The objective of this study is to investigate the effects of treadmill exercise on motor deficits in chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)–induced chronic Parkinson’s disease (PD) mice and the underlying mechanisms. Healthy male C57BL/6 mice were randomly divided into the following groups: Control, PD model (PD), treadmill exercise (PD+Exe8), and treadmill exercise combined with the STING agonist DMXAA (PD+Exe8+DMXAA). Motor function was assessed using gait analysis, rota-rod test, wire hang test, pole test, and open field test. Fecal short-chain fatty acid (SCFA) levels were measured by gas chromatography-mass spectrometry (GC-MS). Colonic morphological changes were observed via H E and PAS staining. Immunofluorescence staining was used to examine the colonic barrier and pathological protein accumulation. Western blot, qPCR, and ELISA were performed to assess immune responses, gut barrier integrity, blood-brain barrier (BBB) function, and inflammatory markers. (1) Chronic PD mice exhibited significant motor deficits, a decreased number of tyrosine hydroxylase (TH)–positive cells in the substantia nigra, and increased α-synuclein (α-syn) expression. (2) Treadmill exercise increased fecal valeric acid levels, ameliorated Th17/Treg immune imbalance in the colon and brain, and these beneficial effects were abolished by DMXAA. (3) Treadmill exercise improved gut barrier and BBB integrity, reversed colon pathology, and these improvements were blunted by DMXAA. (4) Treadmill exercise reduced inflammatory responses in both the colon and brain, and this anti-inflammatory effect was abolished by DMXAA. (5) DMXAA blunted the improvement in motor dysfunction induced by 8-week treadmill exercise. Treadmill exercise significantly improves motor dysfunction in mice with chronic PD, this effect is associated with STING-mediated SCFA valeric acid-Th17/Treg immune imbalance and impaired intestinal and blood-brain barriers.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder worldwide after Alzheimer's disease, is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the abnormal intracellular aggregation of alpha-synuclein into Lewy bodies. Traditionally, the clinical symptoms of PD have focused on motor dysfunction, which includes characteristic signs such as resting tremor, rigidity, bradykinesia, and postural instability. However, increasing evidence from both clinical and basic research suggests that the clinical presentation of PD is highly diverse, with neuropsychiatric complications representing a significant and unavoidable aspect of the disease's overall burden. From the perspective of clinical phenotypes, the range of neuropsychiatric symptoms associated with PD is extensive, primarily including depressive disorders, generalized anxiety, apathy, impulse control disorders, and cognitive impairments related to executive function and memory. Notably, emotional and cognitive dysfunctions often manifest years prior to the onset of motor symptoms. This clinical observation indicates that the pathological processes of PD may originate within the non-motor circuits of the central nervous system (CNS), particularly in neural networks closely linked to emotional regulation and cognitive function. As one of the human body's most lipid-rich organs, the CNS comprises lipids that account for approximately 50%-60% of the dry weight of brain tissue. These lipid molecules serve not only as structural components but also actively participate in the formation of cell membrane phospholipid bilayers, myelin sheath insulation layers, and various signal transduction complexes. From a functional perspective, lipids not only provide the structural foundation necessary for maintaining neuronal membrane fluidity, synaptic plasticity, and ion channel activity, but also act as essential molecules in energy metabolism, signal transduction, and epigenetic regulation. Notably, the frontal cortex- particularly its evolutionarily specialized prefrontal cortex (PFC)-functions as the brain's "executive center for cognition and emotion". This region is pivotal for higher cognitive functions, including working memory, decision-making, and behavioral inhibition, as well as for the complex regulation of emotions, such as reward and risk assessment. This region displays an exceptionally high synaptic density and is abundant in structural lipids, including unsaturated fatty acids and cholesterol, which makes it particularly vulnerable to disturbances in lipid metabolism. In PD research, lipid imbalance has become a central focus. As investigations progress, the importance of lipid metabolic pathways becomes increasingly apparent. Simultaneously, pharmacological therapies aimed at lipid regulation show considerable efficacy in addressing cognitive and emotional deficits associated with PD. In light of this, the present study utilizes bioinformatics analysis to identify differentially expressed genes in the peripheral blood of PD patients, demonstrating significant enrichment in processes such as chronic depression, cholesterol metabolism, fatty acid metabolism, AMPK signaling pathways, and insulin resistance. Expanding on this groundwork, the present review systematically explores the connections between dysregulated lipid metabolism and metabolic reprogramming in cognitive and emotional impairments associated with PD. Through the analysis findings, intervention approaches focusing on various fundamental pathological pathways such as neuroinflammation, mitochondrial dysfunction, imbalance in lactate homeostasis, and disrupted protein homeostasis are suggested. These proposals provide innovative perspectives for advancing mechanistic investigations and therapeutic advancements targeting cognitive and emotional disorders in PD.

Objective Depressive-like behaviors is one of the most prevalent non-motor symptoms in Parkinson's disease(PD),severely compromising patients'quality of life.Dihydromyricetin(DHM),a natural flavonoid,exhibits neuroprotective effects,but its ability to ameliorate PD-related depressive-like behaviors and the underlying mechanisms remain unclear.This study aimed to investigate DHM's mechanism for improving depressive-like behaviors in PD and identify its key molecular targets.Methods Thirty-two 7 weeks old male C57BL/6J mice(weighting 24.5±1.5 g)were randomly divided into 4 groups(n=8):Control,PD model,PD+Madopar(positive control),and PD+DHM.Except the control group,all groups received intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)to establish subacute PD models.Motor function was assessed via rotarod,pole and wire hang tests;depressive-like behaviors were evaluated using the open field,forced swimming,and tail suspension tests.Network pharmacology,dataset mining,and molecular docking predicted DHM's key targets for PD treatment.Western blotting and immunofluorescence detected DHM's effects on synaptic plasticity,astrocyte polarization,and ferroptosis.Conditioned medium experiments further validated the predicted mechanisms.Results Compared with the PD group,PD+DHM mice showed significantly prolonged rotarod duration and suspension time(P<0.001),reduced pole descent time(P=0.005 5),increased total distance(P<0.001)and velocity(P<0.001)in open field test,with higher central activity distance/time ratios(P<0.01),and shorter immobility times in forced swimming and suspension tests(P<0.01).Network pharmacology and molecular docking identified the Lipocalin-2(LCN2)/NOD-like receptor thermal protein domain associcated protein 3(NLRP3)axis as DHM's potential target.DHM intervention reversed neuronal loss and Nissl body reduction while upregulating synaptic plasticity markers BDNF,SYN1 and PSD95,compared with the PD group(P<0.01).DHM significantly downregulated LCN2,NLRP3,and A1-astrocyte marker complement component 3(C3;P<0.001),but upregulated A2-marker S100 calcium binding protein A10(S100A10;P<0.01).Compared with the PD gruop,immunofluorescence revealed reduced GFAP/C3-positive cells and increased GFAP/S100A10 cells in the prefrontal cortex of PD+DHM group(P<0.05).Additionally,DHM decreased acyl-CoA synthetase long chain family member 4(ACSL4)and Transferrin receptor(TFRC)expression(P<0.001),while increasing GPX4 and SLC7A11 levels(P<0.001)in the prefrontal cortex.Conditioned medium experiments confirmed that DHM and NLRP3 inhibitor MCC950 reversed abnormal ferroptosis-related changes in dopaminergic neurons(P<0.01).Conclusion DHM may ameliorate depressive-like behaviors in PD mice by inhibiting the LCN2/NLRP3 axis which promotes A2-astrocyte polarization,mitigates imbalance in astrocyte polarization and alleviates neuronal ferroptosis.

Diabetic sarcopenia (DS) is a common but often ignored skeletal muscle complication in individuals with diabetes mellitus. It is characterized by progressive loss of skeletal muscle mass, reduced muscle strength, and impaired physical performance, which may further increase the risk of falls, disabilities, metabolic disorders, and adverse clinical outcomes. Traditionally, DS has been attributed mainly to hyperglycemia, insulin resistance, aging-related muscle decline, and chronic complications of diabetes. However, increasing evidence suggests that lipid metabolic disturbance and pathological lipid metabolic reprogramming are not merely secondary consequences of diabetes, but may actively participate in the initiation and progression of DS. Under diabetic conditions, impaired fatty acid uptake, transport, oxidation, and storage disrupt skeletal muscle metabolic homeostasis, leading to ectopic lipid deposition and accumulation of lipotoxic intermediates. These lipid-derived metabolites can aggravate insulin resistance, impair mitochondrial energy production, enhance oxidative stress, activate chronic low-grade inflammation, and disturb protein synthesis and degradation balance, thereby accelerating skeletal muscle atrophy and functional decline. Lipid metabolic dysregulation may also interact with multiple pathological processes involved in DS, including mitochondrial dysfunction, inflammatory signaling, oxidative damage, impaired autophagy, and gut microbiota imbalance. These mechanisms do not occur independently; instead, they form a complex bidirectional vicious cycle with diabetes-related metabolic disorders. Specifically, mitochondrial dysfunction reduces fatty acid oxidative capacity, which further promotes lipid accumulation and lipotoxicity. Inflammatory activation can impair insulin signaling and muscle protein metabolism, while lipid overload may in turn amplify inflammatory responses. Similarly, gut microbiota dysbiosis and altered microbial metabolites may influence systemic inflammation, lipid metabolism, and skeletal muscle homeostasis. Therefore, lipid metabolic reprogramming provides an important mechanistic perspective for understanding the progression of DS from metabolic disturbance to structural and functional muscle impairment. Exercise intervention is an effective and clinically feasible non-pharmacological strategy for the prevention and management of DS. Both aerobic exercise and resistance training have been shown to improve insulin sensitivity, enhance fatty acid oxidation, increase mitochondrial biogenesis, reduce ectopic lipid deposition, and attenuate lipotoxic metabolite accumulation. These adaptations not only improved glucose and lipid metabolism, but also increased the preservation of muscle mass, muscle strength, and physical function. Moreover, combined exercise strategies may provide complementary benefits by integrating the metabolic advantages of aerobic exercise with the anabolic and functional effects of resistance training. Based on analyses of publicly available datasets and literature evidences, this review systematically summarizes the role of lipid metabolic disorders in the pathogenesis of DS, with particular attention to the molecular mechanisms linking lipid dysregulation to insulin resistance, chronic inflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota disturbance. Furthermore, this review discusses the potential mechanisms by which exercise intervention improves DS through the regulation of lipid metabolic reprogramming, and outlines exercise prescription strategies in terms of modality, intensity, frequency, and duration. Understanding the interaction between lipid metabolism and skeletal muscle dysfunction may provide new theoretical evidence for early identification, mechanistic research, and precision exercise therapy in DS. Overall, targeting pathological lipid metabolic reprogramming through exercise intervention represents a promising and clinically actionable approach for improving muscle health and prognosis in individuals with DS.

Alzheimer's disease (AD) is a chronic, progressive, and irreversible neurodegenerative disorder that typically begins with a subtle onset and progresses slowly. Pathologically, it is characterized by two hallmark features: the extracellular accumulation of amyloid (3-protein (A(3), forming senile plaques, and the intracellular hyperphosphorylation of tau protein, resulting in neurofibrillary tangles (NFTs). These pathological changes are accompanied by substantial neuronal and synaptic loss, particularly in critical brain regions such as the cerebral cortex and hippocampus. Clinically, AD presents as a gradual decline in memory, language abilities, and spatial orientation, significantly impairing the quality of life of affected individuals. With the aging population steadily increasing in China, the incidence of AD is rising, making it a major public health concern that requires urgent attention. The growing societal and economic burden of AD underscores the pressing need to identify effective diagnostic biomarkers and develop novel therapeutic strategies. Among the various molecular signaling pathways involved in neurological disorders, the Notch signaling pathway is especially noteworthy due to its evolutionary conservation and regulatory roles in cell proliferation, differentiation, development, and apoptosis. In the central nervous system, Notch signaling is essential for neurodevelopment and synaptic plasticity and has been implicated in several neurodegenerative processes. Although some studies suggest that Notch signaling may influence AD-related pathology, its precise role in AD remains poorly understood. In particular, the interaction between Notch signaling and non-coding RNAs (ncRNAs)-key regulators of gene expression-has received limited attention. NcRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are known to exert extensive regulatory functions at both transcriptional and post-transcriptional levels. Dysregulation of these molecules has been widely associated with various diseases, including cancers, cardiovascular conditions, and neurodegenerative disorders. Notably, interactions between ncRNAs and major signaling pathways such as Notch can produce widespread biological effects. While such interactions have been increasingly reported in several disease models, comprehensive studies investigating the regulatory relationship between Notch signaling and ncRNAs in the context of AD remain scarce. Given the capacity of ncRNAs to modulate signaling cascades and form complex regulatory networks, a deeper understanding of their crosstalk with the Notch pathway could provide novel insights into AD pathogenesis and reveal potential targets for diagnosis and treatment. In this study, we investigated the regulatory landscape involving the Notch signaling pathway and associated ncRNAs in AD using bioinformatics approaches. By integrating data from multiple public databases, we systematically identified significantly dysregulated Notch pathway-related genes and their interacting ncRNAs in AD. Based on this analysis, we constructed a lncRNA-miRNA-mRNA regulatory network to elucidate the potential mechanisms linking Notch signaling to ncRNA-mediated gene regulation in AD pathogenesis. Furthermore, we explored the internal relationships and molecular mechanisms within this network and assessed the feasibility and clinical relevance of these molecules as early diagnostic biomarkers and potential therapeutic targets for AD. This study aims to deepen our understanding of the molecular basis of AD and offer novel strategies for its diagnosis and treatment.

This study aimed to explore the effects and molecular mechanisms of 8-week treadmill exercise on constipation symptoms in mice with chronic Parkinson's disease (PD). Forty C57BL/6 mice were randomly divided into four groups: control group, model (PD) group, 8-week treadmill exercise (PD+Ex) group, and 8-week treadmill exercise+3-methyladenine (3MA) (PD+Ex+3MA) group, with n = 10 in each group. A chronic PD mouse model was prepared using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) combined with probenecid (MPTP/p). The PD+Ex group underwent 8 weeks of treadmill exercise training, while the PD+Ex+3MA group received an additional 5 weeks of 3MA intraperitoneal injection (simultaneously with modeling). Constipation symptoms were evaluated using indicators such as defecation parameters, colon length, and colon to body weight ratio. Immunofluorescence staining was used to detect α-synuclein (α-syn) deposition in the colon. RT-qPCR was used to detect the mRNA expression levels of key enzymes of neurotransmitters in the colon, and Western blot was used to detect pathological and autophagy-related protein expression levels. The results showed that, compared with the control group, the PD group mice exhibited motor dysfunction and significant constipation symptoms. In the PD group, the protein expression of tyrosine hydroxylase (TH) in the striatum was significantly downregulated, while α-syn deposition in the colon was significant and its protein expression was significantly up-regulated. The mRNA expression of neuronal nitric oxide synthase (nNOS) was up-regulated, while the expression levels of TH protein and choline acetyltransferase (ChAT) mRNA were down-regulated in the colon. The protein expression of p62 was up-regulated, and the protein expression levels of Beclin1 and LC3II were down-regulated in the colon. After treadmill exercise intervention, all the above changes in the PD group were significantly improved, and autophagy inhibitor 3MA could counteract these improving effects of treadmill exercise intervention. These results suggest that 8-week treadmill exercise can improve constipation symptoms in MPTP/p-induced chronic PD mice, and its protective effect may be achieved by activating autophagy.

Notch signaling, a classical signaling pathway of neurogenesis, is downregulated during the aging and age-related neurodegenerative diseases. Exercise has been proposed as an effective lifestyle intervention for delaying cognitive decline. However, it remains unclear whether exercise intervention could alleviate cognitive decline by modulating neurogenesis in naturally aging rats. In this study, 21-month-old natural aging rats were used to study brain aging. The natural aging rats underwent different forms of exercise training (aerobic exercise or strength training or comprehensive exercise with aerobic exercise and strength training) for 12 consecutive weeks. The cognitive function of natural aging rats was determined by Morris Water Maze. Notch signaling, autophagy-related proteins and hippocampal neurogenesis were examined by immunofluorescence, qRT-PCR and Western blot. Results showed that natural aging rats exhibited cognitive decline, accumulation of AD pathological proteins (APP and Aβ), and decreased neurogenesis (decreased DCX, Ki67 and GFAP), compared with the young control rats. Moreover, a significant decline in Notch signaling and autophagy was found in the hippocampus of natural aging rats. However, different forms of exercise upregulated Notch signaling and its downstream target genes, as well as autophagy-related proteins, including LC3, Beclin1, and p62. In summary, our data suggest that different forms of exercise can mitigate brain aging by upregulating Notch signaling and autophagy, thereby increasing hippocampal neurogenesis and improves spatial learning and memory abilities.

Objective Parkinson's disease (PD) is a common progressive neurodegenerative disease whose incidence increases with age. An increasing number of studies have identified depression in PD (DPD) as one of the most common non-motor symptoms, characterized by decreased interest, sleep disturbances, and even suicidal tendencies that severely impact patient quality of life. Although the drugs used clinically to treat DPD can alleviate symptoms to some extent, research on the long-term safety and efficacy of these medications remains limited. Recently, 40 Hz light flicker stimulation has gained attention for its non-invasive, safe, effective, well-tolerated nature, and high patient compliance. Therefore, this study investigates the effects of 40 Hz light flicker stimulation on inflammatory responses, microglial polarization, and pyroptosis in PD mice with depressive-like behaviors, and explores the mechanisms underlying its effects on these behavioral and pathological changes, providing a clinical basis for this treatment in DPD. Methods Eight-month-old C57BL/6 mice were randomly divided into Control, PD, and 40 Hz+PD groups, with eight mice in each group. The 40 Hz+PD group received 40 Hz light flicker stimulation intervention for four weeks. After the intervention, the visual function of the mice was assessed using dark and light box tests. After grouping, a subacute PD model was established in the PD and PD+40 Hz groups via intraperitoneal injection of MPTP. The Control group received no MPTP injection. The motor abilities of the mice were evaluated using rotarod, wire hanging, and open field tests. Tail suspension and forced swimming tests were used to detect depression-like behavior in mice. Immunofluorescence was used to measure the colocalization level of Iba-1, CD206, and iNOS in the prefrontal cortex. ELISA was used to detect the content of IL-18 and IL-1 beta in the serum. RT-PCR and Western Blot were used to detect the mRNA and protein expression levels of synaptic plasticity-related proteins, microglial markers, pyroptosis-related proteins, and components of the Sirt1/PGC-1 alpha signaling pathway. NAD(+), ATP, and LDH contents in the cortex were measured using kits. Results and Discussions The results show that 40 Hz light flicker stimulation does not affect the visual function of C57BL/6 mice. Compared with the Control group, the PD group shows motor dysfunction and a prolonged immobility time in the forced swimming and tail suspension tests (Fig. 1), suggesting that PD mice exhibit depressive-like behaviors. Simultaneously, the expression levels of BDNF and PSD95 decrease (Fig. 2). The expression levels of CD206 and Arg1 and the levels of Iba-1 and CD206 colocalization significantly decrease (Fig. 3), but the expression levels of iNOS, NLRP3, Cleaved-Caspase1, GSDMD-N, IL-18, IL-1 beta, the levels of Iba-1 and iNOS colocalization, and IL-18 and IL-1 beta contents significantly increase (Fig. 4). Furthermore, the levels of NAD(+), ATP, Sirt1, and PGC-1 alpha significantly decrease (Fig. 5), suggesting that the NAD(+)/Sirt1/PGC-1 alpha signaling pathway is inhibited in PD mice. After the four week 40 Hz light flicker intervention, motor dysfunction in PD mice is alleviated, and the immobility time during the forced swimming and tail suspension tests is significantly shortened (Fig. 1). The expression levels of PSD95 and BDNF show increasing trends (Fig. 2), suggesting their role in alleviating depressive-like behaviors in PD mice. The expressions of the M2-type microglial cell marker CD206 and Arg1 increase (Fig. 3) and the expression of cell pyroptosis decreases (Fig. 4), reducing the occurrence of inflammatory reactions. In addition, the expressions of NAD(+), ATP, Sirt1, and PGC-1 alpha increase (Fig. 5). Conclusions This study investigates the effects of 40 Hz light flicker stimulation therapy on depression-like behaviors in PD mice by establishing an MPTP-induced PD model. The 40 Hz light flicker stimulation therapy activates the NAD(+)/Sirt1/PGC-1 alpha signaling pathway in the cortex of PD mice, promoting the polarization of microglia towards the M2 phenotype. This alleviates the vicious cycle of microglial polarization imbalance and pyroptosis, alleviates neuroinflammation, and ultimately relieves depressive-like behaviors in PD mice.

OBJECTIVES:To investigate the effects of formulated granules of Tianma Gouteng Yin (TGY) on motor deficits in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute Parkinson's disease (PD) and explore the possible molecular mechanisms. METHODS:Ninety C57BL/6 mice were randomized equally into 6 groups, including a control group, a PD model group, a NEC-1 (6.5 mg/kg) treatment group, two TGY treatment groups at 5 and 2.5 g/kg, and a Madopar (76 mg/kg) treatment (positive control) group. Mouse models of PD were established by intraperitoneal injection of MPTP (30 mg/kg) for 5 consecutive days with the corresponding treatments for 15 days. The mice were randomly selected for motor function tests. Western blotting was used to detect the changes in expressions of TH, α-syn, RIPK1, RIPK3 and MLKL in the striatum of the mice. Network pharmacology analysis and molecular docking studies were performed to explore TGY-mediated regulation of the necroptosis pathway for PD treatment. RESULTS:Compared with those in the control group, the PD model mice exhibited obvious motor deficits with significantly increased α-syn protein expression and lowered TH protein expression in the striatum. Treatment with NEC-1 obviously improved motor deficits, inhibited the necroptosis pathway, and alleviated the changes in TH and α‑syn proteins in PD mice. Network pharmacology and molecular docking analyses suggested that the therapeutic effect of TGY in PD was associated with the modulation of RIPK1, a key protein in the necroptosis pathway. In PD mouse models, TGY treatment at the two doses significantly improved motor deficits of the mice, increased TH expression, and decreased the expressions of α-syn and necroptosis-related proteins in the striatum. CONCLUSIONS:TGY can effectively inhibit the necroptosis pathway, increase TH expression and decrease α-syn expression in the striatum to improve motor deficits in PD mice.

The study aimed to explore the effect and mechanism of resistance exercise (RE) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) mice. Six 8-week-old male m/m mice were used as control (Con) group, and db/db mice of the matched age were randomly divided into model control (db/db) group and db+RE group, with 6 mice in each group. The db+RE group was given 8 weeks of resistance climbing ladder exercise intervention. The fasting blood glucose and body weight of the mice were measured weekly. After the intervention, the spatial learning and memory of the mice were detected by Morris water maze, and the neuronal damage in the hippocampus of the mice was detected by Nissl staining. The protein expression levels of PSD93, PSD95, BDNF, CREB, p-CREB, IL-6, IL-1β, TNF-α, Iba-1, iNOS, CD206, Arg1, triggering receptor expressed on myeloid cells 2 (TREM2), NF-κB, p-STAT3, and STAT3 were detected by Western blot. The mRNA expression levels of inflammatory factors and TREM2 in hippocampus were evaluated by qRT-PCR, and the expression and localization of Iba-1, CD206, CD86, and TREM2 were determined by immunofluorescence staining. The results showed that the spatial learning and memory of the db/db group were significantly declined, the neurons in the hippocampus were damaged, the protein levels of PSD93, PSD95, BDNF, CD206, Arg1, TREM2 and the ratio of p-CREB/CREB were significantly down-regulated, the mRNA and protein expression levels of IL-6, IL-1β and TNF-α were significantly up-regulated, and the protein levels of iNOS, Iba-1, NF-κB and the ratio of p-STAT3/STAT3 were significantly increased compared with the Con group. However, the 8-week RE improved the spatial learning and memory of db/db mice, alleviated the damage of hippocampal neurons, promoted the polarization of M2 microglia, and inhibited the neuroinflammation. The above results suggest that RE can improve cognitive dysfunction in T2DM mice, and its mechanism may be related to regulating microglia polarization via TREM2/NF-κB/STAT3 signaling pathway.

The main characteristics of neurodegenerative diseases represented by Alzheimer's disease (AD) and Parkinson's disease (PD) is the progressive irreversible loss of neurons, leading to varying degrees of pathological changes and loss of cognitive function. There is still no effective treatment. With the acceleration of global aging society, the incidence of neurodegenerative diseases is rapidly increasing, becoming a serious global public health concern that urgently requires the development of effective therapeutic strategies. The Hippo signaling pathway, a highly evolutionarily conserved pathway, consists of the core components MST1/2, LATS1/2,and downstream effectors, transcriptional co-activators YAP and TAZ. It plays a crucial role in the regulation of various biological processes such as cell proliferation, differentiation, development, and apoptosis. Dysregulation of the Hippo pathway contributes to the development of many diseases, including cancer, cardiovascular diseases, immune disorders, etc. Therefore, targeting the dysregulated components of the Hippo pathway may be an effective strategy for treating various diseases. Increasing evidence indicates that the Hippo pathway is excessively activated in the development of neurodegenerative diseases, manifested by increased expression of MST1 and downregulation of YAP. Stabilizing the Hippo pathway levels has shown improvements in AD and PD. However, most studies on the Hippo pathway in AD and PD focus on changes in the expression levels of Hippo pathway components, and research in other neurodegenerative diseases is still lacking. Therefore, further investigation is needed to fully understand the mechanistic role of the Hippo pathway in neurodegenerative diseases. Meanwhile, miRNA, similarly dysregulated in neurodegenerative diseases and serving as biomarkers, is a primary target for miRNA therapy in neurodegenerative diseases, including AD and PD. Activating or inhibiting dysregulated miRNAs is the main strategy of miRNA therapy during the neurodegenerative disease development. Evidence suggests that the interaction between the Hippo pathway and miRNA can result in widespread biological effects and crosstalk in the occurrence of different types of diseases. However, studies on the interplay between the Hippo pathway and miRNA in neurodegenerative diseases are relatively scarce. In this paper, we predicted the miRNAs related to Hippo pathway through bioinformatics database, and further screened the miRNAs with crosstalk relationship with Hippo signaling pathway through experiments in combination with PubMed. Then, the mechanism of action of Hippo signaling pathway related miRNAs in AD and PD is further elucidated. It is reported that the Hippo pathway and its related miRNA may exert neuroprotective effects by reducing oxidative stress, improving neuroinflammation, stabilizing autophagy levels, maintaining neuronal mitochondrial function, and ameliorating blood-brain barrier dysfunction, thereby delaying the progression of AD and PD. However, research on miRNA directly regulating the Hippo pathway to improve AD and PD is limited, and observations of the Hippo pathway and its related miRNA in other neurodegenerative diseases are scarce. However, considering the regulatory relationship between the Hippo pathway and miRNA in multiple diseases and their respective roles in key mechanisms of neurodegenerative diseases, such as oxidative stress and neuroinflammation, the crosstalk between miRNA and the Hippo pathway holds a crucial regulatory role in the development of neurodegenerative diseases. Thus, the interaction pathways of the Hippo pathway and its related miRNA may be a pivotal avenue for exploring effective therapeutic strategies for neurodegenerative diseases in the future.

Objective To explore the mechanism of treadmill exercise against type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD) based on the regulator effects of exercise on ferroptosis. Methods Eight 8-week-old male m/m mice were used as control group (Con, n=8), and db/db mice of the matched age were randomly divided into T2DM model group (db/db, n=8), exercise group (db+Exe, n=8), p38 mitogen-activated protein kinase (MAPK) inhibitor group (db+SB203580, n=8) and exercise combined with p38 MAPK inhibitor group (db+Exe+SB203580, n=8). After one-week adaptive feeding, the mice in the db+Exe group and db+Exe+SB203580 group underwent moderate intensity treadmill exercise for 40 min/d, 5 d/week lasting 8 weeks. The db+SB203580 group and db+Exe+SB203580 group were treated with SB203580 (a specific inhibitor of p38 MAPK) with a dose of 5 mg/kg, 5 d/week for 8 weeks. And the exercise intervention was performed 2 h later after the intraperitoneal injection of SB203580. The body weight and fasting blood glucose of mice were measured regularly every week during the experiment. After 24 h of the last intervention, the mice were weighted, the liver tissues were taken, weighted and the liver index was calculated. The pathological changes of liver were determined by Oil Red O and hematoxylin-eosin (HE) staining. The levels of blood lipids, liver function, Fe2+ and oxidative stress markers of liver were measured by enzyme linked immunosorbent assay (ELISA). The related mRNA expression levels of lipogenesis and inflammation were evaluated by quantitative reverse transcriptase-mediated PCR (qRT-PCR). The related protein expression levels of lipogenesis and ferroptosis in liver were determined by immunohistochemical (IHC) staining and Western blot. Results The body weight, fasting blood glucose, liver index, blood lipid and transaminase levels in the db/db group were significantly increased compared with the Con group. HE and Oil Red O staining showed severe lipid accumulation and ballooning change in the liver of db/db mice. Biochemical tests showed that Fe2+ and MDA level of liver constitution homogenate increased, while GSH level decreased significantly. The results of qRT-PCR showed that the mRNA levels of MCP-1, IL-6, SREBF1 and ACC1 in liver tissue of db/db mice were all significantly increased. Western blot results showed that the expression levels of SREBF1, ACC1 increased, ferroptosis relative proteins were significantly decreased. The 8 weeks of exercise significantly reduced the rise in body weight, blood glucose, liver index and blood lipid levels in db/db mice. Exercise intervention also alleviated hepatic steatosis and reduced the expression levels of Fe2+, MDA, MCP-1, IL-6, ACC1 and SREBF1, upregulated the expression levels of GSH, NRF2, HO-1, SLC7A11 and GPX4 in liver tissue of db/db mice. The intervention of exercise combined with SB203580 significantly down-regulated the mRNA expression levels of ACC1, MCP-1, IL-6, reduced the levels of Fe2+ and MDA, and up-regulated the level of GSH in db/db mice. Compared with the db+Exe group, the expression of Fe2+, MDA, MCP-1, and SREBF1 in the liver of the db+Exe+SB203580 group mice significantly increased, while the expression level of GSH and expression levels of ferroptosis relative proteins also significantly decreased. In addition, compared with db+SB203580 group, the iron accumulation and lipid peroxidation in the liver of db+Exe+SB203580 group were significantly improved. Conclusion The 8-week treadmill exercise can effectively alleviate liver injury and steatosis, and its mechanism may be related to the inhibition of hepatocyte ferroptosis through p38 MAPK signal.

Overtraining is a condition characterized by various functional disorders or pathological states caused by continuous fatigue, which occurs after a persisting imbalance between training-related load and physical function and recovery. Generally speaking, it's a state of imbalance between training and recovery, exercise and exercise performance, and stress and stress tolerance. Overtraining can cause various phenotypic changes or pathological remodeling, such as decreased skeletal muscle strength and exhaustive exercise endurance, skeletal muscle fatigue damage and dysfunction, skeletal muscle atrophy and loss, skeletal muscle glycogen depletion, skeletal muscle soreness and stiffness, skeletal muscle glucose intolerance, inattention, memory decline, anxiety, depression, abnormal emotions and behaviors, sleep disorders, cognitive function impairment, poor appetite, weight loss, liver/heart fat deposition, compensatory increase of liver/heart insulin signaling and glycogen storage, cardiac pathological hypertrophy, exercise-induced arrhythmias, myocardial fibrosis, ectopic and visceral fat deposition, and increased risk of injury. Unfortunately, its underlying mechanism is largely unclear. Recently, the enrichment of molecular and cellular signal pathway theory offers us a new explanatory paradigm for revealing its internal mechanisms. Based on the traditional explanation mechanisms and molecular and cellular signal pathway theory, we thoroughly analyzed the key mechanisms of health damage caused by overtraining from the perspective of oxidative stress, mitochondrial quality control disorder, inflammatory response, endoplasmic reticulum stress, cell apoptosis, and so forth. Specifically, overtraining-induced excessive reactive oxygen species (ROS) leads to serious oxidative stress damage in organisms at least via depressing Kelch like ECH associated protein 1(Keap1)/nuclear factor erythroid-2-related factor (Nrf2)/antioxidant response element (ARE) antioxidant pathway and activating p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Overtraining induces mitochondrial quality control disorder and mitochondrial dysfunction, and thus triggers health impairment through inhibiting mitochondrial biogenesis and fusion, stimulating mitochondrial fission, and over-activating autophagy/mitophagy. Overtraining can also produce muscle, skeletal and joint trauma, then circulating monocytes are abundantly activated by injury-related cytokines, and in turn generate large quantities of proinflammatory IL-1 (3, IL-6, TNF-alpha, causing systemic inflammation and inflammatory health injury. Overtraining induces excessive pathological endoplasmic reticulum stress (ERS) and severe health damage via PERK-eIF2 alpha, alpha, IRE1 alpha-XBP1 alpha- XBP1 and ATF6 pathways which activated by proinflammatory signals. Overtraining also induces excessive apoptosis and harmful health consequences via Bax/Bcl2-Caspase 3-mediated mitoptosis which activated by oxidative stress and inflammation or even CHOP and Caspase 12-dependent ERS apoptosis. Nonetheless, it should be importantly emphasized that oxidative stress and inflammation are the central and preemptive mechanisms of overtraining and its health damage. Although the efficient strategies for preventing and controlling overtraining are scientifically and reasonably arranging and planning training intensity, training volume, and recovery period, as well as accurately assessing and monitoring physical function status in the early stage, yet various anti-inflammatory, anti-oxidant, anti-apoptotic, or anti-aging drugs such as curcumin, astaxanthin, oligomeric proanthocyanidins, silibinin, hibiscus sabdariffa, dasatinib, quercetin, hydroxytyrosol, complex probiotics, astragalus polysaccharides, semaglutide and fasudil also have an irreplaceable positive effect on preventing overtraining and its relevant health damage via depressing oxidative stress, mitochondrial quality control disorder, proinflammatory signals, endoplasmic reticulum stress, apoptosis and so on. We hope that this review can help us further grasp the features, mechanisms and regularity of overtraining, and provide an important reference for athletes and sports fan to conduct scientific training, improve training effectiveness, extend exercise lifespan, and promote physical and mental health.

Network pharmacology,molecular docking and animal experimental studies were used to investigate the mechanism of dihydromyricetin(DHM)in improving renal fibrosis in type 2 diabetic db/db mice.Initially,a 10-week DHM intervention was observed to ameliorate renal fibrosis in db/db mice.The chemical structure and targets of DHM were further obtained by TCMSP and PharmMapper,and the disease targets were retrieved by DisGeNET database.Venn analysis was performed on DHM targets and disease targets,and the intersection targets were uploaded to the String database to construct the PPI net-work.The'drug-target-disease'network was constructed by Cytoscape software.The GO enrichment analysis and KEGG en-richment analysis of the intersection target genes were performed by the David database.At the same time,the top 10 intersec-tion targets of PPI network were visualized,and the top 5 intersection targets were subjected to molecular docking with DHM using PDB database,Pymol software and AutoDock Tools software.The first core target AKT and related signaling pathways were verified by Western blot.Animal experiments showed that DHM intervention could reduce the body weight of db/db mice and improve the levels of blood glucose,creatinine,urea nitrogen and urine protein in db/db mice.HE,Masson and PAS stai-ning showed that renal fibrosis of db/db mice was alleviated.In addition,a total of 37 intersections of drugs and disease tar-gets were obtained by network pharmacology,300 GO-related items and 108 related pathways were obtained by enrichment a-nalysis.Molecular docking results showed that DHM could spontaneously bind to key targets.Western blot analysis results showed that DHM intervention could reduce the protein expression of Notch1,NICD,Hes1 and Hey1 in the kidney of db/db mice,up-regulate the level of PTEN protein,inhibit the phosphorylation of AKT,thus improve renal fibrosis.Taken together,DHM may alleviate renal fibrosis in db/db mice by regulating Notch/PTEN/AKT pathway.

美国在老年慢性病社区健康管理方面进行了长期实践探索,主要有自然形成退休社区、综合性老人健康护理计划、体验团队3种模式,为我国提供了有益的经验启示:扩大患者服务范围,分类推进病情管理计划;加快医疗体系改革,深入对接社区健康服务;贯通服务应用机制,持续优化健康管理链;汇聚优质平台资源,集中建设慢性病服务窗口.

该文旨在探讨8周跑台运动改善Ⅱ型糖尿病小鼠非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)的作用及分子机制.将SPF级别的8周龄的雄性m/m小鼠作为阴性对照组(Con组),8周龄的雄性db/db小鼠随机分为4组:Ⅱ型糖尿病模型组(db组)、Ⅱ型糖尿病跑台运动组(db+EX组)、Ⅱ型糖尿病跑台运动联合p38MAPK抑制剂组(db+EX+SB203580组)、单纯p38MAPK抑制剂组(db+SB203580组),每组各10只.腹腔注射p38MAPK抑制剂2h后进行跑台运动干预,每天运动干预40min,每周5天,连续8周.通过小鼠体质量、血糖、肝体比、血脂以及HE、油红和Mas-son 染色评价运动干预对 NAFLD 的干预效果.通过Western blot和qRT-PCR测定相关蛋白和mRNA表达水平.结果显示,8周跑台运动可以明显减轻db/db小鼠体质量、血糖、肝体比值的增加,降低小鼠血脂水平.运动干预减少了小鼠肝脏脂肪变性、胶原蛋白沉积及ACC1、SREBF1脂肪从头合成酶的表达水平.单纯p38MAPK抑制剂干预加重了肝脏脂肪变性和胶原蛋白的沉积,而运动联合p38MAPK抑制剂不具有协同作用.与db模型组相比,跑台运动上调了小鼠肝脏和肌肉中FNDC5的蛋白表达水平,同时也增加了小鼠肝脏中FNDC5 mRNA表达水平.跑台运动还降低了db/db小鼠促凋亡蛋白BAX、Caspase8、Caspase9的表达水平,增加了抗凋亡蛋白BCL2的表达水平.除此之外,单纯p38MAPK抑制剂组不仅降低了db/db小鼠肝脏中磷酸化p38蛋白表达水平,同时也降低了db/db小鼠肝脏和腓肠肌中FNDC5蛋白表达水平,继而导致过度的细胞凋亡.运动联合p38MAPK抑制剂干预降低了磷酸化p38蛋白表达水平,但对FNDC5和凋亡相关蛋白没有明显改变.以上结果表明,8周跑台运动可有效缓解Ⅱ型糖尿病小鼠NAFLD,其机制可能是通过p38MAPK依赖途径上调FNDC5表达、降低肝脏纤维化、减轻小鼠肝细胞凋亡的.

2型糖尿病(T2DM)是一种代谢性疾病,易造成认知功能障碍.T2DM小鼠脑内自噬水平与认知功能下降有关.运动可以改善T2DM认知水平,但具体机制仍不清楚.本研究旨在探讨自噬在不同形式的运动干预改善T2DM小鼠认知功能障碍中的作用及分子机制.取雄性4周龄C57BL/6小鼠随机分成:对照组(C)、T2DM模型组(DM)、T2DM运动组和T2DM自噬抑制剂组.T2DM小鼠通过高脂饲养联合腹腔注射STZ造模.运动组采取跑台(T)、爬梯(R)、跑台联合爬梯(M);抑制剂组采用腹腔注射氯喹(CQ)(10 mg/kg),分为T2DM单纯抑制剂组(DM+CQ)、T2DM+CQ+跑台干预组(DM+T+CQ).免疫荧光染色显示,3种运动干预均可降低T2DM小鼠海马组织Iba-1阳性细胞数量及荧光强度(P＜0.05),降低小胶质细胞NLRP3荧光强度(P＜0.05).Western印迹结果显示,3种运动干预均可降低T2DM小鼠海马iNOS、GFAP、Iba-1蛋白质表达,增加Arg-1蛋白质表达,其中M组均有显著性差异(P＜0.05);3种运动干预均可降低T2DM小鼠海马NLRP3复合物蛋白质表达,其中M组均有显著性差异(P＜0.05),T组除NLRP3蛋白外均有显著性差异(P＜0.05);3种运动干预均可降低T2DM小鼠海马Bax、p62蛋白质表达,增加Bcl-2、LC3蛋白质表达,其中M组与T组均有显著性差异(P＜0.05).加入氯喹的水迷宫结果显示,抑制 自噬加重T2DM小鼠认知障碍(P＜0.05),降低运动对T2DM小鼠认知的保护作用;免疫荧光染色及Western印迹显示,DM+T+CQ组较T组存在自噬功能障碍.Western印迹结果显示,与DM组相比,DM+CQ组iNOS、GFAP、NLRP3、切割胱天蛋白酶1(cleaved caspase-1)蛋白质表达增加,Iba-1、胱天蛋白酶1、Bax蛋白质显著增加(P＜0.05);与T组相比,DM+T+CQ组NLRP3、切割胱天蛋白酶1、Bax蛋白质显著增加(P＜0.05),Bcl-2蛋白显著减少(P＜0.05).综上所述,不同形式的运动干预均能改善T2DM小鼠神经炎症及神经细胞凋亡,综合比较,有氧运动和有氧联合抗阻运动干预效果较好,其机制可能是运动激活神经元自噬、降低神经炎症与胶质细胞活化、抑制神经元凋亡.

目的:探讨运动对2型糖尿病模型db/db小鼠肾损伤的保护作用及机制.方法:将8周龄的雄性db/db小鼠随机分为4组:db/db组(n=8)、db/db+跑台运动(Exe)组(n=7)、db/db+Exe+Notch抑制剂二苯并氮?(DBZ)组(n=7)和db/db+DBZ组(n=6);同月龄雄性m/m小鼠作为阴性对照(Con)组(n=10).db/db+DBZ组和db/db+Exe+DBZ组小鼠进行DBZ干预(灌胃8周,每周5 d,0.04 mg/kg),db/db+Exe组和db/db+Exe+DBZ组小鼠进行跑台运动(运动8周,每周5 d;db/db+Exe+DBZ组小鼠在灌胃2 h后进行运动).HE染色和PAS染色评价肾组织形态学变化;Masson染色观察肾组织纤维化程度;试剂盒检测血尿素氮(BUN)和血清肌酐(SCr)水平;Western blot检测肾组织纤维化指标、Notch/PTEN/AKT信号通路相关蛋白和自噬相关蛋白的表达.结果:(1)与Con组相比,db/db组小鼠体重和血糖显著升高(P＜0.01),运动干预后显著降低(P＜0.05).(2)与Con组相比,db/db组小鼠BUN和SCr水平显著升高(P＜0.01),组织学染色显示肾组织损伤加重,运动干预后BUN和SCr水平均显著降低(P＜0.01),肾组织损伤减轻.(3)Western blot结果显示,与db/db组相比,db/db+Exe组Ⅰ型胶原(Col-Ⅰ)和α-平滑肌肌动蛋白(α-SMA)表达显著减少(P＜0.05),Col-Ⅲ和转化生长因子β1(TGF-β1)表达有下降趋势,免疫荧光显示小鼠肾脏中α-SMA、Col-Ⅰ和纤连蛋白荧光染色阳性信号显著减弱;db/db+DBZ组TGF-β1蛋白表达下降(P＜0.01);db/db+Exe+DBZ组Col-Ⅰ、α-SMA、Col-Ⅲ和TGF-β1 蛋白表达有下降趋势,但差异无统计学意义.(4)与db/db组相比,db/db+Exe组和db/db+DBZ组Notch1、Hes1和Hey1表达水平及p-AKT/AKT比值均显著降低(P＜0.05),PTEN蛋白表达上调(P＜0.05),而db/db+Exe+DBZ组Notch1、Hes1、Hey1和p-AKT/AKT蛋白表达无显著差异,PTEN蛋白显著升高(P＜0.01).(5)与db/db组相比,db/db+Exe组和db/db+DBZ组LC3-Ⅱ/LC3-Ⅰ比值显著升高(P＜0.01),p62表达显著减少(P＜0.01);db/db+Exe+DBZ组LC3-Ⅱ/LC3-Ⅰ比值升高(P＜0.01),p62表达无显著差异.(6)与db/db+DBZ组相比,db/db+Exe组Hey1蛋白下调(P＜0.05);与db/db+Exe组相比,db/db+Exe+DBZ组PTEN蛋白上调(P＜0.01).结论:运动减轻db/db小鼠肾功能损伤和肾纤维化,其机制可能与其抑制Notch/PTEN/AKT信号通路而促进细胞自噬有关.

OBJECTIVE: Whole-body vibration training has been widely used in the postoperative rehabilitation after anterior cruciate ligament reconstruction. However,its efficacy remains controversial. In this study, meta-analysis was conducted to systematically evaluate the effect of whole-body vibration training on anterior cruciate ligament reconstruction, in order to provide evidence-based medicine evidence for the clinical use of whole-body vibration training.METHODS: Randomized controlled trials about effects of whole-body vibration training on anterior cruciate ligament reconstruction were electronically searched from PubMed, Embase, The Cochrane Library, Web of Science, EBSCO, CNKI, WanFang, and VIP databases, from inception to July 16, 2022. The outcome measures included five continuous variables: quadriceps peak torque, hamstring peak torque, knee angle recurrence error, Biodex migration index,and Lysholm knee score. The Cochrane Risk Bias Assessment Tool and Jadad Scale were used to evaluate the quality of the included literature, and RevMan 5.3software was used for meta-analysis.RESULTS:（1） Ten randomized controlled trials involving 372 patients with anterior cruciate ligament reconstruction were finally included. The overall quality of the included literature was high.（2） The results of meta-analysis: Compared with the control group, whole-body vibration training significantly improved quadriceps peak torque（SMD=0.75, 95%CI: 0.20 to 1.30, P=0.008） and hamstring peak torque（SMD=0.90, 95%CI: 0.03 to 1.77, P=0.04）, reduced knee angle recurrence error（SMD=-0.60, 95%CI:-1.04 to-0.17, P=0.007） and Biodex migration index（SMD=-0.93, 95%CI:-1.46 to-0.41, P=0.0005）, and improved Lysholm knee score（MD=4.69, 95%CI: 0.79 to 8.60, P=0.02）.CONCLUSION: Whole-body vibration training may help to improve quadriceps peak torque and hamstring peak torque, proprioception and balance function,and knee joint function scale score in patients after anterior cruciate ligament reconstruction.

Abstract Microglial polarization and NRLP3 inflammasome mediated inflammation response are known to be involved in the pathological procession of AD. Ampelopsin, a natural flavonoid compound from Chinese herb Ampelopsis grossedentata, has been reported to have neuroprotective functions. However, there have been no reports on whether DHM suppresses microglial polarization and NLRP3-Caspase-1 inflammasome via autophagy pathway in an Alzheimer’s disease model. We aimed to study the effects of ampelopsin on M1/M2 polarization and the mechanism to regulate anti-inflammation both in vivo and vitro models. BV2 cells were treated with LPS in the presence or absence of DHM, and SAMP8 mice were orally administered 100 or 200 mg/kg/day of DHM for 8 weeks. Our results showed that ampelopsin significantly mitigated cognitive impairment and AD-like pathological proteins（BACE1 and APP）levels in AD mice. Treatment with different dose of ampelopsin efficiently suppressed NLRP3-Caspase-1 inflammasome activation, IL-1β and IL-18 production as well as microglia activation in the hippocampus of SAMP8 mice. Mechanistically, DHM promoted the transition from M1 to M2 microglia by up-regulating SIRT1 signaling. Transmission electron microscopy results further confirmed that DHM reversed impaired autophagy in AD mice. However, CQ, as an autophagy inhibitor, not only blocked the above protective effects of DHM in vivo, but also exacerbated those pathological changes. Our findings reveals activation of autophagic induced by DHM promote M2 polarization, NLRP3 inflammasome degradation, inhibiting inflammatory response, in turn, improving cognitive function in SAMP8 mice.