Vascular calcification is a serious complication of hyperphosphatemia that causes cardiovascular morbidity and mortality. Previous studies have reported that plasmalemmal phosphate (Pi) transporters, ...such as PiT-1/2, mediate depolarization, Ca
influx, oxidative stress, and calcific changes in vascular smooth muscle cells (VSMCs). However, the pathogenic mechanism of mitochondrial Pi uptake in vascular calcification associated with hyperphosphatemia has not been elucidated. We demonstrated that the phosphate carrier (PiC) is the dominant mitochondrial Pi transporter responsible for high Pi-induced superoxide generation, osteogenic gene upregulation, and calcific changes in primary VSMCs isolated from rat aortas. Notably, acute incubation with high Pi markedly increased the protein abundance of PiC via ERK1/2- and mTOR-dependent translational upregulation. Genetic suppression of PiC prevented Pi-induced ERK1/2 activation, superoxide production, osteogenic differentiation, and vascular calcification of VSMCs in vitro and aortic rings ex vivo. Pharmacological inhibition of mitochondrial Pi transport using butyl malonate (BMA) or mersalyl abolished all pathologic changes involved in high Pi-induced vascular calcification. BMA or mersalyl also effectively prevented osteogenic gene upregulation and calcification of aortas from 5/6 subtotal nephrectomized mice fed a high-Pi diet. Our results suggest that mitochondrial Pi uptake via PiC is a critical molecular mechanism mediating mitochondrial superoxide generation and pathogenic calcific changes, which could be a novel therapeutic target for treating vascular calcification associated with hyperphosphatemia.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that ...lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD
modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD
levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD
levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC-1α in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS.
Thyroid dysfunction has been reported to be an extrapulmonary symptom of COVID-19. It is important to identify the tissue subset that expresses angiotensin-converting enzyme 2 (ACE2) and ...transmembrane protease serine 2 (TMPRSS2), which are essential for host infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in order to understand the viral pathogenesis of COVID-19-related thyroid dysfunction. We investigated the expression and distribution of ACE2- and TMPRSS2-expressing cells in the thyroid gland. RT-PCR and Western blotting were performed on human thyroid follicular cells (Nthy-ori3-1) and rat thyroid tissues to detect the expression levels of ACE and TMPRSS2 mRNA and proteins. We also analyzed the expression patterns of ACE2 and TMPRSS2 in 9 Sprague-Dawley rats and 15 human thyroid tissues, including 5 normal, 5 with Hashimoto's thyroiditis, and 5 with Graves' disease, by immunohistochemistry (IHC) and immunofluorescence. Both ACE2 and TMPRSS2 mRNAs and proteins were detected in the thyroid tissue. However, ACE2 and TMPRSS2 proteins were not expressed in thyroid follicular cells. In IHC, ACE2 and TMPRSS2 were not stained in the follicular cells. No cells co-expressed ACE2 and TMPRSS2. ACE2 was expressed in pericytes between follicles, and TMPRSS2 was mainly stained in the colloid inside the follicle. There was no difference in expression between the normal thyroid, Hashimoto's thyroiditis, and Graves' disease. SARS-CoV-2 does not directly invade the thyroid follicular cells. Whether SARS-CoV-2 infection of pericytes can affect COVID-19-related thyroid dysfunction warrants further study.
The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current ...understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.
All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. ...However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions.
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•Gut epithelia mount innate immunity by sensing bacterial-derived uracil•Uracil induces DUOX-dependent intestinal ROS generation•Uracil from allochthonous pathogenic bacteria induces homeostatic inflammation•Long-term uracil release from colitogenic pathobionts causes chronic inflammation
Different gut bacteria have distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, determining homeostasis or pathogenesis in gut-microbe interactions.
Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 ...phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72.
Background
Massage and aromatherapy massage are used to relieve cancer‐related symptoms. A number of claims have been made for these treatments including reduction of pain, anxiety, depression, and ...stress. Other studies have not shown these benefits.
Objectives
To evaluate the effects of massage with or without aromatherapy on pain and other symptoms associated with cancer.
Search methods
We searched the following databases and trials registries up to August 2015: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 7), MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), PubMed Cancer Subset, SADCCT, and the World Health Organization (WHO) ICTRP. We also searched clinical trial registries for ongoing studies.
Selection criteria
Randomised controlled studies (RCTs) reporting the effects of aromatherapy or massage therapy, or both, in people with cancer of any age. We applied no language restrictions. Comparators were massage (using carrier oil only) versus no massage, massage with aromatherapy (using carrier oil plus essential oils) versus no massage, and massage with aromatherapy (using carrier oil plus essential oils) versus massage without aromatherapy (using carrier oil only).
Data collection and analysis
At least two review authors selected studies, assessed the risk of bias, and extracted data relating to pain and other symptoms associated with cancer, using standardised forms. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created two 'Summary of findings' tables.
Main results
We included 19 studies (21 reports) of very low quality evidence with a total of 1274 participants. We included 14 studies (16 reports) in a qualitative synthesis and five studies in a quantitative synthesis (meta‐analysis). Thirteen studies (14 reports, 596 participants) compared massage with no massage. Six studies (seven reports, 561 participants) compared aromatherapy massage with no massage. Two studies (117 participants) compared massage with aromatherapy and massage without aromatherapy. Fourteen studies had a high risk of bias related to sample size and 15 studies had a low risk of bias for blinding the outcome assessment. We judged the studies to be at unclear risk of bias overall. Our primary outcomes were pain and psychological symptoms. Two studies reported physical distress, rash, and general malaise as adverse events. The remaining 17 studies did not report adverse events. We downgraded the GRADE quality of evidence for all outcomes to very low because of observed imprecision, indirectness, imbalance between groups in many studies, and limitations of study design.
Massage versus no‐massage groups
We analysed results for pain and anxiety but the quality of evidence was very low as most studies were small and considered at an unclear or high risk of bias due to poor reporting. Short‐term pain (Present Pain Intensity‐Visual Analogue Scale) was greater for the massage group compared with the no‐massage group (one RCT, n = 72, mean difference (MD) ‐1.60, 95% confidence interval (CI) ‐2.67 to ‐0.53). Data for anxiety (State‐Trait Anxiety Inventory‐state) relief showed no significant difference in anxiety between the groups (three RCTs, n = 98, combined MD ‐5.36, 95% CI ‐16.06 to 5.34). The subgroup analysis for anxiety revealed that the anxiety relief for children was greater for the massage group compared with the no‐massage group (one RCT, n = 30, MD ‐14.70, 95% CI ‐19.33 to ‐10.07), but the size of this effect was considered not clinically significant. Furthermore, this review demonstrated no differences in effects of massage on depression, mood disturbance, psychological distress, nausea, fatigue, physical symptom distress, or quality of life when compared with no massage.
Massage with aromatherapy versus no‐massage groups
We analysed results for pain, anxiety, symptoms relating to the breast, and quality of life but the quality of evidence was very low as studies were generally at a high risk of bias. There was some indication of benefit in the aromatherapy‐massage group but this benefit is unlikely to translate into clinical benefit. The relief of medium‐ and long‐term pain (medium‐term: one RCT, n = 86, MD 5.30, 95% CI 1.52 to 9.08; long‐term: one RCT, n = 86, MD 3.80, 95% CI 0.19 to 7.41), anxiety (two RCTs, n = 253, combined MD ‐4.50, 95% CI ‐7.70 to ‐1.30), and long‐term symptoms relating to the breast in people with breast cancer (one RCT, n = 86, MD ‐9.80, 95% CI ‐19.13 to ‐0.47) was greater for the aromatherapy‐massage group, but the results were considered not clinically significant. The medium‐term quality of life score was lower (better) for the aromatherapy‐massage group compared with the no‐massage group (one RCT, n = 30, MD ‐2.00, 95% CI ‐3.46 to ‐0.54).
Massage with aromatherapy versus massage without aromatherapy groups
From the limited evidence available, we were unable to assess the effect of adding aromatherapy to massage on the relief of pain, psychological symptoms including anxiety and depression, physical symptom distress, or quality of life.
Authors' conclusions
There was a lack of evidence on the clinical effectiveness of massage for symptom relief in people with cancer. Most studies were too small to be reliable and key outcomes were not reported. Any further studies of aromatherapy and massage will need to address these concerns.
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