Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.

Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.

Alpha-lipoic acid could attenuate the effect of chemerin-induced diabetic nephropathy progression.

OBJECTIVES: Chemerin is associated with insulin resistance, obesity, and metabolic syndrome. α-lipoic acid (α-LA) is a potent antioxidant involved in the reduction of diabetic symptoms. This study aimed to investigate the relationship between chemerin and P38 MAPK in the progression of diabetic nephropathy (DN) and examine the effects of α-LA on chemerin-treated human mesangial cells (HMCs). MATERIALS AND METHODS: HMCs were transfected with a chemerin-overexpressing plasmid. HMCs were also treated with high-glucose, chemerin, α-LA, PDTC (pyrrolidine dithiocarbamate ammonium, NF-κB p65 inhibitor), and/or SB203580 (P38 MAPK inhibitor). Cell proliferation was tested using the Cell Counting Kit-8 assay. Collagen type IV and laminin were tested by ELISA. Chemerin expression was detected by qRT-PCR. The chemerin receptor was detected by immunohistochemistry. Interleukin-6 (IL-6), tumor necrosis factor-a (TNF-α), nuclear factor-κBp-p65 (NF-κB p-p65), transforming growth factor-ß (TGF-ß), and p-P38 mitogen-activated protein kinase (p-P38 MAPK) were evaluated by western blot. RESULTS: High-glucose culture increased the expression of the chemerin receptor. α-LA inhibited HMC proliferation. Chemerin overexpression increased collagen type IV and laminin expression. P38 MAPK signaling was activated by chemerin, resulting in up-regulation of IL-6, TNF-α, NF-κB p-p65, and TGF-ß. SB203580, PDTC, and α-LA reversed the effects of chemerin, reducing IL-6, TNF-α, NF-κB p-p65, and TGF-ß expression. CONCLUSION: Chemerin might be involved in the occurrence and development of DN. α-LA might prevent the effects of chemerin on the progression of DN, possibly via the P38 MAPK pathway.

Robust and Fast Lithium Storage Enabled by Polypyrrole-Coated Nitrogen and Phosphorus Co-Doped Hollow Carbon Nanospheres for Lithium-Ion Capacitors.

Lithium-ion capacitors (LICs) have been proposed as an emerging technological innovation that integrates the advantages of lithium-ion batteries and supercapacitors. However, the high-power output of LICs still suffers from intractable challenges due to the sluggish reaction kinetics of battery-type anodes. Herein, polypyrrole-coated nitrogen and phosphorus co-doped hollow carbon nanospheres (NPHCS@PPy) were synthesized by a facile method and employed as anode materials for LICs. The unique hybrid architecture composed of porous hollow carbon nanospheres and PPy coating layer can expedite the mass/charge transport and enhance the structural stability during repetitive lithiation/delithiation process. The N and P dual doping plays a significant role on expanding the carbon layer spacing, enhancing electrode wettability, and increasing active sites for pseudocapacitive reactions. Benefiting from these merits, the NPHCS@PPy composite exhibits excellent lithium-storage performances including high rate capability and good cycling stability. Furthermore, a novel LIC device based on the NPHCS@PPy anode and the nitrogen-doped porous carbon cathode delivers a high energy density of 149 Wh kg-1 and a high power density of 22,500 W kg-1 as well as decent cycling stability with a capacity retention rate of 92% after 7,500 cycles. This work offers an applicable and alternative way for the development of high-performance LICs.

microRNA-103 Contributes to Progression of Polycystic Ovary Syndrome Through Modulating the IRS1/PI3K/AKT Signal Axis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a frequent gynecological endocrine disorder, and the majority of PCOS patients experience different degrees of insulin resistance (IR). Nevertheless, the functions of microRNAs (miRNAs) in IR of PCOS remain unclear. In this study, we desired to elucidate the mechanisms of miR-103 in IR of PCOS. METHODS: The ovarian pathological morphology of established PCOS rats was detected by HE staining. Following miR-103 expression determination in the ovarian tissues of PCOS rats, the relationship between its expression and IR was studied. A PCOS/IR cell model was established, and the effect of miR-103 on granulosa cells was determined by CCK-8 assay and flow cytometry. Through online website prediction and consulting related literatures, the target gene of miR-103 and the pathway regulated by the target genes were discovered, which was verified by further experiments. RESULTS: PCOS rats showed polycystic changes in the ovary and a decrease in granulosa cells, and these symptoms were more pronounced in rats showed IR. miR-103 expressed highly in PCOS and was positively related to IR. miR-103 inhibitor led to improved PCOS-related symptoms. In addition, miR-103 directly targeted IRS1, which was poorly expressed in PCOS, and IRS1 silencing promoted PCOS development. Furthermore, miR-103 regulated the PI3K/AKT pathway by targeting IRS1, and PI3K/AKT pathway suppression reduced the therapeutic effect of miR-103 inhibitor. CONCLUSION: This study indicates that miR-103 disrupts the PI3K/AKT pathway activation by targeting IRS1, thereby aggravating PCOS development. miR-103 inhibition may be a promising molecular target for treatment of PCOS.

Anomalous expression of miR-103 in polycystic ovary syndrome influenced by hormonal, and metabolic variables.

BACKGROUND: Polycystic ovary syndrome (PCOS), a common endocrine disorder in reproductive-aged women, is correlated with obesity and insulin resistance (IR), androgens excess, chronic anovulation, and infertility. MicroRNAs (miRNAs) are small, single-stranded, noncoding RNA molecules that participate in inflammation, reproduction and metabolism, may contribute to PCOS. Current study aiming to manifest the correlation of body mass index (BMI) and testosterone (T) with miR-103 expression before and after fat loss. METHODS: 46 controls (N = 23 with BMI < 24 kg/m2, N = 23 with BMI ≥ 28 kg/m2) and 46 patients with PCOS (N = 23 with BMI < 24 kg/m2, N = 23 with BMI ≥ 28 kg/m2) aged between 20 and 30 were recruited. Waist-to-hip (WHR) and Body fat% (BF%) was measured and calculated. Serum hormones, serum lipid, metabolism parameters, and serum miR-103 were measured. All the assessments were measured before and after fat loss in a three-month intervention period. RESULTS: miR-103 was correlated with BMI rather than testosterone (T), and there was a significant difference between the non-obese and obese groups in miR-103 expression. Compared to before fat loss, miR-103 expression showed a slight downward trend. CONCLUSIONS: Serum miR-103 differentially expressed between controls and PCOS subjects, miR-103 was positively correlated with BMI. There was significant difference between the non-obese and obese groups in miR-103 expression.