Dihydroartemisinin, a derivative of artemisinin, exhibits antimalarial, antitumour, antiviral, anti-inflammatory, immunomodulatory, antiparasitic, antifibrotic, and antihypertensive pharmacological activities. To investigate pharmacokinetics, oral bioavailability, and dose-exposure relationship of dihydroartemisinin in Beagle dogs, this study established and validated a rapid and sensitive quantitative ultra-performance liquid chromatography-mass spectrometry(UPLC-MS/MS) method for quantifying dihydroartemisinin in Beagle dog plasma. This validated method was then applied to the pharmacokinetic study of Beagle dog plasma after intravenous injection of a single dose of dihydroartemisinin and after gavage administration of different doses of dihydroartemisinin, to clarify the absolute bioavailability of dihydroartemisinin after gavage administration to Beagle dogs and to investigate the relationship between the different doses of dihydroartemisinin and its exposure(C_(max), AUC_(0-t)) in Beagle dogs. The results revealed that the specificity, linearity, accuracy, precision, stability, and matrix effect of this method met the requirements for the determination of biological samples. Rapid elimination of dihydroartemisinin was observed in Beagle dogs following intravenous administration of dihydroartemisinin. The half-life(t_(1/2)) of dihydroartemisinin in the plasma after intravenous injection was 0.37 h for females and 0.35 h for males. The area under the curve(AUC_(0-t)) for dihydroartemisinin was 395 ng·h·mL~(-1) for females and 428 ng·h·mL~(-1) for males. The mean residence time(MRT_(0-t)) was 0.73 h for females and 0.6 h for males. The clearance rate(CL) was 3.12 L·h~(-1)·kg~(-1) for females and 2.91 L·h~(-1)·kg~(-1) for males. Following gavage administration of dihydroartemisinin, concentrations of the drug peaked rapidly in dog plasma, all between 0.08 and 0.25 h. The absolute bioavailability was 0.46% for males and females at a dose of 1.2 mg·kg~(-1), 0.55% and 1.07% at 2.4 mg·kg~(-1), and 0.29% and 0.37% at 9.6 mg·kg~(-1), respectively. This established UPLC-MS/MS method for dihydroartemisinin in plasma exhibited good specificity and sensitivity. Dihydroartemisinin was metabolized very rapidly in dogs with low oral bioavailability, and the exposure levels(C_(max), AUC_(0-t)) increased with doses(1.2-9.6 mg·kg~(-1)) but showed a non-linear correlation.

Introduction Neutrophil extracellular traps (NETs) contribute to chronic inflammation in chronic obstructive pulmonary disease (COPD). Jinwei Guben Formula (JWGB) is a clinically used TCM for COPD, but its mechanism regarding NETs and glucocorticoid sensitivity is unclear. This study aimed to investigate whether JWGB modulates NETs formation and glucocorticoid efficacy via HDAC2 in COPD.Methods An integrated approach combining UHPLC-MS/MS, network pharmacology, molecular docking, and human neutrophil experiments was used.Results We identified 168 compounds in JWGB. Network analysis predicted 42 active ingredients and highlighted the NETs formation pathway. Key ingredients showed strong binding to HDAC2 and MPO. Experimentally, JWGB inhibited CSE-induced NETs release and inflammation. Notably, JWGB upregulated HDAC2 expression in COPD neutrophils and synergized with methylprednisolone, allowing a low dose (100 mu M) to match the efficacy of a high dose (500 mu M).Discussion Our findings reveal that JWGB alleviates COPD by simultaneously inhibiting NET formation and restoring HDAC2 function. This dual action provides a mechanistic basis for its clinical efficacy and suggests its potential as a steroid-sparing strategy to overcome glucocorticoid resistance.Conclusion JWGB may alleviate neutrophilic inflammation in COPD by inhibiting NET formation and upregulating HDAC2. Its synergy with glucocorticoids suggests potential as a steroid-sparing therapy.

Accumulating evidence suggests that pharmacological restoration of microglial homeostasis in the hippocampus may be a promising strategy for treating depression. In this study, we evaluated whether gardiquimod (GDQ), a selective Toll-like receptor 7 (TLR7) agonist, produces antidepressant effects in mice subjected to chronic unpredictable stress (CUS). A single intraperitoneal injection of GDQ at 1 or 1.5 mg/kg, but not 0.5 mg/kg, improved depression-related behaviors within 5 h of administration. Time-course analyses showed that the antidepressant efficacy of GDQ (1.5 mg/kg) appeared between 5 and 8 h, persisted for up to 7 days, and diminished by 14 days after a single dose. Notably, a second GDQ injection at 14 days restored the behavioral improvements, indicating sustained responsiveness to the drug. Mechanistically, the antidepressant effects of GDQ were abolished by both pharmacological inhibition (minocycline) and genetic depletion (PLX3397) of microglia, highlighting the necessity of these cells. Furthermore, GDQ reversed the CUS-induced reduction in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus in a microglia-dependent manner. The critical role of BDNF signaling was confirmed by three complementary approaches: intra-hippocampal infusion of a BDNF-neutralizing antibody, genetic disruption of activity-dependent BDNF release via the Val68Met knock-in mutation, and pharmacological blockade of the TrkB receptor with K252a. Each intervention abolished the behavioral effects of GDQ. Together, these findings identify GDQ as a promising candidate for antidepressant development and highlight the restoration of microglia-supported BDNF signaling in the dentate gyrus as a key mechanism underlying TLR7-mediated mood regulation.

Insulin resistance (IR) serves as a core pathogenic mechanism underlying metabolic diseases and critically drives their progression. Obesity exacerbates the risk of developing IR and metabolic diseases and has now risen to epidemic proportions globally. There is growing evidence that obesity, IR and metabolic diseases are closely linked. tRNA-derived small RNAs (tsRNAs) are non-coding RNAs (ncRNAs) that are widely found in prokaryotes and eukaryotes and are stably expressed in body fluids such as blood and urine. Moreover, mounting evidence has established a strong association between tsRNAs and metabolic disorders. And tsRNAs are involved in disease pathology. In this paper, we review the mechanism of IR and its association with inflammation, obesity, Type 2 Diabetes Mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic syndrome (MetS), and we also introduce the role of tsRNAs therein and their potential as biomarkers and therapeutic targets. However, the study of tsRNAs in IR and metabolic diseases is still in its infancy, and this paper also suggests some possible future research directions.

ATE1 is a conserved enzyme that catalyzes the covalent addition of arginine to proteins bearing N-terminal or mid-chain Asp and Glu residues. N-terminal (Nt) arginylation can also occur on Cys, Asn, and Gln following enzymatic conversion, often marking proteins for degradation. Essential for development, this pathway contributes to protein quality control and stress responses. Despite growing insight into ATE1 structure and function, the mechanisms governing its substrate selectivity and coordination with upstream oxygenase and deamidase remain poorly defined. Here, we reconstitute the human processing cascades that generate Nt-arginylated proteins in E. coli, enabling step-resolved analysis of arginylation outcomes in a cellular context. By co-expressing human ADO, NTAN1, or NTAQ1 with ATE1 in a modular system, we achieved efficient conversion of Nt-Cys, Asn, and Gln into arginylation-permissive forms, recapitulating key features of upstream processing. Using this platform, we demonstrated that N-terminal processing is efficient and that ATE1 preferentially modifies protein N-termini over internal acidic residues. Mid-chain arginylation of α-synuclein was detectable but occurred at low frequency, with no major differences in site selectivity observed across the ATE1 isoforms tested. Together, this bacterial reconstitution system provides a scalable experimental platform for quantitative, protein-level analysis of ATE1 substrate specificity under defined conditions.

INTRODUCTION:Neutrophil extracellular traps (NETs) contribute to chronic inflammation in chronic obstructive pulmonary disease (COPD). Jinwei Guben Formula (JWGB) is a clinically used TCM for COPD, but its mechanism regarding NETs and glucocorticoid sensitivity is unclear. This study aimed to investigate whether JWGB modulates NETs formation and glucocorticoid efficacy via HDAC2 in COPD. METHODS:An integrated approach combining UHPLC-MS/MS, network pharmacology, molecular docking, and human neutrophil experiments was used. RESULTS:We identified 168 compounds in JWGB. Network analysis predicted 42 active ingredients and highlighted the NETs formation pathway. Key ingredients showed strong binding to HDAC2 and MPO. Experimentally, JWGB inhibited CSE-induced NETs release and inflammation. Notably, JWGB upregulated HDAC2 expression in COPD neutrophils and synergized with methylprednisolone, allowing a low dose (100 μM) to match the efficacy of a high dose (500 μM). DISCUSSION:Our findings reveal that JWGB alleviates COPD by simultaneously inhibiting NET formation and restoring HDAC2 function. This dual action provides a mechanistic basis for its clinical efficacy and suggests its potential as a steroid-sparing strategy to overcome glucocorticoid resistance. CONCLUSION:JWGB may alleviate neutrophilic inflammation in COPD by inhibiting NET formation and upregulating HDAC2. Its synergy with glucocorticoids suggests potential as a steroid- sparing therapy.

Cerebrospinal fluid (CSF) biomarkers are used to identify or detect the condition of multiple neurodegenerative diseases, even psychiatric disorders. However, discordant results between observational studies failed to meet the expectations of identifying neurodegenerative diseases and psychiatric disorders. We conducted this systematic review and network meta-analyses to investigate the CSF biomarkers in neurodegenerative diseases and psychiatric disorders, which contribute to the diagnosis of these diseases. Studies before September 2023 were searched based on databases. We included observational studies that compared the CSF levels of these biomarkers (Aβ1–​42, tau, p-tau181, and α-synuclein) between healthy controls, neurodegenerative diseases, and psychiatric disorders. We conducted traditional pairwise analysis and network meta-analysis to evaluate the evidence concerning these CSF biomarkers between these neurodegenerative diseases and psychiatric disorders. This network meta-analysis included 117 studies with 25,210 patients to investigate the CSF biomarkers in multiple neurodegenerative diseases and psychiatric disorders (primarily depression, bipolar disorder, and schizophrenia). For CSF Aβ1–​42 levels, there were no statistically significant differences between these groups in network analysis. Regarding CSF t-tau and p-tau181 levels, statistical significance was observed in comparing Alzheimer’s disease (AD) and other diseases, e.g., amyotrophic lateral sclerosis (ALS). Regarding CSF α-synuclein levels, statistical significance was observed in several comparisons, e.g., AD vs. ALS. Conclusively, we identified that CSF Aβ1–​42, t-tau, and p-tau181 might be promising markers distinguishing AD from other neurodegenerative diseases and cognitive impairment. It is conflicting that CSF α-synuclein acts as a marker for diagnosing neurodegenerative diseases and predicts the presence of psychiatric disorders.

Objective This study aims to investigate the effect of Percutaneous Needle Fasciotomy intervention on angiogenesis in disuse-induced gastrocnemius muscle atrophy in rats and its relationship with the HIF-1α/VEGF signaling pathway. Methods : Twenty-four male Wistar rats were randomly divided into four groups: blank, model, Percutaneous Needle Fasciotomy, and stretching, with six rats in each group. Atrophy was induced by 4-week immobilization. The PNF group received a single fascial incision followed by dorsiflexion stretching; the stretching group received stretching alone. After the intervention, the range of motion (ROM) of the ankle joint and the hindlimb grip strength in each group of rats were assessed. Subsequently, the expression of proteins related to the HIF-1α/VEGF signaling pathway was analyzed using molecular biology techniques. Results : Compared with the blank group, the model group showed significant reductions in functional indicators (ankle ROM and grip strength), vascular markers (CD31, CD34, and related mRNAs), and key proteins of the HIF-1α/VEGF pathway (Tie-2, Ang-1, Src, VEGF) (P < 0.05), while HIF-1α expression was upregulated (P < 0.05). The stretching group showed no significant improvement versus the model group. In contrast, the PNF group exhibited a significant reversal of all these impairments (P < 0.05), with effects superior to the stretching group (P < 0.05). Conclusion : Percutaneous Needle Fasciotomy intervention promotes angiogenesis and facilitates the recovery of atrophied muscle, potentially via the HIF-1α/VEGF signaling pathway.

Major depressive disorder (MDD) is a debilitating neuropsychiatric condition of complex multifactorial etiology, with pathophysiology increasingly attributed to disruptions in neuroendocrine homeostasis and central neurotransmitter signalling. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the brain that modulates multiple physiological and psychological consequences through gamma-aminobutyric acid A (GABAA) and gamma-aminobutyric acid B (GABAB) receptors. GABAergic dysfunction, along with alterations in GABA levels and GABA receptor function, has been identified in MDD across animal and human studies. However, research on GABA in MDD is still relatively insufficient. Therefore, this review summarizes the GABAergic system in MDD and provides insight into these complex interactions.

Major depressive disorder (MDD) is a heterogeneous disease with complex etiology, accompanied by high morbidity and disability. Recently, neuroinflammation has been identified as a crucial mechanism in major depressive disorder. Mangiferin (MGF) is a natural flavonoid polyphenolic compound primarily extracted from Anemarrhenae Rhizome or mango that exhibits promising anti-inflammatory activity in the preclinical treatment of MDD. The present research used network pharmacology and bioinformatics to identify 3 core targets (ICAM1, MAPK3, and MMP9) associated with MGF for treating neuroinflammation in MDD. We have identified MDD as being closely associated with immunity and neuroinflammation, with core targets primarily related to calcium and the NOD-like receptor signaling pathway, among others. Based on molecular docking studies, MGF has good binding activity with MAPK and MMP9. This research suggests that MGF has the potential to treat neuroinflammation in MDD, providing a basis for further exploration of its clinical application in treating neuroinflammation associated with MDD.

Microglial decline in the dentate gyrus is an important mechanism in the development of depression-like behaviors in stressed animals. Reversing this decline with low-dose lipopolysaccharide (LPS) can produce rapid antidepressant effects, yet the underlying mechanisms remain incompletely understood. Our previous work identified a critical role for astrocytic P2Y1 receptor (P2Y1R) activation and subsequent dentate gyrus extracellular signal-regulated kinase 1/2 (ERK1/2)-brain-derived neurotrophic factor (BDNF) signaling in the antidepressant effect of low-dose LPS. This study elucidates the signaling cascade linking astrocytic P2Y1R mobilization to the antidepressant effect of low-dose LPS. We found that low-dose LPS promoted glutamate release through ATP-triggered astrocytic P2Y1R signaling. Blockade of N-methyl-D-aspartic acid (NMDA) receptors, but not metabotropic receptors, and the GluN2B subtype of NMDA receptors abolished the antidepressant effect of low-dose LPS. GluN2B knockdown also abolished the reversal effect of low-dose LPS on CUS-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Moreover, chelating intracellular Ca2+ or suppressing Ca2+/calmodulin-dependent protein kinase II (CaMKII) abolished the reversal effect of low-dose LPS on chronic unpredictable stress (CUS)-induced depression-like behaviors and impairment of dentate gyrus ERK1/2-BDNF signaling. Additionally, suppression of protein kinase A (PKA) and protein kinase C (PKC) did not abolish the antidepressant effect of low-dose LPS. These findings demonstrate that activation of the GluN2B-CaMKII signaling cascade in the dentate gyrus is required for the rapid antidepressant action of low-dose LPS, as well as the reversal effect of LPS on impaired ERK1/2-BDNF signaling in the hippocampus, which may help to elucidate the microglial deficiency hypothesis of depression.

Schisandrin B (Sch B), a key bioactive lignan extracted from Schisandra chinensis (Turcz.) Baill, exhibits lipid lowering and anti-inflammatory properties in vivo and in vitro. However, few studies investigate the anti-metabolic dysfunction associated steatohepatitis (MASH) effect of Sch B. In this study, we employed a methionine and choline-deficient high fat diet (MCDHF)-induced MASH mouse model and palmitate acid (PA)-induced MASH cell models to evaluate the anti-inflammatory and anti-steatosis effects of Sch B. We also explore the molecular targets of Sch B for its anti-MASH effect. The results showed that Sch B treatment markedly suppressed the production of inflammatory factors and lipid accumulation in MASH mice, as well as in PA-exposed HepG2 cells and mouse primary hepatocytes (MPHs). It also reduced the content of hepatic lipid profiles and the serum levels of AST and ALT in MASH mice. Mechanistic studies revealed that Sch B treatment activated the PXR signaling pathway. Sch B treatment also suppressed the phosphorylation of key proteins involved in NF-κB signaling in PA-treated HepG2 cells, and modulated the expression of lipid metabolism related enzymes in PA-treated MPHs. PXR inhibitor reversed the lipid reducing effect of Sch B in PA-exposed MPHs. Our results suggest that Sch B could ameliorate the hepatic steatosis and inflammation via activation of the PXR signaling.

BACKGROUND:Neuropathic pain (NP) is a frequent sequel to peripheral nerve injury and maladaptive nervous system function. Daphnetin (DAP), a bioactive 7,8-dihydroxycoumarin derived from the traditional Chinese medical plant Daphne giraldii Nitsche, has potential anti-nociceptive effects and alleviated NP following intrathecal injection. However, the molecular target of DAP for this action remains unknown. PURPOSE:This study aims to investigate the underlying mechanisms of DAP against NP. METHODS:Chronic constriction injury (CCI) rat model and lipopolysaccharide (LPS)-treated HAPI microglial cells were established to evaluate the analgesic and anti-inflammatory effects and underlying mechanisms of DAP. Rat behavioral assessments included mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and gait analysis. The expression of mRNA was determined by qRT-PCR. Protein expression levels were detected by Western blot, immunofluorescence, and enzyme linked immunosorbent assay. Molecular docking, surface plasmon resonance, molecular dynamics simulation, and site-directed mutagenesis were employed to investigate the interaction between Kelch-like ECH-associated protein 1 (Keap1) and DAP. RESULTS:DAP treatment significantly increased MWT and TWT in CCI rats. It also improved gait parameters and attenuated spinal inflammation, neuronal damage, and hyperexcitability in CCI rats. DAP treatment markedly increased the expression of Nrf2 and its nuclear translocation in the rat spinal cord and HAPI cells. DAP treatment inhibited the activation of NLRP3 inflammasome and microglial M1 phenotype polarization, while promoting M2 phenotype polarization. Furthermore, the NLRP3 inhibitor MCC950 also alleviated hyperalgesia in CCI rats, inhibited NLRP3 inflammasome activation, suppressed microglial M1 polarization, and promotes M2 polarization, whereas the Nrf2 inhibitor ML385 exerted the opposite effect. It reversed the regulatory effect of DAP on spinal microglial polarization in the CCI rat spinal cord and LPS-induced HAPI cells. Molecular interaction studies further demonstrated that DAP binds to Tyr334 and Tyr572 residues in the Kelch domain of Keap1, thereby blocking Keap1/Nrf2 interaction to activate Nrf2. CONCLUSION:DAP treatment inhibits microglial M1 polarization and promotes M2 polarization via the Nrf2/NLRP3 inflammasome pathway, attenuates neuroinflammation and central sensitization, and finally achieves analgesic effects. These findings identify DAP as a novel Nrf2 activator with therapeutic potential for the management of NP.

Leontopodium leontopodioides (Wild.) Beauv. (LLB) was investigated to determine its metabolite profiles and bioactivities across different growth stages. Ultrasound-assisted extraction was employed to obtain total flavonoids and phenolic acids from LLB samples collected at the vegetative and reproductive stages, and their in vitro antioxidant capacities were then evaluated. UHPLC-MS/MS-based metabolomics was subsequently used to compare the metabolite changes between the two growth stages. Finally, network pharmacology analysis was conducted to predict potential diuretic components and elucidate their mechanisms of action. The results revealed that samples from the vegetative stage contained higher levels of bioactive compounds and exhibited stronger antioxidant activity than those from the reproductive stage. A total of 1,817 metabolites were identified, belonging to 12 compound classes such as flavonoids, phenolic acids, lipids, amino acids and derivatives, and terpenoids. Comparative analysis revealed 305 differentially expressed metabolites between growth stages, predominantly flavonoids. KEGG pathway enrichment analysis showed significant enrichment of these differential metabolites in three biosynthetic pathways: flavone and flavonol biosynthesis, flavonoid biosynthesis, and isoflavonoid biosynthesis. Through integrated ingredient screening and network pharmacology, five potential diuretic components in Leontopodium leontopodioides (Wild.) Beauv were predicted: 3,4-dimethoxycinnamic acid, jasmonic acid, chrysin, rivularin, and tangeretin. Molecular docking validation suggested that these compounds likely exert diuretic effects by targeting key proteins such as AKT1, MAPK1, and MAPK3. Collectively, this work systematically elucidates the metabolic variations in Leontopodium leontopodioides (Wild.) Beauv. during different growth stages, predicts its diuretic potential from a multi-component, multi-target perspective, and reveals the underlying material basis and molecular mechanisms. These findings provide critical evidence for active compound screening and mechanistic clarification, supporting the future development of Leontopodium leontopodioides (Wild.) Beauv. into standardized diuretic agents or functional products with well-defined mechanisms of action.

BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a common metabolic disorder characterized by hepatic steatosis, obesity, abnormal liver function, and dyslipidemia, with limited effective drug options available. Increasing evidence links MAFLD to dysbiosis of the gut microbiota and microbial metabolites, including short-chain fatty acids (SCFAs). We hypothesized that Yinchen Wuling San (YCWLS) mitigates MAFLD by remodeling gut microbiota and associated SCFAs profiles.AIM To determine whether YCWLS alleviates MAFLD by inducing gut microbiota remodeling in rats.METHODS A high-fat diet was used to induce MAFLD in rats. The animals were assigned to control, model, positive drug (Bifidobacterium quadruple live bacteria tablets, 2.1 g/kg), and YCWLS (6.38 g/kg) groups and treated for 4 weeks. Liver and adipose histopathology was evaluated using hematoxylin-eosin staining. Serum lipids and liver enzymes were measured, gut microbiota was profiled by 16S rRNA sequencing, and fecal SCFAs were quantified using gas chromatography-mass spectrometry.RESULTS Compared to the model group, YCWLS reduced the liver index and improved liver injury markers, specifically alanine aminotransferase and aspartate aminotransferase (alanine aminotransferase model 50.05 +/- 8.98 vs YCWLS 22.97 +/- 2.40 P < 0.01; aspartate aminotransferase model 217.32 +/- 13.70 vs YCWLS 122.65 +/- 6.49 P < 0.01), alleviating hepatic steatosis and tissue injury. YCWLS also decreased serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol (triglycerides model 1.26 +/- 0.18 vs YCWLS 0.61 +/- 0.09 P < 0.01; total cholesterol model 2.83 +/- 0.30 vs YCWLS 1.79 +/- 0.09 P < 0.01; low-density lipoprotein cholesterol model 0.49 +/- 0.16 vs YCWLS 0.17 +/- 0.02 P < 0.01; high-density lipoprotein cholesterol model 0.50 +/- 0.11 vs YCWLS 1.01 +/- 0.09 P < 0.01). Microbiota analysis revealed a reduction in Firmicutes-related taxa (including Ruminococcaceae and Clostridiales) and an increase in Verrucomicrobia, Lachnospiraceae, Peptostreptococcaceae, and Akkermansia. Most fecal SCFAs exhibited modest, non-significant increases; however, butyrate displayed a near-significant upward trend (P = 0.052).CONCLUSION Yinchen Wuling San improves liver injury and dyslipidemia in MAFLD rats and is associated with the enrichment of Akkermansia and Lachnospiraceae, supporting a gut microbiota-linked mechanism.

Depression, characterized by sustained low moods and even suicidal tendencies, has been intimately linked with mitochondrial dysfunction. This dysfunction is significantly connected with various psychiatric disorders, suggesting its potential role in the pathogenesis and progression of depression. Sirtuin 3 (SIRT3), a potent deacetylase enzyme primarily located within mitochondria, orchestrates mitochondrial function and mitigates various dysfunctions, e.g., insufficient cellular energy supply and oxidative stress. Insufficient cellular energy supply and oxidative stress disrupt normal neuroplasticity and neuroinflammation in the nervous system, as well as disturbances of the hypothalamic-pituitary-adrenal axis in peripheral systems. This review aims to elucidate that SIRT3 can be a potential target for depression, thereby summarizing the mechanisms by which SIRT3 is involved in the pathogenesis and progression of depression by regulating mitochondrial function.

Major depressive disorder (MDD) is a recurrent episodic mood disorder characterized by persistent low mood and loss of interest. The pathogenesis of major depressive disorder (MDD) involves a neuroinflammatory response, neurotransmitter dysfunction, blood-brain barrier disruption, oxidative stress, and mitochondrial dysfunction. Neuroinflammation, caused by the overactivation of microglia, is considered a key factor in the development of the disease. Metabolic reprogramming has been shown to play a crucial role in microglial activation and executive function. In MDD, microglia have the potential to become activated and transform into either pro-inflammatory or anti-inflammatory phenotypes. These variations in cellular phenotypes lead to differences in cellular energy metabolism. Mitochondria are involved in the energy metabolism of microglia and have intricate connections with microglia-mediated metabolic reprogramming and neuroinflammation. However, the specific changes in the metabolic reprogramming of microglia in depression, the numerous signaling pathways and cytokines involved, and the mechanisms by which they mediate phenotypic transitions remain unclear. Therefore, this review summarizes the metabolic reprogramming of microglia in MDD, as well as the involved signaling pathways, mitochondrial involvement and cytokines, and elaborates on their interaction with phenotypic transformation. The effects of drugs on regulating immune metabolic reprogramming to suppress neuroinflammation were summarized, providing potential for new research approaches in the treatment of MDD.

Targeting endothelial cell ferroptosis is a potential approach for the treatment of atherosclerosis (AS). 6-Gingerol (6-Gin) is an active substance in ginger that is beneficial for improving AS. We conducted this study to explore whether 6-Gin mediated AS progression by regulating ferroptosis of endothelial cells. ApoE-/- mice were fed a high-fat diet to establish AS mouse model. Additionally, oxidized low-density lipoprotein (ox-LDL) was used to treat human umbilical vein endothelial cells (HUVECs) to generate injured cell model. Ferroptosis was evaluated by propidium iodide staining assay, western blot, and detecting iron, glutathione, malonaldehyde, and reactive oxygen species levels. The results showed that ox-LDL inhibited the proliferation and induced inflammation and ferroptosis of HUVECs, which was reversed by 6-Gin treatment. Moreover, 6-Gin upregulated HO-1 and NQO1 levels and promoted nuclear translocation of NRF2 in ox-LDL-treated HUVECs. ATRA, an NRF2 inhibitor, abrogated the promotion of proliferation and the inhibition of inflammation and ferroptosis induced by 6-Gin. Additionally, 6-Gin alleviated AS and suppressed ferroptosis in vivo. In conclusion, 6-Gin inhibited endothelial cell ferroptosis by inactivating the NRF2/HO-1 pathway, thereby improving abnormal lipid metabolism in AS mice. These findings suggest that 6-Gin may be a novel therapeutic drug for AS.

BACKGROUND:Mangiferin (MGF), kaempferol (KMP), and diosgenin (DIO) are active compounds extracted from the dried rhizomes of Anemarrhena asphodeloides Bunge. that are proven to have antidepressant activity. However, no studies comprehensively compare and analyze the efficacy of MGF, KMP, and DIO. METHODS:We searched electronic databases (e.g., Cochrane Library, Embase, Scopus, and PubMed) for studies of three compounds in rodents from inception to October 2024, performing a systematic review and network meta-analysis. We used animal behavioral tests as outcome indicators, including the forced swimming test, tail suspension test, and sucrose preference test. RESULTS:A total of ten studies were included, involving 440 animals and six interventions. In the forced swimming test, the efficacy of fluoxetine was superior to KMP, MGF, and DIO. In the tail suspension test, DIO was more effective than fluoxetine, MGF, and KMP. In the sucrose preference test, the efficacy of fluoxetine was superior to MGF, DIO, and KMP. Specifically, MGF, KMP, and DIO significantly reduced the immobility time of the FST or TST and increased the sucrose preference index. CONCLUSIONS:MGF, KMP, and DIO significantly improved depression-like behaviors of rodents, providing evidence for further development of new clinical antidepressants. Also, MGF, KMP, and DIO exert antidepressant effects primarily through anti-inflammatory, anti-oxidative stress, and regulation of neurotrophic factor and neurotransmitter levels.

Introduction: Nicotinamide Mononucleotide (NMN) has gained attention as a precursor to Nicotinamide Adenine Dinucleotide (NAD+) in recent years, commonly utilized in anti-aging therapies. The anti-aging effects of NMN on muscle and liver functions in middleaged and elderly people are still unclear. Objective: Based on available randomized controlled trials, we conducted a meta-analysis to evaluate the impact of NMN on muscle and liver functions in middle-aged and elderly individuals. Methods: We conducted searches on three electronic databases (PubMed, Embase, Web of Science) for randomized controlled trials involving NMN interventions in middle-aged and elderly populations. Through the Cochrane Handbook, we assessed the specific methodological quality. All statistical analyses were obtained by Stata15, and statistical significance was set as P<0.05. Results: There were 412 participants from 9 studies in this meta-analysis. Based on changes in gait speed (SMD: 0.34 m/s, 95%CI [0.03, 0.66] p = 0.033), NMN had significant effects on muscle mass. Moreover, NMN had a better effect on ALT (SMD: -0.29 IU/L, 95%CI [-0.55, -0.03] p = 0.028). Subgroup analysis indicated that administering a small dose of NMN exerted the most prominent impact on Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). Conclusion: NMN has positive efficacy in enhancing muscle function, reducing insulin resistance and lowering aminotransferase levels in middle-aged and elderly individuals. NMN is an encouraging and considerable drug for anti-aging treatment.