PEG35 and Glutathione Improve Mitochondrial Function and Reduce Oxidative Stress in Cold Fatty Liver Graft Preservation

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation.

Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity

Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.

Gold Nanoclusters Eliminate Obesity Induced by Antipsychotics

Obesity induced by antipsychotics have plagued more than 20 million people worldwide. However, no drug is available to eliminate the obesity induced by antipsychotics. Here we examined the effect and potential mechanisms of a gold nanoclusters (AuNCs) modified by N-isobutyryl-L-cysteine on the obesity induced by olanzapine, the most prescribed but obesogenic antipsychotics, in a rat model. Our results showed that AuNCs completely prevented and reversed the obesity induced by olanzapine and improved glucose metabolism profile in rats. Further mechanism investigations revealed that AuNCs exert its anti-obesity function through inhibition of olanzapine-induced dysfunction of histamine H1 receptor and proopiomelanocortin signaling therefore reducing hyperphagia, and reversing olanzapine-induced inhibition of uncoupling-protein-1 signaling which increases thermogenesis. Together with AuNCs’ good biocompatibility, these findings not only provide AuNCs as a promising nanodrug candidate for treating obesity induced by antipsychotics, but also open an avenue for the potential application of AuNCs-based nanodrugs in treating general obesity

Role of Pterostilbene in Metabolic Diseases through SIRT1 pathway- A Review

Pterostilbene (PTE) (3-5 dimethoxy-4-hydroxy-trans-stilbenes) is an analogue of resveratrol. It is extracted and isolated from a natural source of the heartwood of Pterocarpus marsupium Roxb., red grape skin, and blueberries (Vaccinium spp.). Substantial evidence suggested that PTE displayed numerous preventive and therapeutic properties in many metabolic disorders such as diabetes and obesity. Metabolic diseases result in Insulin resistance (IR) which advances to impaired sensitivity to insulin-mediated glucose disposal. The prominent role of SIRT (silent information regulator proteins) is now getting emphasized in metabolic disorders. SIRT1 represses Uncoupling protein 2 (UCP2) expressions which are further responsible for improving synthesis of ATP from glucose. This results in improving glucose utilization and insulin secretion, thus preventing IR. SIRT1 also exhibits prominent role in facilitating fatty acid mobilization thereby inhibiting adiposity. Metabolic disorders are therefore the consequences of SIRT1 downregulation. Pterostilbene, being a SIRT1 activator, increases insulin sensitivity reduces adiposity, therefore can prove to be beneficial in diabetes as well as obesity. The review summarizes therapeutic effects portrayed by Pterostilbene via the SIRT1 pathway in metabolic diseases.

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

Pengaruh Irisin pada Pencoklatan Lemak Putih

Pendahuluan: Irisin merupakan miokin baru yang menghubungkan aktivitas fisik yang berhubungan dengan peningkatan kinerja metabolisme dan berkaitanan dengan pencoklatan jaringan adiposa putih menjadi coklat. Tujuan: Mengetahui pengaruh irisin pada pencoklatan lemak putih. Metode: Menggunakan studi literatur dari sumber ilmiah dengan meringkas dari publikasi dan membandingkan hasil yang disajikan. Hasil: Irisin yang disekresikan dari otot, akan menstimulasi ekspresi dari uncoupling protein 1 (UCP1) dalam adiposit yang menyebabkan pencoklatan jaringan adiposa putih melalui p38 mitogen-activated protein kinase (MAPK) dan melalui extracellular-signal regulated kinase (ERK). Kesimpulan: Irisin yang disekresikan otot rangka akan mengekspresikan UPC-1 di jaringan adiposa yang menyebabkan jaringan adiposa putih menjadi coklat dan peningkatan aktivitas thermogenesis.

Proses Pencokelatan Jaringan Adiposa

Obesity is a common, serious, and detrimental condition. In 2014, more than 1.9 billion adults were overweight. Obesity is associated with many diseases and the increase in obesity has become a major health problem. Obesity is caused by an imbalance between energy intake and energy consumption. Adipose tissue is an endocrine organ that secretes many hormones and cytokines that can affect metabolism. There are two types of adipose tissue in the body with different functions, namely white adipose tissue and brown adipose tissue. White fat has a major function in storing energy and is increased in obesity, while brown fat produces heat (thermogenesis) and then increases energy consumption. Therefore, brown fat and the induction of brown fat-like properties in white fat, have been considered as targets in the fight against obesity. The complex process of cell differentiation leading to the appearance of active brown adipocytes has been identified. There are classic brown adipocytes and cream adipocytes. Beige adipocytes are brown adipocytes that appear on precursor cells of white adipose tissue due to stimuli. Brown adipocytes are equipped with mitochondria containing uncoupling protein 1 (UCP1), which, when activated, controls ATP synthesis and stimulates respiratory chain activity. The browning process of adipose tissue is controlled by factors such as exercise. Obesitas merupakan keadaan yang umum, serius, dan merugikan. Tahun 2014, lebih dari 1,9 milyar orang dewasa mengalami kelebihan berat badan. Obesitas berasosiasi dengan banyak penyakit dan peningkatan obesitas telah menjadi masalah kesehatan utama. Obesitas disebabkan oleh ketidakseimbangan antara energi yang masuk dan konsumsi energi. Jaringan adiposa dalam tubuh ada dua tipe yang fungsinya berbeda, yakni jaringan adiposa putih dan jaringan adiposa cokelat. Lemak putih berfungsi utama dalam menyimpan energi dan meningkat pada obesitas, sedangkan lemak cokelat menghasilkan panas (termogenesis) dan kemudian meningkatkan konsumsi energi. Oleh karena itu, lemak cokelat dan induksi sifat seperti lemak cokelat pada lemak putih, telah dipertimbangkan sebagai target dalam melawan obesitas. Tujuan penelitian ini adalah untuk mengetahui proses pencoklatan jaringan adiposa putih. Metode penelitian yang digunakan adalah metode penelusuran ilmiah. Hasil penelitian diperoleh bahwa adiposit krem merupakan adiposit cokelat yang muncul pada sel prekursor dari jaringan adiposa putih karena adanya stimuli. Adiposit krem sama seperti adiposit cokelat dilengkapi dengan mitokondria yang mengandung uncoupling protein 1 (UCP1), yang ketika teraktivasi akan mengendalikan sintesis ATP dan menstimulasi aktivitas rantai respirasi. Beberapa regulator seperti PPAR γ, PGC-1α, dan PRDM16 muncul sebagai pelaku utama dalam proses diferensiasi adiposit krem.