Liver diseases are a significant global health issue, characterized by elevated levels of disorder and death. The substantial impact of ageing on liver diseases and their prognosis is evident. Multiple processes are involved in the ageing process, which ultimately leads to functional deterioration of this organ. The process of liver ageing not only renders the liver more susceptible to diseases but also compromises the integrity of other organs due to the liver's critical function in metabolism regulation. A growing body of research suggests that long non-coding RNAs (lncRNAs) play a significant role in the majority of pathophysiological pathways. They regulate gene expression through a variety of interactions with microRNAs (miRNAs), messenger RNAs (mRNAs), DNA, or proteins. LncRNAs exert a major influence on the progression of age-related liver diseases through the regulation of cell proliferation, necrosis, apoptosis, senescence, and metabolic reprogramming. A concise overview of the current understanding of lncRNAs and their potential impact on the development of age-related liver diseases will be provided in this mini-review.

Atorvastatin (ATV), a commonly prescribed lipid-lowering drug, has been widely detected in various aquatic environments due to its large use and low degradation rate. Since the target gene inhibited by ATV is highly conserved in organisms, many studies have shown that ATV can interfere with lipid metabolism in aquatic non-target organisms. However, studies on mitochondria, energy metabolism, and developmental toxicity of ATV on non-target organisms are limited. In this study, Mugilogobius chulae embryos were exposed to ATV (0.5 and 50 µg/L) until 96 hour post fertilization (hpf). The results confirmed that the environmental concentrations of ATV caused toxic effects including developmental malformations, pathological damage, hepatotoxicity, and oxidative stress in M. chulae larvae. Both transcriptomic and metabolomic analyses showed that ATV exposure interfered the normal processes of oxidative phosphorylation and TCA cycle, resulting in energy metabolic disorder. In addition, ATV exposure also damaged the mitochondrial structure of M. chulae larvae. Thus, M. chulae could regulate PI3K/AMPK/FoxO proteins to promote mitochondrial regeneration, support autophagy, and even initiate apoptosis to maintain metabolism homeostasis. Taken together, our findings suggested that mitochondrial dysfunction and metabolic disorder were involved in ATV-induced toxicity which may cause developmental malformations and abnormalities, providing novel insight into the toxic mechanisms of ATV.

Recurrent spontaneous abortion (RSA) affects female reproduction worldwide, yet its pathological mechanisms are still unclear. It has been reported that cellular metabolism reprogramming is a critical step for trophoblasts during embryo implantation. Herein, MTHFD2 was recognized as a key metabolic checkpoint attributed to RSA occurrence. This work figured out that the expression level of MTHFD2 was significantly inhibited in villus tissues from RSA patients, suggesting the potential role of MTHFD2 in RSA occurrence. Moreover, MTHFD2 knockdown impaired cellular folate-nucleotide metabolism, induced the accumulation of AICAR, and thereby impairing the EMT process to inhibit the invasion and migration of trophoblasts Besides, the AICAR accumulation further activated the downstream AMPK which deactivated the JAK/STAT/Slug pathway and ultimately deactivated the EMT process. Using a mouse model, MTHFD2 inhibition was observed to induce embryo implantation failure in vivo. Our results highlighted MTHFD2 as a metabolic checkpoint that remodeled folate-nucleotide metabolism to regulate the EMT process and ultimately altered the migration and invasion of trophoblasts in RSA occurrence. Our findings suggested that MTHFD2 was a promising therapeutic target in recurrent spontaneous abortion treatment.

Nucleic Acid Binding Protein 2 (NABP2), a crucial regulator in the single-stranded DNA-binding protein family, has been linked to the progression of hepatocellular carcinoma (HCC) and poor prognosis. However, the precise mechanisms by which NABP2 regulates HCC development, especially through metabolic pathways, remain unclear. In this study, we evaluated NABP2 expression in clinical HCC samples and analyzed its correlation with patient survival outcomes. Functional assays, including cell proliferation, migration, and lipid metabolism analyses, were performed in vitro and in vivo to investigate the role of NABP2 in tumorigenesis. Additionally, we examined the molecular interactions of NABP2 with the E3 ubiquitin ligase STUB1 and its impact on the LKB1/AMPK signaling pathway. Our results revealed that NABP2 was overexpressed in HCC tissues and associated with worse survival outcomes. NABP2 promoted tumor cell proliferation, migration, and disrupted lipid metabolism. Mechanistically, NABP2 regulated the proteostasis of liver kinase B1 (LKB1) by recruiting STUB1, leading to the inhibition of the LKB1/AMPK signaling axis and mitochondrial dysfunction. In conclusion, our findings suggest that NABP2 may serve as both a biomarker and a potential therapeutic target for HCC, offering novel insights into its role in metabolic reprogramming and tumor progression.

Postoperative insulin resistance (IR) is a metabolic disorder characterized by decreased insulin sensitivity and elevated blood glucose levels following major surgery. Our previous clinical study identified a notable correlation between postoperative IR and gut microbiota, particularly butyrate-producing bacteria, yet the mechanisms remain unclear. In this study, we established gastric resection SD rat models to evaluate the impact of Clostridium butyricum NCU-27 (butyrate-producing bacteria) on postoperative IR. The results demonstrated significant reductions in fasting blood glucose (FBG), fasting insulin (FIns) levels, and HOMA-IR (6.64 ± 0.76 vs. 11.47 ± 1.32; 4.27 ± 0.59 vs. 7.40 ± 0.54) in the postoperative period compared to the control group (P < 0.05). Additionally, glucose tolerance and hepatic glycogen content were markedly improved (P < 0.001). Further exploration of butyrate demonstrated effects similar to C. butyricum NCU-27, potentially mediated through the gut-liver axis by inhibiting mTORC1 expression in liver cells, activating the IRS1/AKT pathway, enhancing glucose uptake and glycogen synthesis, suppressing gluconeogenesis, increasing insulin sensitivity, and improving IR. Finally, the use of mTORC1 agonists and inhibitors further confirmed the critical role of the mTORC1 pathway in mediating the beneficial effects of C. butyricum NCU-27 and butyrate on postoperative IR. In conclusion, this study elucidated that C. butyricum NCU-27 improves postoperative IR by regulating butyrate metabolism and inhibiting the mTORC1 pathway, offering new insights for preventing and treating post-gastrectomy IR.

Leukocyte recruitment to sites of inflammation is vital for orchestrating an effective immune response. Key to this process is the ability of leukocytes to migrate through venular walls, engaging in sequential interactions with endothelial cells, pericytes, and the venular basement membrane. The aging process exerts profound effects on the molecular and functional properties of the vasculature, thereby influencing the profile and dynamics of leukocyte trafficking during inflammation. In this review, by focusing mainly on neutrophils, we summarize key examples of how the aged microvasculature and perivascular stroma cells promote dysregulated leukocyte-venular wall interactions and present the associated molecular mechanisms. Additionally, we discuss the functional implications of such aberrant leukocyte behavior to age-related and chronic inflammatory pathologies.

Inflammation is a major risk factor for a variety of human diseases, such as sepsis, Inflammatory Bowel Disease (IBD) and also major cardiovascular disease including atherosclerosis. Solidago canadensis is used as a traditional medicine to treat inflammation-related diseases. However, the component with anti-inflammatory activity of Solidago canadensis is not clear. In this study, we aimed to search for new bioactive steroids from Solidago canadensis and investigate their anti-inflammatory activity both in vitro and in vivo. Lipopolysaccharides (LPS)-stimulated RAW264.7 cells, mouse bone marrow-derived macrophages (BMDMs) and peripheral blood mononuclear cells (PBMCs) were used to induce an inflammation response. Compound 10 outperformed other compounds for superior anti-inflammatory activity and significant inhibition of NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation. Mechanistically, compound 10 induced mitophagy by activating AMP-activated protein kinas (AMPK) to suppress NLRP3 inflammasome activation. Inhibiting AMPK by inhibitor BML-275 significantly attenuated compound 10 induced mitophagy and subsequent the NLRP3 inflammasome. Besides, the NF-κB activation, key step in NLRP3 inflammasome priming, was also suppressed by compound 10 via activation of AMPK. In addition, the in vivo experiments showed that compound 10 could alleviate LPS-induced inflammatory and dextran sulfate sodium salt -induced colitis in C57BL/6 mice. Collectively, the present study, for the first time, shows that the steroids compound 10 exhibited anti-inflammatory effect via AMPK/mitophagy/NLRP3 as well as AMPK/NF-κB/NLRP3 signaling pathway, which strongly suggests the therapeutic potential of compound 10 in various inflammatory diseases.

The global obesity epidemic highlights the need to understand the molecular mechanisms that regulate energy metabolism. Among emerging research areas, fat browning-the transformation of white adipose tissue into beige fat-has gained significant attention. This review explores the molecular pathways involved in fat browning triggered by fasting, physical exercise, and cold exposure, emphasizing both shared and distinct regulatory mechanisms. These stimuli consistently induce physiological responses such as lipolysis, mitochondrial biogenesis, and improved insulin sensitivity. Notably, PGC-1α and SIRT3 are upregulated across all three conditions, underscoring their central roles in mitochondrial function and energy metabolism and identifying them as promising therapeutic targets. In contrast, UCP1 and PRDM16 exhibit condition-specific regulation, suggesting they may not be universally essential for fat browning. In addition, the review discusses species-specific differences in brown adipose tissue (BAT) activation, particularly between rodents and humans, highlighting the challenges of translating animal model findings to human therapies. Future research should aim to develop selective pharmacological activators of PGC-1α and SIRT3 to enhance therapeutic outcomes while minimizing adverse effects. This review also proposes that integrating fasting, exercise, and cold exposure could provide innovative strategies to promote metabolic health.

Ferroptosis contributes to neuronal destruction after ischemic stroke which may be improved by inhibiting BTB domain and CNC homolog 1 (BACH1), a recently recognized ferroptosis facilitator. Axon guidance molecule netrin-1 (Ntn1) functions in neuroprotection against ischemic insult by engaging into its receptor of uncoordinated-5 homolog B (UNC5b) via adenosine 5'-monophosphate-activated protein kinase (AMPK), which potentially binds to BACH1. Whether Ntn1/UNC5b regulates post-stroke ferroptosis through AMPK-BACH1 pathway remains unclear. Ntn1 supplementation and UNC5b knockdown by siRNA were performed in photo-thrombosis stroke mice and oxygen-glucose deprivation-treated HT22 neurons. AMPK inhibitor BAY3827 and BACH1 activator Leptomycin B (LMB) were administrated. Ferroptosis was determined by ferroptosis-associated proteins (FSP1, GPX4 and ACSL4), Fe2+, malondialdehyde and mitochondrial morphology. BACH1 and p-AMPK/AMPK as well as the interaction between them were examined by Western blot and co-immunoprecipitation. Neuronal ferroptosis and the protein levels of BACH1 and p-AMPK were increased after photo-thrombosis and oxygen-glucose deprivation. Ntn1 supplementation or UNC5b knockdown relieved neuronal ferroptosis and neurological impairment with downregulated BACH1 and upregulated p-AMPK, nonetheless, UNC5b knockdown prevented the beneficial role of Ntn1. Both BAY3827 and LMB could reverse the change of ferroptosis caused by Ntn1 where BAY3827 inhibited the effects of Ntn1 to p-AMPK and BACH1 while LMB only inhibited the effect of Ntn1 to BACH1 without p-AMPK, suggesting BACH1 was regulated by AMPK. Co-immunoprecipitation verified that AMPK could physically bind to BACH1. Our results demonstrate UNC5b-evoked neuronal ferroptosis post stroke, and favor that Ntn1 improves post-stroke ferroptosis by its interaction with UNC5b via the AMPK-BACH1 pathway.

Emerging evidences about paracetamol-induced kidney injury in clinical settings are concerning, especially when administered at high doses. Empagliflozin, an oral SGLT2 inhibitor, employed in the management of diabetes mellitus, exhibits antioxidant, anti-inflammatory, and anti-apoptotic attributes. Thus, the objective of this study is to investigate whether empagliflozin may alleviate paracetamol-triggered nephrotoxicity and unravel the mechanistic insights responsible for its protective impact. In this regard, male mice were assigned to four groups: normal, paracetamol, empagliflozin 10, and empagliflozin 20. Kidney function tests, histopathological examination, immunohistochemistry, oxidative stress biomarkers, inflammatory cytokines, and other molecular targets were detected. Our results showed that paracetamol administration impaired kidney functions along with causing aberrations in renal histoarchitecture. Additionally, paracetamol triggered oxidative stress, inflammation, and apoptosis via hindering the AMPK/SIRT1/PGC-1α cascade and Nrf2/HO-1 while activating the NF-κB hub. Nevertheless, pretreatment with empagliflozin markedly enhanced the kidney function tests and mitigated histopathological alterations caused by paracetamol. Additionally, empagliflozin suppressed the oxidative stress as confirmed by an upregulation of Nrf2, which subsequently increased HO-1, SOD, and GSH, while reducing the MDA level. Moreover, it inhibited the NF-κB-mediated inflammatory process by dampening NF-κB, IL-1β, and TNF-α expressions as well as lowering Bax expression-induced apoptosis. The observed safeguards effects were facilitated via boosting AMPK/SIRT1/PGC-1α signaling trajectory. Collectively, our study verified the enduring reno-protective potential of empagliflozin, particularly at high dose, in the context of paracetamol-induced renal injury by instigating the AMPK/SIRT1/PGC-1α hinge.

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), an emerging contaminant (EC), is widely used in the production of brominated flame retardants and is biotoxic to marine organisms. However, our understanding of the mechanism of polybrominated diphenyl ethers (PBDEs)-induced toxicity remains incomplete. In this study, BDE-47 cytotoxicity after short-term exposure was investigated in PCK cells. BDE-47 significantly decreased cell viability, and morphological alterations were observed. Moreover, BDE-47 exposure induced apoptosis and ferroptosis, a newly described form of iron-mediated cell death, as demonstrated by transcriptomic analysis and physiological/biochemical tests. The observed cell death was associated with mitochondrial damage and a decrease in ATP production. Pharmacological intervention of cytotoxicity via 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of the adenosine monophosphate-activated protein kinase (AMPK) protein, a regulator of energy, strongly confirmed the causal relationship between cell death and energy metabolism dysfunction. Furthermore, lipidomic analysis revealed lipid metabolism disorders resulting from the accumulation of triglycerides (TGs) and glycerophospholipids (GPs) and the suppression of β-oxidation, ultimately inhibiting ATP synthesis. Molecular docking analysis revealed the binding potential of BDE-47 with energy metabolism checkpoints AMPK and Carnitine Palmitoyltransferase 1 (CPT1). Thus, our study broadens the understanding of the toxicity of BDE-47 and provides a new potential cellular and molecular mechanism.

Extreme heat and traffic-related air pollution (TRAP) have been linked to worsening chronic health disorders, however, their combined effects on diabetic nephropathy (DN) are little understood. Type II diabetic mice were exposed to heat (40 °C) and NO2 (5 ppm) separately for 4 h per day over 6 weeks to investigate the synergistic effects on the progression of DN. We found that exposure to high temperature and NO2 elevated blood glucose levels and exacerbated histopathological changes. Additionally, there were increased oxidation indicators (ROS, MDA, 8-OHdG) and decreased antioxidant indicators (CAT, SOD, GSH-PX), along with elevated inflammation markers (TNF-α, IL-1β, IL-6). The expressions of transient receptor potential (TRP) ion channels (TRPV1, TRPV4, TRPA1, TRPM2) were also upregulated. Our findings suggest that simultaneous exposure to high temperature and NO2 impairs metabolic and autophagy pathways. Exposure to both high temperature and NO2 produces a synergistic effect, leading to more severe damage than exposure to either factor individually. This resulted in increased expression of APOA1, P62, and p-mTOR/mTOR while decreasing the expression of p-AMPKα/AMPKα and LC3-II/I. This disruption promoted the progression of DN. In contrast, capsazepine (CZP) reduced TRP expression, inflammatory markers, oxidative stress, metabolic and autophagy disorders, thereby mitigating renal damage and alleviating the progression of diabetic nephropathy. Our study provides some potential strategies for early prevention and effective reduction of DN.

Many metabolic diseases show mitochondrial abnormalities because of dysfunction of complex I (CI). Therefore, the discovery of drugs that target the CI is of great interest. Berberine (BBR) is a botanic agent and has been included in the latest ESC/EAS Guidelines for the management of dyslipidemias. Here, we showed that BBR enters hepatocyte mitochondria after oral administration and improves glucose and lipid metabolism by reducing oxidative phosphorylation in hepatocytes. BBR inhibits CI function rapidly, selectively, and reversibly, not by directly inhibiting CI enzyme activity but by reducing the abundance of CI in the mitochondria through dissociation of CI. BBR directly binds to and activates Sirtuin 3 (SIRT3), thereby reducing acetylation of the catalytic subunit NDUFS1 in the N-module of CI, leading to dissociation of mitochondrial CI. Conclusively, BBR, as a mitochondria-homing agent, selectively and reversibly dissociates mitochondrial CI through SIRT3-dependent NDUFS1 deacetylation to improve hepatocellular glucose and lipid metabolism, highlighting that CI may be a promising target for innovative natural products to treat metabolic diseases.

Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.

Lipids metabolism is crucial in regulating aging and metabolic diseases. Lipid droplets (LDs) are dynamic, complex organelles responsible for the storage and release of neutral lipids, essential for maintaining lipid homeostasis and energy metabolism. Aging accelerates the accumulation of LDs, functional deterioration, and metabolic disorders, thereby inducing age-related metabolic diseases (ARMDs). This review examines published datasets on the association between LDs and ARMDs, focusing on the structure and function of LDs, their interactions with other organelles, and associated proteins. Furthermore, we explore the potential mechanisms by which LDs mediate the onset of ARMDs, including Alzheimer's disease (AD), sarcopenia, metabolic cardiomyopathy, non-alcoholic fatty liver disease (NAFLD), and cancer. Lastly, we discuss intervention strategies aimed at targeting LDs to improve outcomes in ARMDs, including exercise, dietary, and pharmacological interventions.

High glucose-induced dysfunction of endothelial cells is a critical and initiating factor in the genesis of diabetic vascular complications. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical intervention. It has been reported that it exhibits protective effects on high glucose-induced osteoblast dysfunction, but little was known on diabetic vascular complications. In this work, we aim to clarify the role of LMHFV on high glucose-induced endothelial dysfunction and hypothesized that the protective effects functioned through adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. We cultured primary murine aortic endothelial cells (MAECs) in normal or HG medium, respectively, before exposing to LMHFV. The tube formation, paracellular permeability assay, and aortic ring sprouting assay showed that the high glucose injured-function of MAECs was improved after LMHFV treatment. The intracellular ROS generation analysis, mitochondrial complex I activities measurement, ATP measurement and mitochondrial membrane potential (MMP), and mitochondrial ROS generation analysis of MAECs indicated that mitochondrial function was restored by LMHFV loading in a high glucose environment. Mechanically, western blot assays showed that AMPK phosphorylation was promoted and mTOR was inhibited in LMHFV-induced endothelial function restoration. After the administration of the AMPK inhibitor, Compound C, these protective effects resulting from LMHFV are reversed. These findings suggest that LMHFV plays a significant role in protecting endothelial cells' function and mitochondrial function in high glucose-induced injured MAECs via AMPK/mTOR signalling.

Fabry disease is a monogenic disease characterized by a deficiency or loss of α-galactosidase A (GLA). Cardiomyopathy is the leading cause of death in Fabry patients; however, a lack of understanding of the pathological mechanism impedes the development of effective therapies. Here, we used a Gla knockout (KO) mouse model and investigated its impact on cardiomyopathy. We found that globotriaosylceramide (Gb3) increased the uptake and accumulation of fatty acids in KO hearts by increasing the expression levels of CD36 and ACC2. The augmented fatty acid metabolism further increased autophagy activity, leading to age-related late-onset cardiac hypertrophy. Additionally, increased autophagy facilitates disturbances in fatty acid metabolism. The inhibition of autophagy by supplementation with 3-methyladenine (3-MA) or the overexpression of GLA by the cardiomyocyte-specific adeno-associated virus for 2 months could rebalance abnormal fatty acid metabolism and ameliorate cardiac hypertrophy and dysfunction in KO hearts, suggesting a central role of autophagy in GLA deficiency-related cardiomyopathy.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck; however, the efficacy of existing treatment is limited and new effective strategies need to be explored. Our previous work demonstrates that isoguanosine (isoG) is a promising nucleoside molecule with superior self-assembly capability and significant anti-OSCC potential. However, the antitumor mechanism of isoG remains unclear. In this study, we reveal that the antiproliferative effect of isoG is mediated by its cellular metabolite, isoguanosine 5'-monophosphate (isoGMP), which induces excessive endoplasmic reticulum (ER) stress and cell death through adenosine monophosphate-activated protein kinase (AMPK) activation. IsoG activates AMPK and induces ER stress at low concentrations, with minimal impact on cell viability at these concentrations. To further explore the therapeutic potential of isoG, we investigated its role in modulating chemosensitivity. Our findings show that AMPK activation enhances the sensitivity of OSCC cells to 5-fluorouracil (5-FU), and the combination of isoG and 5-FU exhibits a synergistic anticancer effect. Building on the self-assembly characteristics of isoG, we developed an innovative treatment platform by introducing dynamic borate ester bonds to form an isoguanosine-phenylenediboronic acid-isoguanosine (isoGPBisoG) structure. When combined with 5-FU, this platform achieved remarkable therapeutic efficacy in 2 OSCC cell-derived xenograft models, with tumor inhibition rates of 71.0% and 56.6%, respectively, compared with control. These findings establish isoG as a potent enhancer of chemotherapeutic efficacy in OSCC via AMPK activation. More importantly, the isoGPBisoG and 5-FU combination represents a significant paradigm of a synergistic therapy platform. This novel approach offers a promising direction for the development of more effective OSCC treatments.

Diabetic wound healing presents a significant clinical challenge due to disrupted neuro-immune interactions. This study identifies the α7 nicotinic acetylcholine receptor (α7nAChR) as a key regulator of wound repair by linking cholinergic signaling to macrophage reprogramming. GEO analysis of diabetic foot ulcer (DFU) microenvironments revealed neuronal loss, M1 macrophage dominance, and chronic inflammation, all driven by impaired acetylcholine (ACh) secretion and α7nAChR inactivation. Mechanistically, taurine (TA) restored PC12 cell function under high glucose conditions by activating AMPK, alleviating oxidative and endoplasmic reticulum stress, and promoting ACh production. ACh activated macrophage α7nAChR, modulating M1/M2 polarization through JAK2/STAT3 activation and NF-κB suppression. To enhance TA bioavailability, ultrasound-responsive Ccr2-targeted TA nanoparticles (Ccr2@TA@LNP) were developed for site-specific delivery via Ccl2/Ccr2 chemotaxis. In diabetic neuropathy (DPN) mice, Ccr2@TA@LNP accelerated wound healing by increasing ACh levels, enhancing α7nAChR/CD206 expression, and reducing Ccl2-mediated inflammation. By integrating neuroprotection, macrophage reprogramming, and targeted nanotherapy, this study highlights TA as a multi-target agent that restores neuro-immune balance through the AMPK/α7nAChR/JAK2-STAT3 axis, offering a novel therapeutic strategy for diabetic wound treatment.

Renal fibrosis is a common pathological process associated with chronic kidney disease (CKD) progression. Intelectin-1, a newly identified adipokine, has been demonstrated to protect renal function in mice with type 2 diabetic nephropathy. However, the role of intelectin-1 in renal fibrosis and the underlying mechanisms remain unclear. This study aimed to: (1) investigate the effects of intelectin-1 on renal fibrosis in mice, and (2) explore the potential involvement of intelectin-1 in regulating renal tubular epithelial cells (TECs) senescence and mitochondrial dysfunction. To our knowledge, these findings represent the first demonstration that intelectin-1 treatment significantly attenuates renal fibrosis in unilateral ureteral obstruction (UUO) in mice by effectively inhibiting TECs senescence. Furthermore, intelectin-1 treatment alleviated mitochondrial dysfunction in TECs, as evidenced by improved mitochondrial membrane potential and decreased mitochondrial reactive oxygen species (mtROS) production. Mechanistically, intelectin-1 treatment activated AMPK signaling that subsequently inhibited the mTOR and p38 pathways. In conclusion, our findings suggest that intelectin-1 attenuates renal fibrosis in mice by inhibiting TECs senescence and alleviating mitochondrial dysfunction via AMPK/mTOR/p38MAPK signaling. These results provide a potential therapeutic target for the treatment of renal fibrosis in CKD. Further studies are warranted to explore the clinical relevance and translational potential of adipokines, including intelectin-1, in human renal fibrosis.

Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.

In this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic-killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.

Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.

We identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic-immune checkpoint and highlight its druggable vulnerability in osteomyelitis.

In times of climate change, frequency and intensity of extreme weather events are rising and thus demand a higher resilience of crop plants to environmental influences, such as flooding events, to minimize yield losses. Flooding causes acute oxygen deprivation in plants, accompanied by an energy crisis, starvation, growth retardation and ultimately increased harvest losses. At a molecular level, fluctuating oxygen concentrations are sensed via plant cysteine oxidases (PCOs) that, as part of the N-degron pathway, oxygen-dependently oxidize substrates such as vernalization 2, little zipper 2 and, most prominently, transcription factors of the group VII ETHYLENE RESPONSE FACTORS (ERFVIIs) to render them for degradation. When stabilized under hypoxia owing to the lack of oxygen, ERFVIIs act as transcriptional activators of hypoxia-response genes to evoke appropriate acclimation. Crop engineering for improved submergence resilience is an important goal for future food security, and prolonging ERFVII stability is a promising strategy. Here we discuss the potential molecular consequences of this strategy in terms of stabilization of Cys-initiating proteins in commercially relevant crop species, as well as ways in which this may be achieved, including via PCO engineering.This article is part of the theme issue 'Crops under stress: can we mitigate the impacts of climate change on agriculture and launch the 'Resilience Revolution'?'.

An unmet clinical need in chronic lymphocytic leukemia (CLL) is emerging due to the rapidly expanding group of patients with double refractory (Bruton's tyrosine kinase- and B-cell lymphoma 2-inhibitor) disease. So far, autologous T-cell-based therapies, including chimeric antigen receptor (CAR) T cells, have limited success in CLL, which has been attributed to an acquired CLL-mediated T-cell dysfunction and subset skewing toward effector cells at the expense of memory formation. T-cell responses rely on dynamic metabolic processes, particularly mitochondrial fitness. Although mitochondrial disruptions have been observed in solid tumor-infiltrating lymphocytes, their impact on T-cell immunity in lymphoproliferative disorders is unknown. Recent findings indicate that mitochondrial mass in CAR T cells correlates with CLL clinical outcomes. This prompted our investigation into the mitochondrial fitness in CLL T cells. Integrated metabolic and functional analyses revealed impaired, depolarized mitochondria across all T-cell subsets in untreated patients with CLL, leading to further ex vivo and in vivo mouse studies on the underlying signaling alterations. Multiomics profiling of transcriptome and epigenome revealed significant alterations in mitochondrial signaling, diminished adenosine monophosphate-activated protein kinase and autophagy activity, and upregulated glycolysis coupled with hyperactivation of Akt. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway during CLL T-cell culture induced metabolic reprogramming, enhancing mitochondrial activity, expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, and memory differentiation. Underscoring clinical relevance, supplementation with the PI3Kδ inhibitor idelalisib during CAR T-cell manufacturing improved persistence and long-term leukemia-free remissions in an immunocompetent murine model. Our study suggests that modulating the abnormal CLL T-cell metabolism can enhance the efficacy of autologous T-cell therapies.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

Pre-clinical evidence indicates that mitochondria may be a therapeutic target for luteolin (3',4',5,7-tetrahydroxyflavone; LUT) in different conditions. LUT modulates mitochondrial physiology in in vitro, ex vivo, and in vivo experimental models. This flavone exerted mitochondria-related antioxidant and anti-apoptotic effects, stimulated mitochondrial fusion and fission, induced mitophagy, and promoted mitochondrial biogenesis in human and animal cells and tissues. Moreover, LUT modulated the activity of components of the oxidative phosphorylation (OXPHOS) system, improving the ability of mitochondria to produce adenosine triphosphate (ATP) in certain circumstances. The mechanism of action by which LUT promoted mitochondrial benefits and protection are not completely clear yet. Nonetheless, LUT is a potential candidate to be utilized in mitochondrial therapy in the future. In this work, it is explored the mechanisms of action by which LUT modulates mitochondrial physiology in different pre-clinical experimental models.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

Urban particulate matter (UPM) is a major air pollutant affecting public health, with maternal exposure potentially leading to cardiac developmental disorders in offspring. However, the exact mechanisms underlying the intergenerational effects of UPM remain unclear.

This study aimed to investigate the molecular mechanisms involved in cardiac developmental defects caused by maternal UPM exposure in offspring zebrafish.

Female zebrafish were exposed to UPM for 21 days to examine intergenerational effects. The results indicated that maternal zebrafish in the exposed group exhibited ovarian damage and a reduced number of embryos and fertilization rates. Zebrafish offspring exhibited abnormal cardiac development, including pericardial edema and pathological heart injury. Mechanistically, transcriptomic analysis of the offspring indicated that UPM exposure induced significant modifications in the mitochondrial biogenesis pathway, with altered expression of mitochondrial function-related genes. Maternal UPM exposure impaired respiration in zebrafish embryos and increased angiopoietin-like 4 (ANGPTL4) expression in offspring hearts. In vitro, Angptl4 knockdown alleviated UPM-induced mitochondrial membrane potential reduction and mitochondrial reactive oxygen species overproduction in cardiomyocytes, whereas Angptl4 overexpression exacerbated UPM-induced mitochondrial toxicity.

These findings show that maternal UPM exposure disrupts mitochondrial homeostasis by upregulating ANGPTL4 expression, leading to abnormal cardiac development in zebrafish offspring.

The methoxylated modification of flavonoids has been reported to enhance stability and permeability; however, its effect on the improvement of activity is not clear. In this study, Citrus depressa flavonoid O-methyltransferase 5 and Sorghum vulgare 7-O-methyltransferase were recombinantly expressed and successfully converted quercetin (QUE) into eight methoxylated products, which were isolated and identified with a purity exceeding 95%. All products except rhamnetin (RHA) showed improved stability, while only 5,7,3',4'-EMQ, 7,3',4'-TMQ, and 3,7,3',4'-EMQ had higher uptake ratios. Compared to QUE, 5,7,3',4'-EMQ and RHA significantly reduced the intracellular triglyceride level, while 3,5,7,3',4'-PMQ, 3,3',4'-TMQ and 3,7,3',4'-EMQ increased it. 5,7,3',4'-EMQ and RHA also significantly downregulated both the mRNA and protein levels of peroxisome proliferator-activated receptor γ, while 3,5,7,3',4'-PMQ and 3,7,3',4'-EMQ upregulated PPARγ at the transcriptional level to about ten times higher than that of QUE. The structure-activity relationship analysis highlighted the importance of C3-OH retention and dual methoxylation of the A-ring. In summary, this study efficiently produced eight structurally well-defined QUE methoxylation products via biotransformation, established an in vitro initial structure-activity relationship for regulating adipogenesis, and provided a potential structure for PPARγ regulation, a central target of lipid metabolism.

Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Aβ) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD.

Abnormal energy metabolism plays a crucial role in the pathogenesis of heart failure (HF). Kanli granule (KLG), as an effective herbal medicine for treating HF, has been used in clinical practice for nearly 30 years. However, its underlying mechanisms have not been fully elucidated.

This study combined network pharmacology, molecular docking, and in vivo experiments to explore KLG's effect on HF. Wistar rats with AAC-induced HF were orally administered KLG (0.675/1.35/2.7 g/kg) for 32 weeks. Assessments included heart weight index, echocardiography, histopathology, fatty acid metabolism (FAM) targets, and myocardial energy metrics. We focused on fatty acid oxidation (FAO) pathway, measuring AMPK, PPARα, and CPT1A at protein and gene levels.

KLG maintained cardiac function in AAC rats. Network pharmacology identified PPAR and AMPK pathways as key in FAM. Molecular docking showed strong affinity of KLG components to FAO targets PPARα and CPT1A. KLG significantly enhanced myocardial energy metabolism, reduced myocardial FFA levels, and increased ATP/ADP ratios. It activated AMPK and upregulated FAO-related genes, including PPARα and CPT1A.

KLG improves FAO in AAC-induced HF rats by activating the AMPK/PPARα/CPT1A pathway, reducing myocardial FFA levels, and improving myocardial microstructure and cardiac function.

The accumulation of reactive oxygen species (ROS) in the skin following UVB exposure is a key contributor to ultraviolet-induced skin photodamage. Orientin, a bioactive flavonoid, has demonstrated antioxidant properties in previous studies. However, its efficacy in treating skin photodamage remains inadequately understood. This study investigates the effects of orientin in preventing UVB-induced immortalized human keratinocytes (HaCaT cells) and BALB/c mouse skin photodamage by activating the AMPK/Nrf2 axis. Results show that orientin protects HaCaT cell viability after UVB exposure, reduces ROS levels, and upregulates antioxidant enzymes, including SOD1, HO-1, and NQO-1, while concurrently suppressing the expression of inflammatory mediators such as COX-2, IL-6, and IL-8. Additionally, orientin promotes AMPK phosphorylation, which facilitates Nrf2 nuclear translocation, thereby enhancing the antioxidant defense of cells. This effect is diminished upon inhibition of AMPK or Nrf2. In the BALB/c mouse model of photodamage, topical application of orientin alleviates symptoms like skin roughness, scaling, and erythema induced by UVB irradiation, while also elevating antioxidant enzyme expression in skin tissues. These findings suggest that orientin mitigates ultraviolet-induced skin photodamage both in vitro and in vivo, boosts cellular antioxidant capacity, and diminishes inflammatory responses, suggesting its potential for further exploration in skin photodamage management.

Metabolic syndrome (MetS) poses considerable toxicological risks due to its association with an increased likelihood of metabolic dysfunction-associated steatotic liver disease (MASLD), and is characterized by hypertension, hyperglycemia, dyslipidemia, and obesity. This study aimed to investigate the therapeutic potential of flavonoid-rich lotus seedpod extract (LSE) in alleviating MetS and MASLD-related hepatic disturbances. In vivo, mice subjected to a high-fat diet (HFD) and streptozotocin (STZ) injection were supplemented with LSE or simvastatin for 6 weeks. Obesity indicators included body weight and epididymal fat, while insulin resistance was measured by fasting serum glucose, serum insulin, homeostasis model assessment-insulin resistance index (HOMA-IR), and oral glucose tolerance (OGTT). Also, the levels of serum lipid profiles and blood pressure were evaluated. Adipokines, proinflammatory cytokines, liver fat droplets, and peri-portal fibrosis were analyzed to clarify the mechanism of MetS. LSE significantly reduced the HFD/STZ-induced MetS markers better than simvastatin, as demonstrated by hypoglycemic, hypolipidemic, antioxidant, and anti-inflammatory effects. In vitro, LSE improved oleic acid (OA)-triggered phenotypes of MASLD in hepatocyte HepG2 cells by reducing lipid accumulation and enhancing cell viability. This effect might be mediated through proteins involved in lipogenesis that are downregulated by adenosine monophosphate-activated protein kinase (AMPK). In addition, LSE reduced reactive oxygen species (ROS) generation and glycogen levels, as demonstrated by enhancing insulin signaling involving reducing insulin receptor substrate-1 (IRS-1) Ser307 phosphorylation and increasing glycogen synthase kinase 3 beta (GSK3β) and protein kinase B (PKB) expression. These benefits were dependent on AMPK activation, as confirmed by the AMPK inhibitor compound C. These results indicate that LSE exhibits protective effects against MetS-caused toxicological disturbances in hepatic carbohydrate and lipid metabolism, potentially contributing to its efficacy in preventing MASLD or MetS.

Intermittent fasting (IF) is a dietary approach that influences key metabolic pathways, including autophagy-a crucial mechanism in maintaining cellular homeostasis. Autophagy plays a dual role in oncogenesis, acting both as a tumor suppressor and a survival mechanism under metabolic stress. IF has shown potential for reducing cancer risk and enhancing therapeutic efficacy by sensitizing tumor cells to chemotherapy and radiotherapy. However, its effects depend heavily on the type and stage of cancer. Potential risks, such as excessive weight loss and malnutrition, require careful evaluation. Further clinical studies are needed to optimize IF protocols as adjuncts to cancer therapy. This review discusses autophagy mechanisms induced by IF, their therapeutic implications in oncology, and the limitations of this dietary strategy.

Periodontitis is a chronic inflammatory disorder arising from an imbalance between oral microbiota and the host's immune response, with macrophages as pivotal targets for prevention and treatment. Endosome-associated Trafficking Regulator 1 (ENTR1) is indispensable for protein trafficking and implant osseointegration. However, its specific role in periodontitis has yet to be clarified. This research seeks to explore the effects of ENTR1 on macrophage polarization, elucidate its mechanisms, and evaluate its regulatory functions in the regeneration of periodontal tissues.

A ligature-induced periodontitis mouse model was established to investigate the correlation between macrophage polarization markers and ENTR1 expression. Techniques including qRT-PCR, Western blot, ELISA, flow cytometry, and immunofluorescence staining were utilized to evaluate the impact of ENTR1 on macrophage polarization under inflammatory stimuli. Micro-CT and histological staining were applied to assess periodontal bone resorption. The interaction between ENTR1 and AMP-activated protein kinase (AMPK) was explored through Western blot and co-immunoprecipitation, further validated by applying the AMPK inhibitor Compound C (CpC).

ENTR1 expression was down-regulated in the mice with periodontitis relative to healthy controls. Overexpressing ENTR1 suppressed macrophage M1 polarization and mitigated bone loss in periodontitis, while knocking down ENTR1 exacerbated these effects. ENTR1 directly interacted with AMPK, enhancing its phosphorylation. Furthermore, the inhibitory impact of ENTR1 on macrophage M1 polarization and inflammation-induced alveolar bone resorption were partially attenuated by CpC treatment.

ENTR1 regulates periodontitis by suppressing macrophage M1 polarization through enhancing AMPK phosphorylation, presenting a promising therapeutic target for its prevention and management.

Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.

Environmental nutrient levels affect cancer cell metabolism, activating adaptive mechanisms in cancer cells to deal with nutrient stress. However, it remains unclear how tumor cells sustain survival under nutrient-stress circumstances through metabolic reprogramming. Our study focused on nutrient deficiency-induced oxidative damage, revealing that increased expression of the iron-sulfur (Fe-S) cluster assembly protein, IscU2, is essential for the survival of pancreatic ductal adenocarcinoma (PDAC) cells in glucose-deficient conditions. Glucose deficiency induces IscU2 expression via the activation of the AMPK pathway, allowing IscU2 to exhibit antioxidant properties that are absent under glucose-sufficient conditions. Upregulated IscU2 stimulates aspartate synthesis by bolstering mitochondrial metabolism, including respiration and the tricarboxylic acid cycle, in a Fe-S cluster-dependent manner. Notably, oxidative stress and apoptosis induced by IscU2 depletion in glucose-deficient PDAC cells can be restored by aspartate-mediated NADPH production. These findings highlight the importance of IscU2 in PDAC cell metabolism and its essential function in supporting cell survival under nutrient-deficient conditions.

Morphine is among the most powerful analgesic, but its long-term use can cause tolerance. Synaptic ATP supply is critical for maintaining synaptic transmission. Microtubule-based mitochondrial transport ensures synaptic energy supply. How synaptic energy changes with morphine and the role of microtubule tracks in synaptic mitochondrial energy supply remain elusive. Chronic morphine treatment can destroy microtubule cytoskeletons. We investigated the effect of the microtubule cytoskeleton on synaptic mitochondrial energy supply and the mechanism of microtubule dynamics after morphine exposure.

Rats were treated with long-term morphine and the effect on thermal pain thresholds was evaluated by the tail-flick latency test. Various antagonists and agonists were used elucidated the role and mechanism of synaptic mitochondrial energy supply and microtubules in morphine tolerance in vivo and in SH-SY5Y cells.

Chronic morphine treatment reduced synaptic mitochondrial ATP production. Improving mitochondrial oxidative phosphorylation (OXPHOS) alleviated the downregulation of synaptic ATP levels. Microtubule-stabilizing agents prevented microtubule disruption and ameliorated synaptic energy deficit via microtubule-based microtubule transport. In SH-SY5Y cells, morphine exposure reduced microtubule expression. And re-opening the synaptic Ca2+ channel by agonist alleviated microtubule decrease by calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMP-activated protein kinase (AMPK) pathway.

This study demonstrates that the microtubule cytoskeleton regulated by the Ca2+-CAMKK2-AMPK axis is critical for synaptic mitochondrial transport and ATP production, explaining an interplay between chronic morphine-induced abnormal neuroadaptation and synaptic energetic dysfunction. These findings implicated a potential clinical strategy for prolonging the opioid antinociceptive effect during long-term pain control.