigatus infecting immunosuppressed patients.

The metal and metalloprotein profile of human plasma as biomarkers for stroke diagnosis.

Stroke, a major cause of disability and mortality, affects someone in the United States every 40s. Stroke biomarkers, including those that could be used as a blood test for diagnosis of stroke, have been particularly elusive. We performed a double blind study to identify human plasma biomarkers for the diagnosis of stroke, including acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH).