Exercise is an effective non-pharmacological strategy for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanism needs further investigation. Sirtuin 2 (Sirt2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that is expressed in multiple tissues, including the liver, whose role in MASH is not well defined. In our study, exercise induces hepatic Sirt2 expression through the DNA demethylation on the Sirt2 gene promoter mediated by α-ketoglutaric acid (α-KG)/ten-eleven translocation (TET) enzymes axis. Hepatocyte-specific knockout of Sirt2 (Sirt2LKO) increases hepatic lipid accumulation, cell death, inflammation, and fibrosis in MASH diet-fed mice and reduces the protective effects of exercise against MASH, while hepatocyte-specific overexpression of Sirt2 works in concert with exercise to alleviate MASH. Mechanistically, Sirt2 promotes deacetylation and proteasomal degradation of poly (ADP-ribose) polymerase 1 (PARP1) in hepatocytes. This decreases polyADP-ribosylation (PAR) and acetylation of high mobility group box 1 (HMGB1), which inhibits HMGB1 nuclei-to-cytosol translocation and secretion from hepatocytes to attenuate free fatty acids (FFAs)-induced hepatocyte injury and blunts dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells (HSCs). Therefore, by regulating the hepatic PARP1/HMGB1 pathway, Sirt2 acts as a downstream effector of exercise to alleviate MASH.

This study employed large-volume thermal injection-gas chromatography-mass spectrometry (LVTI-GC-MS) technique to systematically investigate the effects of glycerol addition and heating temperature on the puff-by-puff release of volatile organic compounds (VOCs) in aerosols from heated tobacco products (HTPs). The method, which uses a large injection volume of 100 µL, achieves high sensitivity, good stability, and is simple and convenient, thus meeting the requirements for efficient and stable analysis of the release of trace volatile organic compounds. The results showed that: (1) the puff-by-puff release of volatile organic compounds initially increased and then decreased. The lower the boiling point of the components, the earlier the release peak appears. (2) The total release of most volatile organic compounds significantly increased with higher glycerol concentrations, and the growth rate exceeded that of glycerol itself. The release of some components stabilized when the glycerol addition ratio reached 20%. (3) The release trends of volatile organic compounds compared to glycerol showed significant differences. Pyrazines, methyl cyclopentenones, and cyclopentenones exhibited the greatest divergence, while nicotine showed the smallest difference. (4) As glycerol concentration and heating temperature increased, earlier puffs showed more complete release of volatile organic compounds, while the release ratio in the last two puffs significantly decreased, likely due to limitations on the total release. (5) Compared to high-boiling components, low-boiling components were less stable in terms of puff-by-puff release, and their stability showed a significant negative correlation with glycerol concentration and heating temperature. There were substantial differences in how glycerol addition and heating temperature affected the release and stability of various volatile organic compounds. These findings may help optimize the glycerol content and heating conditions for HTPs.

Microglia, the resident immune cells of the central nervous system (CNS), act as key sentinels in immune surveillance and mediate critical neuroimmune responses to pathological stimuli, including psychostimulants. Methamphetamine (METH), a widely abused psychostimulant, is known to induce neurotoxicity; however, the cellular mechanisms governing microglial adaptation to METH exposure remain largely elusive. Here, we show that microglia are highly sensitive to METH-induced stress, as short-term moderate METH exposure rapidly triggers microglial activation. However, these activated microglia do not exhibit robust pro-inflammatory cytokine induction, but instead display intracellular stress characterized by mildly reduced mitochondrial membrane potential together with cytosolic accumulation and aggregation of mitochondrial DNA (mtDNA). Mechanistically, METH exposure promotes the formation of homotypic tunneling nanotubes (TNTs) between microglia, likely through actin cytoskeleton remodeling and activation of cGAS-STING signaling. These TNTs may serve as conduits for intercellular mitochondrial transfer, thereby preserving cellular homeostasis. Conversely, pharmacological blockade of TNTs disrupts microglial homeostasis, enhances pro-inflammatory cytokine production, and ultimately alters METH-associated neurobehavioral response. Collectively, our findings identify TNT formation as a stress-induced adaptive mechanism that restrains excessive microglial activation in response to METH, providing novel insights into the regulation of microglial homeostasis under pathological insults.

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing continuously, posing a substantial threat to public health. This study examines the critical role of imbalanced interactions within the gut‒liver-mitochondrial axis in MASLD pathogenesis. Dysregulation of mitochondrial homeostasis, including metabolic disturbances, impaired quality control, and disrupted interorganelle interactions, significantly contributes to MASLD progression. Through the gut‒liver axis, the gut microbiota establishes a bidirectional regulatory network with mitochondria. Dysbiosis disrupts mitochondrial homeostasis via multiple pathways, while mitochondrial dysfunction aggravates imbalances in the gut microbiota, creating a vicious cycle. Therefore, in this study, the molecular basis of mitochondrial abnormalities was investigated, and the mechanisms of reciprocal regulation were clarified. Additionally, targeted intervention strategies, including the modulation of mitochondrial homeostasis and the regulation of the gut microbiota, are explored to provide novel therapeutic perspectives for MASLD.

Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies.

Mitochondrial biogenesis is a fundamental process that ensures energy supply and supports steroidogenesis in ovarian cells. Lactate has recently been identified as a signaling metabolite that promotes mitochondrial biogenesis; however, the underlying regulatory mechanisms remain poorly defined. Here, we identify Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90α) lactylation as a key mediator that links glycolytic metabolism to mitochondrial function. Specifically, lactylation of HSP90α at K58 recruits ULK1, thereby enhancing phosphorylation at S39; lactylation at K616 prevents CDK5-mediated phosphorylation at S596. This dual regulation facilitates the nuclear translocation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and its isoform LRPGC1, which activate NRF1/2-dependent transcription of mitochondrial biogenesis genes, such as Tfb1m, Tfb2m, and Tfam. Functionally, mitochondrial mass expansion both enhances cellular energy metabolism and promotes cholesterol import into mitochondria, thereby driving estrogen biosynthesis. Together, these findings reveal a lactate-HSP90α-PGC1α/LRPGC1 axis that metabolically couples glycolysis to mitochondrial biogenesis and reproductive hormone production, providing insights into the epigenetic regulation of follicular development.

Maternal exercise can improve the metabolic health of the offspring. However, the molecular mechanisms underlying the beneficial effects of maternal exercise on the offspring remain unclear. Here, we show that maternal exercise during pregnancy alleviates high-fat diet (HFD)-induced adipose inflammation and glucose intolerance in offspring mice, accompanied by upregulation of the adipokine serine protease inhibitor A3C (SERPINA3C) both in maternal adipose tissues and the fetal circulation. Adipose SERPINA3C knockdown impairs, but its overexpression in dams mimics, maternal exercise-mediated metabolic benefits in HFD-fed offspring. Maternal SERPINA3C is transported into the fetal circulation and promotes Krüppel-like factor 4 (Klf4) gene promoter demethylation in fetal preadipocytes to increase KLF4 expression, which inhibits adipose inflammation in HFD-fed offspring mice. The SERPINA3C–cathepsin G–integrin β1 axis activates phosphatidylinositol 3-kinase signalling in preadipocytes. This promotes nuclear translocation of the p110β subunit to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the nucleus. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase then binds to PIP3 to promote ten–eleven translocation methylcytosine dioxygenase 1 (TET1) O-GlcNAcylation, thereby enhancing TET1 activity to facilitate Klf4 gene promoter demethylation. These results provide mechanistic insights into maternal exercise-mediated improvement of offspring metabolism. Adipose-secreted SERPINA3C in exercised dams protects their offspring from high-fat diet-induced metabolic disorders by promoting KLF4-mediated anti-inflammatory effects in adipose tissue.

L-Theanine (LTA) is a non-protein amino acid mainly found in tea plants with many beneficial effects. Exercise exerts a wide range of benefits in metabolic health. Here, we show that exercise or gastric lavage intervention on mice with LTA improves diet-induced nonalcoholic steatohepatitis (NASH) in mice. Meanwhile, combinatory therapy shows that exercise and LTA synergistically improve obesity-related metabolic disorders and NASH phenotypes, including hepatic steatosis, inflammation, cell death and oxidative stress. In vivo studies indicate that LTA inhibits free fatty acid (FFA)-induced hepatocyte injury, including steatosis, oxidative stress and apoptosis. Knockdown of Nrf2 blunts the role of LTA in inhibiting FFA-induced hepatocyte oxidative stress and dysfunction. Mechanistically, LTA increases the u03B1-ketoglutarate (u03B1-KG) level in hepatocytes, which increases the transcription of Nrf2 by inducing active DNA demethylation on its promoter. Moreover, LTA promote the above u03B1-KG/Nrf2 axis in synergy with exercise, thereby more efficiently inhibiting hepatic oxidative stress and ameliorating diet-induced NASH in mice. Our results suggest that, through promoting the u03B1-KG/Nrf2 axis-mediated anti-oxidative pathway, the combination of LTA and exercise may provide an effective measure for the prevention and control of NASH.

L-Theanine (LTA) is a non-protein amino acid mainly found in tea plants with many beneficial effects. Exercise exerts a wide range of benefits in metabolic health. Here, we show that exercise or gastric lavage intervention on mice with LTA improves diet-induced nonalcoholic steatohepatitis (NASH) in mice. Meanwhile, combinatory therapy shows that exercise and LTA synergistically improve obesity-related metabolic disorders and NASH phenotypes, including hepatic steatosis, inflammation, cell death and oxidative stress. In vivo studies indicate that LTA inhibits free fatty acid (FFA)-induced hepatocyte injury, including steatosis, oxidative stress and apoptosis. Knockdown of Nrf2 blunts the role of LTA in inhibiting FFA-induced hepatocyte oxidative stress and dysfunction. Mechanistically, LTA increases the α-ketoglutarate (α-KG) level in hepatocytes, which increases the transcription of Nrf2 by inducing active DNA demethylation on its promoter. Moreover, LTA promote the above α-KG/Nrf2 axis in synergy with exercise, thereby more efficiently inhibiting hepatic oxidative stress and ameliorating diet-induced NASH in mice. Our results suggest that, through promoting the α-KG/Nrf2 axis-mediated anti-oxidative pathway, the combination of LTA and exercise may provide an effective measure for the prevention and control of NASH.

Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.

Exercise combats obesity and metabolic disorders, but the underlying mechanism is incompletely understood. KLF10, a transcription factor involved in various biological processes, has an undefined role in adipose tissue and obesity. Here, we show that exercise facilitates adipocyte-derived KLF10 expression via SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 blunts exercise-promoted white adipose browning, energy expenditure, fat loss, glucose tolerance in diet-induced obese male mice. Conversely, adipocyte-specific transgenic expression of KLF10 in male mice enhanced the above metabolic profits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of Pnpla2 and Lipe genes to promote these key lipolytic genes expression by demethylating H3K9me3 on their promoters, which facilitates lipolysis to defend against obesity in male mice. As a downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity.

Exercise is an effective non-pharmacological strategy for the treatment of nonalcoholic steatohepatitis (NASH), but the underlying mechanism needs further investigation. Kruppel-like factor 10 (Klf10) is a transcriptional factor that is expressed in multiple tissues including liver, whose role in NASH is not well defined. In our study, exercise induces hepatic Klf10 expression through the cAMP/PKA/CREB pathway. Hepatocyte-specific knockout of Klf10 (Klf10LKO) increases lipid accumulation, cell death, inflammation and fibrosis in NASH diet-fed mice and reduces the protective effects of treadmill exercise against NASH, while hepatocyte-specific overexpression of Klf10 (Klf10LTG) works in concert with exercise to reduce NASH in mice. Mechanistically, Klf10 promotes the expression of fumarate hydratase 1 (Fh1), thereby reducing fumarate accumulation in hepatocytes. This decreases the trimethyl (me3) levels of histone 3 lysine 4 (H3K4me3) on lipogenic genes promoters to attenuate lipogenesis, thus ameliorating free fatty acids (FFAs)-induced hepatocytes steatosis, apoptosis, insulin resistance and blunting dysfunctional hepatocytes-mediated activation of macrophages and hepatic stellate cells. Therefore, by regulating the Fh1/fumarate/H3K4me3 pathway, Klf10 acts as a downstream effector of exercise to combat NASH.

The physical and chemical properties of tobacco ( Nicotiana tabacum L.) plants are sensitive to changes in genetics and the environment. However, few studies have investigated the effect of both cultivar and regional factors on tobacco quality at the proteomic level. Here, a TMT-based quantitative proteomics method was used to investigate proteome profiling of different tobacco leaves under various geographical locations. In total, 8587 proteins were detected, among which 300 differentially abundant proteins (DAPs) were identified. Proteins associated with carbohydrate metabolism and amino acid metabolism were more abundant in tobacco plants from Yunnan. In contrast, proteins involved in the response to heat were more abundant in tobacco plants from Henan. We found that proteins related to carbon metabolism and defense signaling played an important role in the characteristics of different cultivars within the same region. In this work, we identified key proteins and pathways involved in the response of Nicotiana tabacum to environmental change and explored the proteomic differences among cultivars. Our results provide a better understanding of the effect of environment and cultivar on the tobacco leaf proteome, which will be helpful for elucidating the molecular mechanisms of the formation of tobacco characteristic quality.

Phosphate (Pi) is an important nutrient element for plant growth and development and it plays an important role in the process of plant life activities. Nitrate is also an essential nutrient element for plant growth and a regulator of various metabolic and developmental pathways. Plant requirements for phosphate and nitrate are interdependent, and the acquisition of one of them must be balanced with the acquisition of the other. Maintaining the steady state of phosphate and nitrate content in plants is a key to the normal development of the plants. However, only a few studies have been carried out on the mechanism of how plants nitrate and phosphate homeostasis regulate. In this paper, we summarized the structure and function of an MYB-related transcription factor NITRATE-INDUCIBLE, GARP-TYPE TRANSCRIPTIONAL REPRESSOR1.2 (NIGT1.2) (also known as HHO2), it regulates phosphate and nitrate uptake in plants. Furthermore, we reviewed the molecular mechanism of NIGT1.2 regulating the dynamic balance of phosphate and nitrate in plants. Under phosphate starvation conditions, NIGT1.2 directly regulates the transcription factor of phosphate transporters PHT1.1 and PHT1.4, increasing phosphate absorption. Conversely, under nitrate starvation conditions, the expression of NIGT1.2 is inhibited by NIN-LIKE PROTEIN (NLP), the inhibition of nitrate transporter by NIGT1.2 will be eliminated, and the expression of nitrate transporter NRT1.1 is upregulated, increasing nitrate absorption. The result will provide the potential guidelines to create high phosphate and nitrate balance uptake and utilization in plants variety for sustainable agricultural and forestry development.

Cysteine dioxygenase type 1 (CDO1), belonging to the mammalian non-heme Fe(II) dioxygenases family, is a key enzyme for cysteine catabolism. Its activity and expression is regulated through multiple mechanisms. CDO1 is involved in a spectrum of physiological processes including lipid metabolism, adipogenesis, osteoblastic differentiation, redox homeostasis, fertility, bile acid metabolism, sulfide metabolism, and organismal growth and development. Many of these processes are regulated directly or indirectly by CDO1-mediated metabolism of cysteine. In pathophysiological processes, the degree of CDO1 promoter methylation is closely related to the progression and malignancy of tumors, and overexpression of CDO1 will promote ferroptosis of cancer cells. Moreover, CDO1 may ameliorate metabolic disorders through the taurine-mediated improvement of lipid metabolism and insulin sensitivity and improve neurodegenerative diseases by regulating cysteine level. Therefore, elucidation of the mechanisms underlying the role of CDO1 would provide a clearer view of the therapeutic potential and possible risks of targeting this important enzyme.

High-intensity Interval Training (HIIT) is a time-efficient form of exercise and has gained popularity in recent years. However, at molecular level, the understanding about the effects of HIIT is not comprehensive, and even less is elucidated about HIIT of different training duration cycles, although different durations always lead to different post-training consequences. In this study, by training SD rats using HIIT protocols lasting for different training duration cycles, we investigated the adaptive response of intramuscular triglyceride abundance as well as mitochondrial and lipid metabolic changes after HIIT training (2, 4, 6, 8, and 10 weeks). We selected 72 h after the last session of training as the time point of sacrifice. The suppressed activation of the cAMP-PKA pathway indicates that skeletal muscle was in the recovery phase at this time point. Intramuscular triglyceride abundance was significantly elevated after 2, 4, and 10 weeks of HIIT. However, the lipid metabolism-related proteins inconsistently changed in a chaotic trend (see Table 1). The expression levels of PGC1-α and COX IV decreased after 2 and 4 weeks of training and raised after 6 and 8 weeks of training. The expression level of citrate synthase (CS) decreased after 2, 4, 8, and 10 weeks of training, and showed an upward trend after 6 weeks of training. While the activity of CS decreased after 2 and 8 weeks of training and showed an upward trend after 6 weeks of HIIT. Given the abovementioned changing trends, we propose two speculations: (A) the damaged mitochondria oxidation capacity might be one of the causes of IMTG accumulation observed after 2 and 4 weeks of HIIT. This phase might be similar to the condition of type 2 diabetes. (B) after 6-week HIIT, mitochondria function and biogenesis might be improved and the IMTG contents declined to baseline. This might be explained as: mitochondrial enhancement increased the capacity of lipid oxidation and then offset the increase in IMTG achieved during the first 4 weeks. For HIIT Rat Modelling, if the aim is to observe HIIT-induced positive effects, caution should be exercised when considering 2 and 4 weeks of training under our HIIT frame. Also, implementing six-week training is at least effective for mitochondrial enhancement when using similar HIIT frame of this study.

Krüppel-like factor 10 (KLF10), also known as TGFβ-inducible early gene-1 (TIEG1), was first found in human osteoblasts. Early studies show that KLF10 plays an important role in osteogenic differentiation. Through decades of research, KLF10 has been found to have complex functions in many different cell types, and its expression and function is regulated in multiple ways. As a downstream factor of transforming growth factor β (TGFβ)/SMAD signaling, KLF10 is involved in various biological functions, including glucose and lipid metabolism in liver and adipose tissue, the maintenance of mitochondrial structure and function of the skeletal muscle, cell proliferation and apoptosis, and plays roles in multiple disease processes, such as nonalcoholic steatohepatitis (NASH) and tumor. Besides, KLF10 shows gender-dependent difference of regulation and function in many aspects. In this review, the biological functions of KLF10 and its roles in disease states is updated and discussed, which would provide new insights into the functional roles of KLF10 and a clearer view of potential therapeutic strategies by targeting KLF10.

Our findings suggested that ClWRKY48 promoted the expression level of Arabidopsis phosphate transporter genes, enhanced phosphate uptake, and delayed the transition from the vegetative stage to the reproductive phase in Arabidopsis. Phosphorus (P) is an essential mineral for plants that influences their growth and development. ClWRKY48, one of the most highly expressed genes in the leaf, was identified by RT-PCR from Chinese fir [Cunninghamia lanceolata (Lamb.) Hook] (C. lanceolata). Furthermore, when treating C. lanceolata with increasing phosphate (Pi) concentration, the expression level of ClWRKY48 rose in leaves, the trends followed the increasing phosphate concentration treatment. ClWRKY48 is a transcription factor in C. lanceolata, according to the results of a yeast one hybridization experiment. Based on subcellular localization studies, ClWRKY48 is a nuclear-localized protein. Under Pi deficiency conditions, the phosphorus concentration of ClWRKY48 overexpressing Arabidopsis increased by 43.2–51.1