Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer.

BACKGROUND: The cyclin-dependent kinase 4 (CDK4) interacts with its canonical and non-canonical substrates modulating the cell cycle in tumor cells. However, the potential substrates and the beyond-cell-cycle-regulated functions of CDK4 in colon cancer (CC) are still unknown. Hernandezine (HER) is previously verified to induce G0/G1 phase arrest and autophagic cell death in human cancer cells, which implies that HER might target G0/G1 phase-related proteins, including CDK4. PURPOSE: The present study tried to investigate the glycolytic metabolism and oxidative stress functions of CDK4 in colon cancer. Furthermore, the inhibitory effects and potential binding sites of HER on CDK4, as well as its anti-tumor activity were investigated in CC cells. METHODS: The mass spectrometry assay was performed to identify potential endogenous substrates of CDK4 and the correlation between glycolytic metabolic rate and CDK4 level in COAD patient tissues. Meanwhile, after inhibiting the activity or the expression of CDK4, the binding capacity of CDK4 to PKM2 and NRF2 and the latter two protein distributions in cytoplasm and nucleus were detected in CC cells. In vitro, the regulatory effects of the CDK4-PKM2-NRF2 axis on glycolysis and oxidative stress were performed by ECAR, OCR, and ROS assay. The inhibitory effect of HER on CDK4 activity was explored in CC cells and the potential binding sites were predicted and testified in vitro. Furthermore, tumor growth inhibition of HER by suppressing the CDK4-PKM2-NRF2 axis was also investigated in vitro and in vivo. RESULTS: PKM2 and NRF2 were identified as endogenous substrates of CDK4 and, high-expressed CDK4 was associated with low-level glycolysis in COAD. In vitro, inactivated CDK4 facilitated CDK4-PKM2-NRF2 complex formation which resulted in 1) inhibited PKM2 activity and retarded the glycolytic rate; 2) cytoplasm-detained NRF2 failed to transcript anti-oxidative gene expressions and induced oxidant stress. Additionally, as a CDK4 inhibitor, HER developed triple anti-tumor effects including induced G0/G1 phase arrest, suppressed glycolysis, and disrupted the anti-oxidative capacity of CC cells. CONCLUSION: The results first time revealed that CDK4 modulated glycolytic and anti-oxidative capacity of CC cells via bound to its endogenous substrates, PKM2 and NRF2. Additionally, 140Asp145Asn amino acid sites of CDK4 were potential targets of HER. HER exerts anti-tumor activity by inhibited the activity of CDK4, promoted the CDK4-PKM2-NRF2 complex formation in the CC cells.

Effectiveness of home-based cardiac telerehabilitation based on wearable ECG or heart rate monitoring devices in patients with heart disease: A meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness of home-based cardiac telerehabilitation based on wearable electrocardiogram or heart rate monitoring devices in patients with heart disease. METHODS: We searched eight electronic databases under the guidance of Cochrane Handbook and PRISMA recommendations. RESULTS: The meta-analysis included data from 14 articles (15 RCTs) representing 1314 participants. A significant improvement in left ventricular ejection fraction [MD = 2.12, 95 % CI (1.21, 3.04), P < 0.001], 6-minute walk distance [MD = 40.00, 95 % CI (21.72, 58.29), P < 0.001] and peak oxygen intake [MD = 2.24, 95 % CI (1.38, 3.10), P < 0.001] were observed in the home-based cardiac telerehabilitation group. But it had no difference in anxiety [SMD = -0.83, 95 % CI (-1.65, -0.02), P = 0.05] and depression [SMD = -0.59, 95 % CI (-1.26, 0.09), P = 0.09]. Subgroup analyses revealed that interventions of no less than 3 months improved anxiety [SMD = -1.11, 95 % CI (-2.05, -0.18), P = 0.02] and depression [SMD = -1.01, 95 % CI (-1.93, -0.08), P = 0.03]. CONCLUSION: Home-based cardiac telerehabilitation based on wearable electrocardiogram or heart rate monitoring devices has a positive effect on cardiac function. Long-term (≥ 3 months) cardiac rehabilitation might benefit individuals suffering from anxiety or depression.

Double Droplets Impact an Inclined Superhydrophobic Surface.

The rebound dynamics of double droplets impacting an inclined superhydrophobic surface decorated with macro-ridges are investigated via lattice Boltzmann method (LBM) simulations. Four rebound regions are identified, that is, the no-coalescence-rebound (NCR), the partial-coalescence-rebound of the middle part bounces first (PCR-M), and the side part bounces first (PCR-S), as well as the complete-coalescence-rebound (CCR). The occurrence of the rebound regions strongly depends on the droplet arrangement, the center-to-center distance of the droplets, and the Weber number. Furthermore, the contact time is closely related to the rebound regions. The PCR-M region can significantly reduce the contact time because the energy dissipation in this region may decrease which can promote the rebound dynamic. Intriguingly, the contact time is also affected by the droplet arrangement; i.e., droplets arranged parallel to the ridge dramatically shorten the contact time since this arrangement increases the asymmetry of the liquid film. Therefore, for multidrop impact, the contact time can be effectively manipulated by changing the rebound region and the droplet arrangement. This work focuses on elucidating the wetting behaviors, rebound regions, and contact time of the multiple-droplet impacting an inclined superhydrophobic surface decorated with macro-ridges.

Photoinduced decarboxylative germylation of α-fluoroacrylic acids: access to germylated monofluoroalkenes.

Herein, a novel strategy is presented for the photoinduced decarboxylative and dehydrogenative cross-coupling of a wide range of α-fluoroacrylic acids with hydrogermanes. This methodology provides an efficient and robust approach for producing various germylated monofluoroalkenes with excellent stereoselectivity within a brief photoirradiation period. The feasibility of this reaction has been demonstrated through gram-scale reaction, conversion of germylated monofluoroalkenes, and modification of complex organic molecules.

Catalytic activity and mechanism of F- and Cl-doped graphene for peroxymonosulfate activation to remove tetracycline hydrochloride.

Highly active catalysts with salt and acid/alkali resistance are desired in peroxymonosulfate (PMS) activation processes and marine environment applications. F- and Cl-doped graphene (F-GN and Cl-GN) were prepared via electronegative and atom radius adjustment for tetracycline hydrochloride (TCH) pollution removal to satisfy these requirements. The introduction of special F and Cl functionalities into graphene exhibits superior electron transfer properties for PMS activation, considering the experimental and density functional theory (DFT) calculation results. The TCH degradation efficiency reached up to 80% under various pH and salt disturbance conditions with F-GN and Cl-GN. Cl-GN exhibited an activity superior to F-GN due to the higher electron polarization effect of C atoms adjacent to Cl atoms. The presence of more positive charged C sites in Cl-GN (around Cl doping) is more favorable for PMS attachment and sequence radical generation than F-GN. In addition, the main active species functionalized during reaction included ·OH and SO4-·, and the stability of F-GN and Cl-GN was confirmed to be over 60% by recycle test. Final research results provide an effective strategy for designing and preparing PMS activators resistant to salt, acid, and alkali, thereby expanding their application potential.

The Role of Ferroptosis in Amyotrophic Lateral Sclerosis Treatment.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a challenging treatment landscape, due to its complex pathogenesis and limited availability of clinical drugs. Ferroptosis, an iron-dependent form of programmed cell death (PCD), stands distinct from apoptosis, necrosis, autophagy, and other cell death mechanisms. Recent studies have increasingly highlighted the role of iron deposition, reactive oxygen species (ROS) accumulation, oxidative stress, as well as systemic Xc- and glutamate accumulation in the antioxidant system in the pathogenesis of amyotrophic lateral sclerosis. Therefore, targeting ferroptosis emerges as a promising strategy for amyotrophic lateral sclerosis treatment. This review introduces the regulatory mechanism of ferroptosis, the relationship between amyotrophic lateral sclerosis and ferroptosis, and the drugs used in the clinic, then discusses the current status of amyotrophic lateral sclerosis treatment, hoping to provide new directions and targets for its treatment.

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2.

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

New sesquiterpenoids from the flowers of pentanema britannicum (L.) D.Gut.Larr.

Five new sesquiterpenoids, (4S, 5S, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (1), (4S, 5 R, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (2), 6-O-propionyl-britannilactone (3), 1ß-hydroxy-3α-acetoxyeudesma-11(13)-en-12,8ß-olide (4) and 1ß,5ß-dihydroxyeudesma-11(13)-en-12,8ß-olide (5), along with twelve known ones were isolated from the flowers of Pentanema britannicum (L.) D.Gut.Larr. Among them, compounds 1 and 2 were stereoisomers which belong to 1,10-seco-eudesmane sesquiterpenoid with rare double bond between C-10 and C-14. The structures of the isolated compounds were elucidated by various spectroscopic methods, including 1D and 2D NMR experiments.

The alleviatory effects of koumine on MSU-induced gouty arthritis via the TLR4/NF-κB/NLRP3 pathway.

The aim of this study was to validate the preventive effects of koumine (KM), a monoterpene indole alkaloid, on gouty arthritis (GA) and to explore its possible mechanisms. C57BL/6 mice were intraperitoneally administered KM (0.8, 2.4 or 7.2 mg/kg), colchicine (3.0 mg/kg) or sterile saline. One hour later, a monosodium urate (MSU) suspension was injected into the right hind paws of the mice to establish an acute gout model. Inflammation symptoms were evaluated at 0, 3, 6, 12 and 24 h, and the mechanical withdrawal threshold was evaluated at 0, 6 and 24 h. After 24 h, the mice were euthanized, and the joint tissue, kidney and blood were collected for subsequent experiments. Histological examination and antioxidant enzyme, kidney index and serum uric acid (UA) measurements were taken. The expression levels of the signalling pathway components were determined. KM effectively alleviated the symptoms of redness, swelling and pain; counteracted inflammatory cell infiltration; and increased antioxidant enzyme levels, reduced kidney index and seru UA levels through regulating UA excretion in MSU-induced mice. The expression of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) signalling pathway proteins and mRNA were reduced in the KM group. These results suggest that KM may be effective in alleviating GA through the TLR4/NF-κB/NLRP3 pathway.

Near-infrared fluorescent probe to track Cys in plant roots under heavy metal hazards and its application in cells and zebrafish.

Heavy metals, including Hg2+, Cr6+ and Cd2+, have always been a major issue in environmental pollution, leading to abnormal changes in the levels of biologically active molecules including Cys in plants, seriously affecting all aspects of the growth and development of plants. This makes it essential to develop a simple and practical method to study the potential impact of heavy metals on plants. In this paper, our research group has developed near-infrared fluorescent probe WRM-S, which has the advantages of fast response, sensitivity to Cys, and successfully applying it to cells and zebrafish. Moreover, it combined the close relationship between heavy metal stress on plants and Cys, using Cys as the detection target, monitoring the internal environment changes of two plants under Hg2+, Cr6+, and Cd2+ stress in the environment, and then conducting 3D imaging. The results indicated that the probe has strong penetration ability in plant tissues, and revealed abnormal changes in plant Cys levels caused by heavy metal stress-induced cellular oxidative stress or cytotoxicity. Thus, the in-situ imaging detection of this probe provides a direction for the physiological dynamics research of plant environmental stress.

Efficacy and safety of acupuncture for postpartum hypogalactia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Postpartum hypogalactia (PH) is prominent during lactation and may negatively impact the mother's or infant's health. Acupuncture is widely used to increase maternal breast milk production. However, the effects of acupuncture on PH remain unclear. Therefore, this review aimed to evaluate the efficacy and safety of acupuncture in individuals with PH. MATERIALS AND METHODS: Articles on potentially eligible randomized controlled trials (RCTs) on acupuncture for PH published from database inception to October 2023 were retrieved from the PubMed, Web of Science, Cochrane Library, EMBASE, EBSCO, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, WanFang, and VIP databases. Two reviewers independently screened the records, extracted essential information, and evaluated the methodological quality of the RCTs using the revised Cochrane risk-of-bias (RoB) tool. The primary outcome was a change in serum prolactin (PRL) levels before and after treatment. Secondary outcomes included milk secretion volume (MSV), total effective rate (TER), mammary fullness degree (MFD), and exclusive breastfeeding rate (EBR). Meta-analyses were performed using RevMan v5.4. Finally, the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. RESULTS: This study included 19 RCTs involving 2,400 participants. The included studies were classified as having an unclear to high RoB. Our findings indicated that, overall, acupuncture showed a significant effect in increasing serum PRL levels (standardized mean differences [SMDs] = 1.09, 95% confidence interval [CI]: 0.50, 1.68), MSV (SMD = 1.69, 95% CI: 0.53, 2.86), TER (relative risk [RR] = 1.25, 95% CI: 1.10, 1.42), and EBR (RR = 2.01, 95% CI: 1.07, 3.78) compared to that in the control group; however, no difference in MFD (SMD = 1.17, 95% CI: -0.09, 2.42) was observed. In the subgroup analysis, acupuncture combined with Chinese herbs or conventional treatment was significantly more effective in increasing serum PRL levels, MSV, and TER than did Chinese herbs or conventional treatment alone. Moreover, acupuncture alone resulted in significantly higher serum PRL levels compared to Chinese herbs; however, this benefit was not observed for TER and MFD. The quality of evidence was critically low. CONCLUSION: Acupuncture may effectively increase milk secretion in women with PH. However, owing to the low quality of evidence, further rigorously designed studies are warranted to confirm our findings.

Ferroptosis inhibitors: past, present and future.

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed the mechanisms of its formation and continue to explore effective inhibitors of ferroptosis in disease. Recent studies have shown a correlation between ferroptosis and the pathological mechanisms of neurodegenerative diseases, as well as diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for the treatment of ferroptosis-mediated diseases. This article specifically describes the metabolic pathways of ferroptosis and summarizes the reported mechanisms of action of natural and synthetic small molecule inhibitors of ferroptosis and their efficacy in disease. The paper also describes ferroptosis treatments such as gene therapy, cell therapy, and nanotechnology, and summarises the challenges encountered in the clinical translation of ferroptosis inhibitors. Finally, the relationship between ferroptosis and other modes of cell death is discussed, hopefully paving the way for future drug design and discovery.

Widely targeted metabolomics analysis of Sanghuangporus vaninii mycelia and fruiting bodies at different harvest stages.

Sanghuangprous vaninii is a medicinal macrofungus cultivated extensively in China. Both the mycelia and fruiting bodies of S. vaninii have remarkable therapeutic properties, but it remains unclear whether the mycelia may serve as a substitute for the fruiting bodies. Furthermore, S. vaninii is a perennial fungus with therapeutic components that vary significantly depending on the growing year of the fruiting bodies. Hence, it is critical to select an appropriate harvest stage for S. vaninii fruiting bodies for a specific purpose. With the aid of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), metabolomics based on ultra-high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS) was used to preliminarily determine 81 key active metabolites and 157 active pharmaceutical metabolites in S. vaninii responsible for resistance to the six major diseases. To evaluate the substitutability of the mycelia and fruiting bodies of S. vaninii and to select an appropriate harvest stage for the fruiting bodies of S. vaninii, we analyzed the metabolite differences, especially active metabolite differences, among the mycelia and fruiting bodies during three different harvest stages (1-year-old, 2-year-old, and 3-year-old). Moreover, we also determined the most prominent and crucial metabolites in each sample of S. vaninii. These results suggested that the mycelia show promise as a substitute for the fruiting bodies of S. vaninii and that extending the growth year does not necessarily lead to higher accumulation levels of active metabolites in the S. vaninii fruiting bodies. This study provided a theoretical basis for developing and using S. vaninii.

Forest-to-Cropland Conversion Reshapes Microbial Hierarchical Interactions and Degrades Ecosystem Multifunctionality at a National Scale.

Conversion from natural lands to cropland, primarily driven by agricultural expansion, could significantly alter soil microbiome worldwide; however, influences of forest-to-cropland conversion on microbial hierarchical interactions and ecosystem multifunctionality have not been fully understood. Here, we examined the effects of forest-to-cropland conversion on intratrophic and cross-trophic microbial interactions and soil ecosystem multifunctionality and further disclosed their underlying drivers at a national scale, using Illumina sequencing combined with high-throughput quantitative PCR techniques. The forest-to-cropland conversion significantly changed the structure of soil microbiome (including prokaryotic, fungal, and protistan communities) while it did not affect its alpha diversity. Both intrakingdom and interkingdom microbial networks revealed that the intratrophic and cross-trophic microbial interaction patterns generally tended to be more modular to resist environmental disturbance introduced from forest-to-cropland conversion, but this was insufficient for the cross-trophic interactions to maintain stability; hence, the protistan predation behaviors were still disturbed under such conversion. Moreover, key soil microbial clusters were declined during the forest-to-cropland conversion mainly because of the increased soil total phosphorus level, and this drove a great degradation of the ecosystem multifunctionality (by 207%) in cropland soils. Overall, these findings comprehensively implied the negative effects of forest-to-cropland conversion on the agroecosystem, from microbial hierarchical interactions to ecosystem multifunctionality.

Trends in maternal and child health in China and its urban and rural areas from 1991 to 2020: a joinpoint regression model.

The long-term trends in maternal and child health (MCH) in China and the national-level factors that may be associated with these changes have been poorly explored. This study aimed to assess trends in MCH indicators nationally and separately in urban and rural areas and the impact of public policies over a 30‒year period. An ecological study was conducted using data on neonatal mortality rate (NMR), infant mortality rate (IMR), under-five mortality rate (U5MR), and maternal mortality ratio (MMR) nationally and separately in urban and rural areas in China from 1991 to 2020. Joinpoint regression models were used to estimate the annual percentage changes (APC), average annual percentage changes (AAPC) with 95% confidence intervals (CIs), and mortality differences between urban and rural areas. From 1991 to 2020, maternal and child mortalities in China gradually declined (national AAPC [95% CI]: NMRs - 7.7% [- 8.6%, - 6.8%], IMRs - 7.5% [- 8.4%, - 6.6%], U5MRs - 7.5% [- 8.5%, - 6.5%], MMRs - 5.0% [- 5.7%, - 4.4%]). However, the rate of decline nationally in child mortality slowed after 2005, and in maternal mortality after 2013. For all indicators, the decline in mortality was greater in rural areas than in urban areas. The AAPCs in rate differences between rural and urban areas were - 8.5% for NMRs, - 8.6% for IMRs, - 7.7% for U5MRs, and - 9.6% for MMRs. The AAPCs in rate ratios (rural vs. urban) were - 1.2 for NMRs, - 2.1 for IMRs, - 1.7 for U5MRs, and - 1.9 for MMRs. After 2010, urban‒rural disparity in MMR did not diminish and in NMR, IMR, and U5MR, it gradually narrowed but persisted. MCH indicators have declined at the national level as well as separately in urban and rural areas but may have reached a plateau. Urban‒rural disparities in MCH indicators have narrowed but still exist. Regular analyses of temporal trends in MCH are necessary to assess the effectiveness of measures for timely adjustments.

Trametinib, an anti-tumor drug, promotes oligodendrocytes generation and myelin formation.

Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.

Assembly of Heterocyclic C-Glycosides by Ru-Catalyzed C-H Activation/Cyclization with Carbonyl Sulfoxonium Ylide Glyco-Reagents.

New carbonyl sulfoxonium ylide glyco-reagents have been developed, enabling the synthesis of versatile heteroarene C-glycosides through a Ru-catalyzed C-H activation/annulation strategy. These reactions tolerate various saccharide donors and represent a significant advance in the stereoselective synthesis of heterocyclic C-glycosides. Furthermore, the strategy and methods could be applied to large-scale reactions and late-stage modifications of some structurally complex natural products or drugs.

Impairment in acquisition of conditioned fear in people with depressive symptoms.

Background: Depression is one of the primary global public health issues, and there has been a dramatic increase in depression levels among young people over the past decade. The neuroplasticity theory of depression postulates that a malfunction in neural plasticity, which is responsible for learning, memory, and adaptive behavior, is the primary source of the disorder's clinical manifestations. Nevertheless, the impact of depression symptoms on associative learning remains underexplored. Methods: We used the differential fear conditioning paradigm to investigate the effects of depressive symptoms on fear acquisition and extinction learning. Skin conductance response (SCR) is an objective evaluation indicator, and ratings of nervousness, likeability, and unconditioned stimuli (US) expectancy are subjective evaluation indicators. In addition, we used associability generated by a computational reinforcement learning model to characterize the skin conductance response. Results: The findings indicate that individuals with depressive symptoms exhibited significant impairment in fear acquisition learning compared to those without depressive symptoms based on the results of the skin conductance response. Moreover, in the discrimination fear learning task, the skin conductance response was positively correlated with associability, as estimated by the hybrid model in the group without depressive symptoms. Additionally, the likeability rating scores improved post-extinction learning in the group without depressive symptoms, and no such increase was observed in the group with depressive symptoms. Conclusion: The study highlights that individuals with pronounced depressive symptoms exhibit impaired fear acquisition and extinction learning, suggesting a possible deficit in associative learning. Employing the hybrid model to analyze the learning process offers a deeper insight into the associative learning processes of humans, thus allowing for improved comprehension and treatment of these mental health problems.