Implication of lncRNA MSTRG.81401 in Hippocampal Pyroptosis Induced by P2X7 Receptor in Type 2 Diabetic Rats with Neuropathic Pain Combined with Depression.

Major depressive disorder (MDD) is a common complication of diabetes and is often observed alongside diabetic neuropathic pain (DNP) as a comorbidity in diabetic patients. Long non-coding RNA (lncRNA) plays an important role in various pathophysiological processes. The P2X7 receptor is responsible for triggering inflammatory responses, such as pyroptosis, linked to pain and depression. The aim of this study was to investigate the effect of lncRNA MSTRG.81401 on hippocampal pyroptosis induced by the P2X7 receptor in diabetic rats with DNP combined with MDD (DNP + MDD). Our results showed that the expression of lncRNA MSTRG.81401 was significantly elevated in the hippocampus of DNP + MDD rats compared with the control group. Following the administration of shRNA targeting lncRNA MSTRG.81401, a notable elevation in mechanical and thermal pain thresholds was observed in rats with comorbid DNP and MDD. Additionally, significant improvements in depression-like behaviors were evident in the open-field test (OFT), sucrose preference test (SPT), and forced swim test (FST). In the DNP + MDD rats, elevated levels in hippocampal P2X7 receptor mRNA and protein were observed, along with increased co-expression of P2X7 and the astrocytic marker glial fibrillary acidic protein (GFAP). Meanwhile, in DNP + MDD rats, the heightened mRNA expression of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), pyroptosis-related protein Gasdermin D (GSDMD), caspase-1, IL-1ß, IL-18, and TNF-α was detected, in addition to increased serum levels of IL-1ß, IL-18 and TNF-α. After shRNA treatment with lncRNA MSTRG.81401, the above abnormal changes in indicators for pyroptosis and inflammation were improved. Therefore, our study demonstrates that shRNA of lncRNA MSTRG.81401 can alleviate the pain and depression-like behaviors in diabetic rats associated with the comorbidity of DNP and MDD by inhibiting the hippocampal P2X7 receptor-mediated pyroptosis pathway and pro-inflammatory responses. This suggests that the P2X7R/NLRP3/caspase-1 implicated pyroptosis and inflammatory scenario may serve as a potential target for the management of comorbid DNP and MDD in diabetes.

The Role of Iron Metabolism in Sepsis-associated Encephalopathy: a Potential Target.

Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction secondary to infection, and the severity can range from mild delirium to deep coma. Disorders of iron metabolism have been proven to play an important role in a variety of neurodegenerative diseases by inducing cell damage through iron accumulation in glial cells and neurons. Recent studies have found that iron accumulation is also a potential mechanism of SAE. Systemic inflammation can induce changes in the expression of transporters and receptors on cells, especially high expression of divalent metal transporter1 (DMT1) and low expression of ferroportin (Fpn) 1, which leads to iron accumulation in cells. Excessive free Fe2+ can participate in the Fenton reaction to produce reactive oxygen species (ROS) to directly damage cells or induce ferroptosis. As a result, it may be of great help to improve SAE by treatment of targeting disorders of iron metabolism. Therefore, it is important to review the current research progress on the mechanism of SAE based on iron metabolism disorders. In addition, we also briefly describe the current status of SAE and iron metabolism disorders and emphasize the therapeutic prospect of targeting iron accumulation as a treatment for SAE, especially iron chelator. Moreover, drug delivery and side effects can be improved with the development of nanotechnology. This work suggests that treating SAE based on disorders of iron metabolism will be a thriving field.

Glutamine metabolic reprogramming in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal disease with limited management strategies and poor prognosis. Metabolism alternations have been frequently unveiled in HCC, including glutamine metabolic reprogramming. The components of glutamine metabolism, such as glutamine synthetase, glutamate dehydrogenase, glutaminase, metabolites, and metabolite transporters, are validated to be potential biomarkers of HCC. Increased glutamine consumption is confirmed in HCC, which fuels proliferation by elevated glutamate dehydrogenase or upstream signals. Glutamine metabolism also serves as a nitrogen source for amino acid or nucleotide anabolism. In addition, more glutamine converts to glutathione as an antioxidant in HCC to protect HCC cells from oxidative stress. Moreover, glutamine metabolic reprogramming activates the mTORC signaling pathway to support tumor cell proliferation. Glutamine metabolism targeting therapy includes glutamine deprivation, related enzyme inhibitors, and transporters inhibitors. Together, glutamine metabolic reprogramming plays a pivotal role in HCC identification, proliferation, and progression.

Ubiquitin like protein FAT10 repressed cardiac fibrosis after myocardial ischemic via mediating degradation of Smad3 dependent on FAT10-proteasome system.

Cardiac fibrosis after myocardial ischemic (MI) injury is a key factor in heart function deterioration. We recently showed that ubiquitin-like protein human HLA-F adjacent transcript (FAT10) plays a novel role in ischemic cardiovascular diseases, but its function in cardiac fibrosis remains unknown. The present study aims to detail the pathophysiological function of FAT10 in MI injury-induced cardiac fibrosis and its underlying mechanism. In vivo, a systemic FAT10 deficiency mouse (Fat10 -/-) model was established which exhibited excessive cardiac fibrosis and deleterious cardiac function after MI when compared to wild-type mice. Cardiac fibrotic-related proteins (α-SMA, collagen I and collagen III) content were increased in MI-Fat10 -/- mice. Similarly, cardiac FAT10 restoration in Fat10-/- mice suppressed fibrosis and improved cardiac function. In vitro, FAT10 overexpression exert a protective effect against the transforming growth ß1 (TGF-ß1)-induced proliferation, migration and differentiation in cardiac fibroblast (CFs), primary CFs from Fat10-/- mice and human induced pluripotent stem cell-derived CFs (hiPSC-CFs). Furthermore, immunoprecipitation-mass spectrometry (IP-MS) data demonstrated that FAT10 might mediate Smad3, a critical factor in cardiac fibrosis. Combined with rescue assays both in vivo and vitro, the protective effects of FAT10 against cardiac fibrosis was detected to be dependent on Smad3. In depth, Smad3 as a FAT10 specific substrate, FAT10 specifically bind to the K378 site of Smad3 directly via its C-terminal glycine residues and mediated the degradation of Smad3 through the FAT10-proteasome system instead of ubiquitin. In conclusion, we here show that FAT10 is a novel regulator against cardiac fibrosis after MI by mediating Smad3 degradation through FAT10-mediated proteasome system. Our study confirms the cardioprotective role of FAT10 in the heart, and providing a new prospective insight into the regulation of cardiac fibrosis after MI.