Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue

Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT

Enterohaemorrhagic Escherichia coli and Shigella dysenteriae type 1-induced haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) can be classified according to the aetiology of the different disorders from which it is composed. The most prevalent form is that induced by shigatoxin producing Escherichia coli (STEC) and, in some tropical regions, by Shigella dysenteriae type 1. STEC cause a zoonosis, are widely distributed in nature, enter the food chain in different ways, and show regional differences. Not all STEC are human pathogens. Enterohaemorrhagic E. coli usually cause attachment and effacing lesions in the intestine. This is not essential, but production of a shigatoxin (Stx) is. Because Stx are encoded by a bacteriophage, this property is transferable to naïve strains. Laboratory methods have improved by identifying STEC either via the toxin or its bacteriophage. Shigella dysenteriae type 1 produces shigatoxin, identical to Stx-1, but also has entero-invasive properties that enterohaemorrhagic Escherichia coli (EHEC) do not. Shigella patients risk bacteremia and benefit from early antibiotic treatment, unlike those with EHEC

Inhibition of the Soluble Epoxide Hydrolase Promotes Albuminuria in Mice with Progressive Renal Disease

Epoxyeicotrienoic acids (EETs) are cytochrome P450-dependent anti-hypertensive and anti-inflammatory derivatives of arachidonic acid, which are highly abundant in the kidney and considered reno-protective. EETs are degraded by the enzyme soluble epoxide hydrolase (sEH) and sEH inhibitors are considered treatment for chronic renal failure (CRF). We determined whether sEH inhibition attenuates the progression of CRF in the 5/6-nephrectomy model (5/6-Nx) in mice. 5/6-Nx mice were treated with a placebo, an ACE-inhibitor (Ramipril, 40 mg/kg), the sEH-inhibitor cAUCB or the CYP-inhibitor fenbendazole for 8 weeks. 5/6-Nx induced hypertension, albuminuria, glomerulosclerosis and tubulo-interstitial damage and these effects were attenuated by Ramipril. In contrast, cAUCB failed to lower the blood pressure and albuminuria was more severe as compared to placebo. Plasma EET-levels were doubled in 5/6 Nx-mice as compared to sham mice receiving placebo. Renal sEH expression was attenuated in 5/6-Nx mice but cAUCB in these animals still further increased the EET-level. cAUCB also increased 5-HETE and 15-HETE, which derive from peroxidation or lipoxygenases. Similar to cAUCB, CYP450 inhibition increased HETEs and promoted albuminuria. Thus, sEH-inhibition failed to elicit protective effects in the 5/6-Nx model and showed a tendency to aggravate the disease. These effects might be consequence of a shift of arachidonic acid metabolism into the lipoxygenase pathway

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines

Differential effects of malignant mesothelioma cells on THP-1 monocytes and macrophages

Malignant mesothelioma (MM) is a highly fatal tumor arising from inner body membranes, whose extensive growth is facilitated by its week immunogenicity and by its ability to blunt the immune response which should arise from the huge mass of leukocytes typically infiltrating this tumor. It has been reported that the inflammatory infiltrate found in MM tissues is characterized by a high prevalence of macrophages. Thus, in this work we evaluated the ability of human MM cells to modulate the inflammatory phenotype of human THP-1 monocytes and macrophages, a widely used in vitro model of monocyte/macrophage differentiation. Furthermore, we tested the hypothesis that the exposure to MM cells could alter the differentiation of THP-1 monocytes favoring the development of alternatively activated, tumor-supporting macrophages. Our data prove for the first time that MM cells can polarize monocytes towards an altered inflammatory phenotype and macrophages towards an immunosuppressive phenotype. Moreover, we demonstrate that monocytes cocultivated with MM cells 'keep a memory' of their encounter with the tumor which influences their differentiation to macrophages. On the whole, we provide evidence that MM cells exert distinct, cell-specific effects on monocytes and macrophages. The thorough characterization of such effects may be of a crucial importance for the rational design of new immunotherapeutic protocols

High-dose steroid treatment increases free water transport in peritoneal dialysis patients

The water channel aquaporin-1 (AQP1) is the molecular counterpart of the ultrasmall pore that mediates free water transport during peritoneal dialysis (PD). Proof-of-principle studies performed in rats have shown that treatment with corticosteroids upregulates the expression of AQP1 in the peritoneal capillaries, causing a significant increase in free water transport. Whether such a beneficial effect could be observed in end-stage renal disease patients treated by PD remains unknown. Peritoneal transport parameters were evaluated in three patients on PD, shortly before and after living-donor renal transplantation and treatment with high-dose methylprednisolone (1.0-1.2 g/m(2)). As compared with pre-transplantation values, the post-transplantation test revealed an ∼2-fold increase in the sodium sieving and ultrasmall pore ultrafiltration volume, suggesting an effect on AQP1 water channels. In contrast, there was no change in the parameters of small solute transport. The direct involvement of AQP1 in these changes is suggested by the expression of glucocorticoid receptors in the human peritoneum and the presence of conserved glucocorticoid response elements in the promoter of the human AQP1 gene

Trans-crocetin improves amyloid-β degradation in monocytes from Alzheimer's Disease patients

Herbal medicines have been recently employed in research and clinical studies for the potential treatment of behavioral and psychological symptoms associated with Alzheimer's Disease (AD) and other types of dementia. The present study investigates the effect of trans-crocetin, an active constituent of Crocus sativus L., to restore in vitro the reduced ability of AD patients' monocytes to degrade amyloid-β(1-42) (Aβ42). CD14(+) monocytes from 22 sporadic AD patients with moderate cognitive impairment were isolated; then, the role of trans-crocetin, purified from saffron extracts, was evaluated in terms of Aβ42 degradation rate through flow cytometry, as well as expression of cathepsin B by Western blotting. We observed that low micromolar doses of trans-crocetin enhanced Aβ42 degradation in AD monocytes through the upregulation of the lysosomal protease cathepsin B. CA074Me, a potent and selective cathepsin B inhibitor, counteracted such trans-crocetin-induced effect. These data suggest that the carotenoid trans-crocetin improves in vitro the clearance of Aβ42 through the involvement of cathepsin B, and this could be of value in developing a new anti-amyloid strategy in AD

Safety of Monoclonal Antibodies in Children Affected by SARS-CoV-2 Infection

: Monoclonal antibody therapies for COVID-19 have been frequently used in adults, whereas there are little data regarding the safety or efficacy of monoclonal antibody treatments in pediatric patients affected by COVID-19. We report our experience in the administration of mAb as a treatment for SARS-CoV-2 infection in children aged from 24 days to 18 years old