OBJECTIVE To explore the improvine mechanism of Yifei xuanfei jiangzhuo formula （YFXF） on vascular dementia （VAD） model rats based on the growth factor receptor-bound protein 2 （GRB2）/extracellular signal-regulated kinase （ERK）/cardiolipin synthase 1 （CRLS1） pathway. METHODS VAD rat model was established by permanent bilateral common carotid artery ligation. Forty-eight successfully modeled rats were randomly divided into the model group （normal saline）， donepezil hydrochloride group （positive control group， 0.2 g/kg）， and YFXF low- and high-dose groups （12.18 and 24.36 g/kg， calculated based on the total amount of crude drug）， respectively. In addition， a sham operation group （normal saline） was set up. There were 12 rats in each group. Daily intragastric administration of drug or normal saline was performed for 30 consecutive days. After the last administration， the spatial cognitive ability of the rats was evaluated， the pathological morphology of the hippocampus was observed， the contents of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） in serum were detected， the expression levels of GRB2/ERK/CRLS1 pathway-related proteins and the mRNA levels of GRB2， CRLS1， NADH dehydrogenase subunit 1（ND1）， Tafazzin （TAZ）， phospholipid scramblase 3（PLSCR3） and the ATP content in hippocampal tissue were measured. RESULTS Compared with the sham operation group， the escape latency of rats in the model group was significantly prolonged （ P ＜0.05）， and the number of crossing platform was significantly reduced （ P ＜0.05）， while the number of pyramidal cells and Nissl bodies in the hippocampus decreased sharply； the content of TNF-α in serum was significantly increased （ P ＜0.05）， and the content of IL-4 was significantly decreased （ P ＜0.05）； the expression levels of GRB2 and CRLS1 proteins， the phosphorylation level of ERK protein， the relative expression levels of GRB2， CRLS1，ND1， TAZ， and PLSCR3 mRNA， and the content of ATP in hippocampal tissue were significantly decreased （ P ＜0.05）. Compared with the model group， the above pathological changes in the hippocampal tissue of each administration group were alleviated， and the quantitative indicators were significantly restored （ P ＜0.05）. CONCLUSIONS YFXF may improve hippocampal neuron injury in VAD rats by activating the GRB2/ERK/CRLS1 pathway, maintaining cardiolipin homeostasis， and improving mitochondrial energy metabolism.

Background Platelet parameters are important indicators of cardiovascular risk, and environmental pollutants such as polychlorinated biphenyls (PCBs) may impair platelet function through oxidative stress. Objective To investigate the differential effects of single and mixed exposure to PCBs on platelet parameters among individuals with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM), and to evaluate the potential modifying role of a healthy lifestyle. Methods This study included 2249 participants (including 707 with NGT, 759 with IFG, and 783 with T2DM). Plasma PCB concentrations were measured using triple quadrupole gaschromatography-tandem mass spectrometry. Generalized linear regression was used to assess the associations between individual PCB congeners and platelet parameters. Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) models were used to evaluate the overall effects of PCBs mixture exposure on platelet parameters across different glycemic states, as well as its interaction with healthy lifestyle score (HLS). Results Generalized linear regression analyses showed significant differences in the effects of PCBs on platelet parameters across different glycemic states (P<0.05). After adjusting for confounders, PCBs mixture exposure was significantly associated with lower platelet counts (PLT) in individuals with NGT (b=−10.60, 95%CI: −16.48, −4.71) and IFG (b=−12.91, 95%CI: −18.90, −6.92), whereas no significant association was observed in individuals with T2DM (P=0.051). Mean platelet volume (MPV) and platelet-large cell ratio (P-LCR) increased significantly with higher PCBs exposure levels across all three groups (P<0.05). BKMR analysis showed a positive association between PCBs mixture exposure and P-LCR, with the strongest association observed in the NGT group. Furthermore, a significant interaction was observed between HLS and PCBs mixture exposure, and a higher HLS attenuated the effects of PCBs on P-LCR. Conclusion Glycemic glycemic states may modify the effects of PCBs on platelets. Individuals with NGT appear more sensitive to PCBs exposure, whereas the T2DM state may attenuate this effect. Moreover, healthy lifestyles, including not smoking, moderate alcohol consumption, maintaining moderate-to-high physical activity, a healthy diet, and an appropriate body mass index (BMI), may mitigate the adverse effects of most PCBs on platelet parameters.

Background Platelet parameters are important indicators of cardiovascular risk, and environmental pollutants such as polychlorinated biphenyls (PCBs) may impair platelet function through oxidative stress. Objective To investigate the differential effects of single and mixed exposure to PCBs on platelet parameters among individuals with normal glucose tolerance (NGT), impaired fasting glucose (IFG), and type 2 diabetes mellitus (T2DM), and to evaluate the potential modifying role of a healthy lifestyle. Methods This study included 2249 participants (including 707 with NGT, 759 with IFG, and 783 with T2DM). Plasma PCB concentrations were measured using triple quadrupole gaschromatography-tandem mass spectrometry. Generalized linear regression was used to assess the associations between individual PCB congeners and platelet parameters. Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) models were used to evaluate the overall effects of PCBs mixture exposure on platelet parameters across different glycemic states, as well as its interaction with healthy lifestyle score (HLS). Results Generalized linear regression analyses showed significant differences in the effects of PCBs on platelet parameters across different glycemic states (P<0.05). After adjusting for confounders, PCBs mixture exposure was significantly associated with lower platelet counts (PLT) in individuals with NGT (b=−10.60, 95%CI: −16.48, −4.71) and IFG (b=−12.91, 95%CI: −18.90, −6.92), whereas no significant association was observed in individuals with T2DM (P=0.051). Mean platelet volume (MPV) and platelet-large cell ratio (P-LCR) increased significantly with higher PCBs exposure levels across all three groups (P<0.05). BKMR analysis showed a positive association between PCBs mixture exposure and P-LCR, with the strongest association observed in the NGT group. Furthermore, a significant interaction was observed between HLS and PCBs mixture exposure, and a higher HLS attenuated the effects of PCBs on P-LCR. Conclusion Glycemic glycemic states may modify the effects of PCBs on platelets. Individuals with NGT appear more sensitive to PCBs exposure, whereas the T2DM state may attenuate this effect. Moreover, healthy lifestyles, including not smoking, moderate alcohol consumption, maintaining moderate-to-high physical activity, a healthy diet, and an appropriate body mass index (BMI), may mitigate the adverse effects of most PCBs on platelet parameters.

OBJECTIVE To investigate the effects and mechanism of Wenpi tongluo kaiqiao formula （WPTL） against neuronal necroptosis in Alzheimer’s disease （AD） mice based on the Z-DNA binding protein 1 （ZBP1）/mixed lineage kinase domain-like protein （MLKL） signaling pathway. METHODS Forty APP/PS1 transgenic AD mice were randomly divided into model group， WPTL low-dose （WPTL-L） group （10.4 g/kg， calculated by the raw medicine）， WPTL high-dose （WPTL-H） group （20.8 g/kg， calculated by the raw medicine） and donepezil hydrochloride group （3 mg/kg）， with 10 mice in each group； another 10 C57BL/6J mice were selected as normal control group. Intragastric administration， once a day， for 30 consecutive days. Twenty-four hours after the last administration， Morris water maze test was performed to evaluate learning and memory abilities； the pathological morphology of hippocampal tissues was observed； the serum levels of tumor necrosis factor-α （TNF-α） and interleukin-4 （IL-4） were determined； the expressions of amyloid precursor protein （APP）， Tau protein， and ZBP1/MLKL signaling pathway-related proteins in hippocampal tissues were detected； the positive expression of phosphorylated receptor-interacting protein kinase 3 （p-RIPK3） in the neurons of hippocampal tissues and mRNA expression of ZBP1 were measured in hippocampal tissues. RESULTS Compared with normal control group， the escape latency of mice in model group was prolonged significantly on day 3 to 5 （P＜0.05）， the times of crossing platform reduced significantly （P＜0.05）， and obvious pathological changes were observed in the hippocampal tissue. The level of TNF- α， the expressions of APP， p-Tau and ZBP1， the phosphorylation levels of RIPK1， RIPK3 and MLKL， the fluorescence intensity of p-RIPK3 as well as the mRNA expression of ZBP1 were significantly increased （P＜0.05）， while the serum level of IL-4 was decreased significantly （P＜0.05）. Compared with model group， above indexes were reversed significantly in administration groups （P＜0.05）， and pathological damage of hippocampal tissue was alleviated. CONCLUSIONS WPTL can inhibit the ZBP1/MLKL signaling pathway， reduce neuronal necroptosis in AD mice， and inhibit inflammatory responses， thereby improving learning and spatial memory abilities in AD mice.

The most common medications for the treatment of zoonotic toxoplasmosis are pyrimethamine and sulfadiazine, which may cause serious undesirable side effects. Thus, there is an urgent need to develop novel therapeutics. Baicalein (BAI, C₁₅H₁₀O₅) has been shown to perform well against protozoan parasites including Leishmania and Cryptosporidium. In this study, the inhibition efficacy of BAI on Toxoplasma gondii was evaluated using plaque, invasion, and intracellular proliferation assays. BAI effectively inhibited T. gondii (half-maximum inhibitory concentration (IC₅₀)=6.457×10^-5 mol/L), with a reduced invasion rate (33.56%) and intracellular proliferation, and exhibited low cytotoxicity (half-maximum toxicity concentration (TC₅₀)=5.929×10^-4 mol/L). Further investigation using a mouse model shed light on the inhibitory efficacy of BAI against T. gondii, as well as the potential mechanisms underlying its anti-parasitic effects. The survival time of T. gondii-infected ICR mice treated with BAI was remarkably extended, and their parasite burdens in the liver and spleen were greatly reduced compared with those of the negative control group. Histopathological examination of live sections revealed effective therapeutic outcomes in the treatment groups, with no notable pathological alterations observed. Furthermore, alterations in cytokine levels indicated that BAI not only effectively suppressed the growth of T. gondii but also prevented excessive inflammation in mice. Collectively, these findings underscore the significant inhibitory efficacy of BAI against T. gondii, positioning it as a promising alternative therapeutic agent for toxoplasmosis.
Animals ; Toxoplasma/drug effects* ; Flavanones/therapeutic use* ; Mice ; Antiparasitic Agents/therapeutic use* ; Mice, Inbred ICR ; Toxoplasmosis/drug therapy* ; Female

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic inflammation of the gastrointestinal tract with unknown etiology. The cause of IBD is widely considered multifactorial, with prevailing hypotheses suggesting that the microbiome and various environmental factors contribute to inappropriate activation of the mucosal immune system in genetically susceptible individuals. Although the incidence of IBD has stabilized in Western countries, it is rapidly increasing in newly industrialized countries, particularly China, making IBD a global disease. Significant changes in multiple biomarkers before IBD diagnosis during the preclinical phase provide opportunities for earlier diagnosis and intervention. Advances in technology have driven the development of telemonitoring tools, such as home-testing kits for fecal calprotectin, serum cytokines, and therapeutic drug concentrations, as well as wearable devices for testing sweat cytokines and heart rate variability. These tools enable real-time disease activity assessment and timely treatment strategy adjustments. A wide range of novel drugs for IBD, including interleukin-23 inhibitors (mirikizumab, risankizumab, and guselkumab) and small-molecule drugs (etrasimod and upadacitinib), have been introduced in the past few years. Despite these advancements, approximately one-third of patients remain primary non-responders to the initial treatment, and half eventually lose response over time. Precision medicine integrating multi-omics data, advanced combination therapy, and complementary approaches, including stem cell transplantation, psychological therapies, neuromodulation, and gut microbiome modulation therapy, may offer solutions to break through the therapeutic ceiling.
Humans ; Inflammatory Bowel Diseases/therapy*

To investigate the mechanism of action of Syngnathus extract in treating knee osteoarthritis of rats, forty-eight male SD rats were randomly divided into the blank group, model group, positive drug group, as well as low-dose, medium-dose, and high-dose groups of Syngnathus extract. The rat model of knee osteoarthritis was constructed by intra-articular injection of sodium iodoacetate. After successful modeling, celecoxib(18 mg·kg~(-1)·d~(-1)) and Syngnathus extract(0.4, 0.8, and 1.6 g·kg~(-1)·d~(-1)) were given in different groups by gavage intervention for two weeks. Hematoxylin-eosin(HE) staining was used to observe the histopathological changes of cartilage in knee joints, and enzyme-linked immunosorbent assay(ELISA) was used to detect the expression level of inflammatory factors in serum. Real-time fluorescence quantitative PCR, Western blot, and immunohistochemistry were used to detect the levels of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target protein of rapamycin(mTOR) pathway-related mRNA and protein expression. The results showed that, comparied with the blank group, the cartilage surface of the knee joints of rats in the model group was uneven, with disorganized levels and defective cartilage tissue. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) and the mRNA levels of PI3K, Akt, and mTOR in cartilage tissue, as well as the protein expression levels of phosphorylated PI3K(p-PI3K)/PI3K, phosphorylated Akt(p-Akt)/Akt, phosphorylated mTOR(p-mTOR)/mTOR, and P62 were significantly increased. Beclin1 protein expression was decreased. Comparied with the model group, the number of chondrocytes in the knee joint of rats in each group of Syngnathus extract increased, and the arrangement of chondrocytes was relatively neat. The cartilage layer was restored, and the serum levels of IL-1β, IL-6, and TNF-α, as well as the mRNA expression levels of PI3K, Akt, and mTOR in cartilage tissue were significantly reduced. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, and P62 were significantly reduced in the rats in the middle-dose and high-dose groups of Syngnathus extract, and the Beclin1 protein expression was significantly increased. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, and P62 in rats in the low-dose group of Syngnathus extract were significantly reduced. In summary, Syngnathus extract may be used to treat knee osteoarthritis by inhibiting the expression of PI3K/Akt/mTOR signaling pathway, so as to alleviate the inflammatory response in the organism, enhance the autophagy activity of chondrocytes, and reduce the apoptosis of chondrocytes.
Animals ; TOR Serine-Threonine Kinases/genetics* ; Male ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Rats ; Osteoarthritis, Knee/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Phosphatidylinositol 3-Kinases/genetics* ; Humans

This paper aimed to investigate the therapeutic effect and mechanism of action of the Yiqi Fumai Formula(YQFM), a kind of traditional Chinese medicine(TCM), on mice with experimental heart failure based on the "heart-gut axis" theory. Based on the network pharmacology integrated with the group collaboration algorithm, the active ingredients were screened, a "component-target-disease" network was constructed, and the potential pathways regulated by the formula were predicted and analyzed. Next, the model of experimental heart failure was established by intraperitoneal injection of adriamycin at a single high dose(15 mg·kg~(-1)) in BALB/c mice. After intraperitoneal injection of YQFM(lyophilized) at 7.90, 15.80, and 31.55 mg·d~(-1) for 7 d, the protective effects of the formula on cardiac function were evaluated using indicators such as ultrasonic electrocardiography and myocardial injury markers. Combined with inflammatory factors in the cardiac and colorectal tissue, as well as targeted assays, the relevant indicators of potential pathways were verified. Meanwhile, 16S rDNA sequencing was performed on mouse fecal samples using the Illumina platform to detect changes in gut flora and analyze differential metabolic pathways. The results show that the administration of injectable YQFM(lyophilized) for 7 d significantly increased the left ventricular end-systolic internal diameter, fractional shortening, and ejection fraction of cardiac tissue of mice with experimental heart failure(P<0.05). Moreover, markers of myocardial injury were significantly decreased(P<0.05), indicating improved cardiac function, along with significantly suppressed inflammatory responses in cardiac and intestinal tissue(P<0.05). Additionally, the species of causative organisms was decreased, and the homeostasis of gut flora was improved, involving a modulatory effect on PI3K-Akt signaling pathway-related inflammation in cardiac and colorectal tissue. In conclusion, YQFM can affect the "heart-gut axis" immunity through the homeostasis of the gut flora, thereby exerting a therapeutic effect on heart failure. This finding provides a reference for the combination of TCM and western medicine to prevent and treat heart failure based on the "heart-gut axis" theory.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Heart Failure/microbiology* ; Mice ; Mice, Inbred BALB C ; Male ; Disease Models, Animal ; Gastrointestinal Microbiome/drug effects* ; Heart/physiopathology* ; Humans ; Signal Transduction/drug effects*

This study predicts the potential mechanism of Hippocampus in the treatment of knee osteoarthritis(KOA) through network pharmacology, with preliminary verification using molecular docking and animal experiments. The database was used to screen the active chemical components of Hippocampus and the targets of KOA, and Gene Ontology(GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and molecular docking were performed on the relevant core targets to preliminarily explore the potential targets and mechanisms of Hippocampus in the treatment of KOA. A rat KOA model was constructed by intra-articular injection of sodium iodoacetate, and the rats were intervened with different doses of Hippocampus decoction and celecoxib. The expression of relevant targets was detected through hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), RT-qPCR, and Western blot to further validate the network pharmacology results. A total of 23 drug-like components of the Hippocampus were screened, and 128 common targets with KOA were identified, involving interleukin-17(IL-17) signaling pathway, transcription factor(FoxO) signaling pathway, tumor necrosis factor(TNF) signaling pathway. Molecular docking results showed that the screened core chemical components exhibited good affinity with key targets. HE staining demonstrated that Hippocampus improved the morphology of the cartilage layer. ELISA confirmed that Hippocampus significantly reduced the levels of IL-6 and TNF-α in the serum of KOA rats. Western blot and RT-qPCR analysis showed that Hippocampus significantly reduced the expression of IL-6, TNF-α, matrix metalloproteinase(MMP) 13, IL-17A, nuclear factor κB activator 1(ACT1), tumor necrosis factor receptor-associated factor 6(TRAF6) and nuclear factor κB(NF-κB) in cartilage tissue. The results suggest that Hippocampus can alleviate the degree of joint damage in the KOA rat model induced by sodium iodoacetate. The mechanism of action is related to the inhibition of the IL-17 signaling pathway, reduction of inflammation, and inhibition of extracellular matrix(ECM) degradation.
Animals ; Molecular Docking Simulation ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Network Pharmacology ; Male ; Osteoarthritis, Knee/metabolism* ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Humans ; Interleukin-17/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Disease Models, Animal ; Hippocampus/chemistry*

OBJECTIVE: To explore clinical efficacy of autologous platelet-rich plasma(PRP) in treating Rockwood type Ⅲ acromioclavicular dislocation. METHODS: From January 2019 to July 2021, 32 patients with Rockwood type Ⅲ acromioclavicular dislocation were treated with minimally invasive adjustable titanium plate internal fixation, and were divided into PRP group and control group according to whether PRP treatment was performed, with 16 patients in each group. In PRP group, there were 10 males and 6 females, aged from 28 to 47 years old with an average of (36.75±7.14) years old;the time from injury to surgery ranged from 1 to 31 h with an average of (26.13±3.98) h;5 patients on the left side and 11 patients on the right side;PRP was injected once during operation and the 4th and 8th weeks after operation respectively. In control group, there were 8 males and 8 females, aged from 30 to 52 years old with an average of (38.50±5.48) years old; the time from injury to surgery ranged from 1 to 29 h with an average of (25.48±3.11) h;7 patients on the left side and 9 patients on the right side; minimally invasive surgical treatment was performed. Visual analogue scale(VAS) was used to evaluate pain and Constant-Murley score for shoulder joint function was used to evaluate the recovery of shoulder joint movement function before operation and 1, 3, 6, and 12 months after operation respectively. RESULTS: All patients were followed up for 12 to 28 months with an average of (18.3±5.2) months. All incisions patients healed well without adverse events such as infection. Postoperative VAS of PRP group at 1, 3, and 6 months were (5.5±1.2), (3.7±1.6), and (2.4±1.2), respectively, while were lower than those of control group (6.6±1.4), (4.9±1.1), and (3.7±1.3), respectively;and had statistical differences between two groups (P<0.05). There was no statistically significant difference in VAS between two groups before operation and 12 months after operation (P>0.05). Postoperative Constant-Murley scores of PRP group at 1, 3, and 6 months were (64.09±11.61), (73.19±12.89), and (82.61±14.81) points, respectively, which were higher than those of control group were (52.32±17.42), (61.65±14.43), and (72.52±11.04) respectively;and the differences were statistically significant (P<0.05). There was no statistically significant difference in Constant-Murley scores at 12 months after operation between two groups (P>0.05). In PRP group, there was no statistically significant difference at 6 months and 12 months after operation (P>0.05), while there were statistically significant differences at the other time points (1 month after operation compared with before operation, 3 months after operation compared with 6 months after operation, and 3 months after operation compared with 1 month after operation) (P<0.05). In control group, there was no statistically significant difference when comparing 1 month and 3 months after operation (P>0.05), while at the other time points (1 month after operation with before operation, 3 months after operation with 6 months after operation, and 6 months after operation with 12 months after operation), the differences were all statistically significant (P<0.05). CONCLUSION Adjustable titanium plate fixation combined with postoperative injection of PRP for the treatment of Rockwood type III acromioclavicular joint dislocation has effect of promoting the recovery of shoulder joint function and reducing pain.
Humans ; Male ; Female ; Adult ; Middle Aged ; Platelet-Rich Plasma ; Acromioclavicular Joint/surgery* ; Bone Plates ; Titanium ; Joint Dislocations/therapy* ; Fracture Fixation, Internal/methods*