Zheng-Hong Qin

Anesthetics are indispensable in clinical practice, yet growing evidence indicates that they can disrupt brain function beyond their intended effects. While research on anesthetic neurotoxicity has largely focused on neurons, microglia are now recognized as central players in determining perioperative outcomes. Lipid metabolism in microglia has emerged as a key regulator of immune responses, synaptic maintenance, and neuroinflammation. Anesthetic exposure disturbs this metabolic balance, leading to lipid droplet accumulation, defective fatty acid oxidation, and pro-inflammatory activation that contribute to cognitive impairment. However, knowledge in this field remains fragmented and has not been systematically synthesized. In this review, we integrate current evidence on how anesthetics perturb microglial lipid metabolism and delineate the mechanistic pathways involved, with the goal of identifying potential therapeutic targets related to microglial lipid metabolism to alleviate anesthesia neurotoxicity.

Glucocorticoid-induced osteoporosis (GIOP) is a public health problem that needs urgently to be resolved, and oxidative stress is closely related to osteogenic impairment. TP53-induced glycolysis and apoptosis regulator (TIGAR) contributes to the occurrence and development of various diseases by reducing reactive oxygen species (ROS). However, it is unknown whether and how TIGAR plays a regulatory role in GIOP. The aim of the present study is to investigate the role of TIGAR in osteogenic differentiation and the underlying molecular mechanism. We explored the protective role and mechanism of TIGAR on osteogenic differentiation and GIOP by using the TIGAR overexpression plasmid and siRNA in vitro, and by constructing systemic TIGAR overexpression (TG-TIGAR) mice in vivo, respectively. In conclusion, our study clarified that TIGAR promotes osteogenic differentiation and improves GIOP by upregulating autophagy-nuclear factor erythroid-2 related factor (Nrf2)-ROS pathway, suggesting that TIGRA may be a potential therapeutic target for GIOP treatment.

The purpose of the study is to provide a method for mass production of nicotinamide mononucleotide (NMN) using an immobilized nicotinamide riboside kinase (NMRK). We synthesized a gene sequence comprising the gene encoding the enzyme. At the 3’ end of this NMRK-encoding gene, an optimized cellulose-binding domain (CBD) sequence was linked via a linker-encoding gene segment.Using the pET-32a plasmid as the vector and Escherichia coli BL21(DE3) as the host cell, the recombinant E. coli strain BL21/pET-32a-nmrk-1 was constructed and cultivated. This recombinant strain BL21/pET-32a-nmrk-1 secreted a significantly higher yield of the NMRK enzyme protein (32 mg/mL), and the secreted recombinant NMRK enzyme exhibited superior activity (80 U/g). Activated microcrystalline cellulose was mixed with the crude enzyme solution containing the recombinant NMRK enzyme. Following processing, the immobilized NMRK enzyme was obtained. This immobilized enzyme catalyzed the synthesis of NMN from 0.07 mol/L nicotinamide riboside (NR), achieving a conversion rate of 90% and a purity of 33%. The recombinant NMRK enzyme retained good activity after immobilization onto the carrier, enabling its reuse for more than 10 cycles. The initial activity of the immobilized NMRK enzyme was 540 U/g. After 11 cycles of use, the activity was 390 U/g, representing only a 27.8% decline in activity. This approach enhances the utilization efficiency of the NMRK enzyme while simultaneously reducing the production cost of NMN.

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is an important coenzyme involved in cellular biosynthetic and redox metabolism. It has been recognized for its role in regulating neuroinflammation through coordinating redox reactions. Whether there are new actions other than redox regulation remain unclear. In this study we investigated a novel mechanism by which NADPH regulated microglia-mediated neuroinflammation. We showed that NADPH application significantly alleviated NLRP3 inflammasome activation in microglia and exerted neuroprotective effects both in vitro and in vivo neuroinflammation models. With P2X7R knockdown microglial cells and P2X7R^cKO mice, we demonstrated that P2X7R was a crucial mediator of the anti-inflammatory effects for the supplemented NADPH. We conducted whole-cell recording from murine microglial cell line BV2 cells, and found that application of ATP (1 mM) elicited an inward current, which was reduced by co-application of P2X7R antagonist A-438079 (20 μM) or NADPH (1 mM). By performing a drug affinity responsive targets stability (DARTS) assay, we revealed that NADPH (not NADP⁺ or NADH), like the P2X7R agonist ATP, bound to the extracellular domain of P2X7R, leading to the suppression of ATP-induced P2X7R activation. Our research provides the first evidence of NADPH as an endogenous inhibitor of P2X7R in modulation of microglia-mediated neuroinflammation. This study expands the biological functions of NADPH and offers a novel target for NADPH-based therapies in neuroimmune-related diseases.

Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, and organelles are degraded and recycled. According to the way the cytoplasmic components are engulfed, autophagy can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy. Recently, many studies have found that autophagy plays an important role in neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, neuronal excitotoxicity, and cerebral ischemia. Autophagy maintains cell homeostasis in the nervous system via degradation of misfolded proteins, elimination of damaged organelles, and regulation of apoptosis and inflammation. AMPK-mTOR, Beclin 1, TP53, endoplasmic reticulum stress, and other signal pathways are involved in the regulation of autophagy and can be used as potential therapeutic targets for neurological diseases. Here, we discuss the role, functions, and signal pathways of autophagy in neurological diseases, which will shed light on the pathogenic mechanisms of neurological diseases and suggest novel targets for therapies.

Background:Lung cancer is one of the most common causes of cancer-related death worldwide due to its rapid growth and metastasis. TIGAR plays a role in promoting survival in various cancer cells, but the molecular mechanisms on metabolic reprogram in tumor cells are not fully understood. Methods: TIGAR expression was detected in lung cancer by western blot and immunohistochemistry. A shRNA interference system was used to knockdown the TIGAR in NSCLC cell lines to delineate its role in NSCLC tumor proliferation using in vitro functional assays and in vivo mouse models. Finally, transcriptomics and metabolomics were used to identify the mechanism of TIGAR. Results: The expression of TIGAR in tumor tissues of NSCLC patients was significantly higher than that of adjacent tissues, which was associated with poor prognosis of NSCLC. The proliferation of NSCLC cells in vitro and the growth of xenografted tumors in vivo were significantly inhibited by TIGAR knockdown. With a combination of transcriptomics and metabolomics, we found that TIGAR maintained intracellular deoxyribonucleotide levels by regulating the expression of the ribonucleotide reductase (RNR) subunit RRM2B, a protein involved in deoxynucleotide synthesis. Further studies with LC-MS and co-immunoprecipitation revealed that TIGAR interacted with the transcription factor YBX1, participated in its phosphorylation and nuclear translocation to induce the expression of its downstream gene RRM2B. In addition, overexpression of RRM2B or exogenous supplementation of dNTPs effectively rescued the restriction of cell proliferation and DNA repair caused by TIGAR knockdown. Conclusion: The present studies revealed a novel mechanism of TIGAR in promoting the proliferation and DNA repair of NSCLC cells through maintaining the intracellular deoxynucleotide level via the YBX1-RRM2B axis.

Background: Ischemic stroke seriously threatens human health because of high rates of morbidity, mortality and disability. This study compared the effects of nicotinamide adenine dinucleotide (NAD⁺) and butylphthalide (NBP) on in vitro and in vivo ischemic stroke models.Methods: Transient middle cerebral artery occlusion/reperfusion (t-MCAO/R) model was established in mice, and the cultured primary cortical neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cerebral infarct volume, neurobehavioral indices, antioxidant activity, ATP level and lactic acid content were determined. The neuroprotective effects of NAD⁺ or NBP were compared using sirtuin inhibitor niacinamide (NAM).Results: Intraperitoneal injection of NBP within 4 h or intravenous injection of NAD⁺ within 1 h after t-MCAO/R significantly reduced the volume of infarcts, cerebral edema, and neurological deficits. Administration of NAD⁺ and NBP immediately after t-MCAO/R in mice showed similar neuroprotection against acute and long-term ischemic injury. Both NAD⁺ and NBP significantly inhibited the accumulation of MDA and H₂O₂ and reduced oxidative stress. NAD⁺ was superior to NBP in inhibiting lipid oxidation and DNA damage. Furthermore, although both NAD⁺ and NBP improved the morphology of mitochondrial damage induced by ischemia/reperfusion, NAD⁺ more effectively reversed the decrease of ATP and increase of lactic acid after ischemia/reperfusion compared with NBP. NAD⁺ but not NBP treatment significantly upregulated SIRT3 in the brain, but the sirtuin inhibitor NAM could abolish the protective effect of NAD⁺ and NBP by inhibiting SIRT1 or SIRT3.Conclusions: These results confirmed the protective effects of NAD⁺ and NBP on cerebral ischemic injury. NBP and NAD⁺ showed similar antioxidant effects, while NAD⁺ had better ability in restoring energy metabolism, possibly through upregulating the activity of SIRT1 and SIRT3. The protection provided by NBP against cerebral ischemia/reperfusion may be achieved through SIRT1.