Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.
Emodin/administration & dosage* ; Bile Acids and Salts/metabolism* ; Animals ; Male ; Liver/injuries* ; Chemical and Drug Induced Liver Injury/genetics* ; Drugs, Chinese Herbal/adverse effects* ; Humans ; Rats, Sprague-Dawley ; Mice ; Rats

In this study, lipopolysaccharide(LPS), ovalbumin(OVA), and compound 48/80(C48/80) were administered to establish non-infectious pneumonia models under simulated clinical conditions, and the correlation between their pathological characteristics and traditional Chinese medicine(TCM) syndromes was compared, providing the basis for the selection of appropriate animal models for TCM efficacy evaluation. An acute pneumonia model was established by nasal instillation of LPS combined with intraperitoneal injection for intensive stimulation. Three doses of OVA mixed with aluminum hydroxide adjuvant were injected intraperitoneally on days one, three, and five and OVA was administered via endotracheal drip for excitation on days 14-18 to establish an OVA-induced allergic pneumonia model. A single intravenous injection of three doses of C48/80 was adopted to establish a C48/80-induced pneumonia model. By detecting the changes in peripheral blood leukocyte classification, lung tissue and plasma cytokines, immunoglobulins(Ig), histamine levels, and arachidonic acid metabolites, the multi-dimensional analysis was carried out based on pathological evaluation. The results showed that the three models could cause pulmonary edema, increased wet weight in the lung, and obvious exudative inflammation in lung tissue pathology, especially for LPS. A number of pyrogenic cytokines, inclading interleukin(IL)-6, interferon(IFN)-γ, IL-1β, and IL-4 were significantly elevated in the LPS pneumonia model. Significantly increased levels of prostacyclin analogs such as prostaglandin E2(PGE2) and PGD2, which cause increased vascular permeability, and neutrophils in peripheral blood were significantly elevated. The model could partly reflect the clinical characteristics of phlegm heat accumulating in the lung or dampness toxin obstructing the lung. The OVA model showed that the sensitization mediators IgE and leukotriene E4(LTE4) were increased, and the anti-inflammatory prostacyclin 6-keto-PGF2α was decreased. Immune cells(lymphocytes and monocytes) were decreased, and inflammatory cells(neutrophils and basophils) were increased, reflecting the characteristics of "deficiency", "phlegm", or "dampness". Lymphocytes, monocytes, and basophils were significantly increased in the C48/80 model. The phenotype of the model was that the content of histamine, a large number of prostacyclins(6-keto-PGE1, PGF2α, 15-keto-PGF2α, 6-keto-PGF1α, 13,14-D-15-keto-PGE2, PGD2, PGE2, and PGH2), LTE4, and 5-hydroxyeicosatetraenoic acid(5S-HETE) was significantly increased, and these indicators were associated with vascular expansion and increased vascular permeability. The pyrogenic inflammatory cytokines were not increased. The C48/80 model reflected the characteristics of cold and damp accumulation. In the study, three non-infectious pneumonia models were constructed. The LPS model exhibited neutrophil infiltration and elevated inflammatory factors, which was suitable for the efficacy study of TCM for clearing heat, detoxifying, removing dampness, and eliminating phlegm. The OVA model, which took allergic inflammation as an index, was suitable for the efficacy study of Yiqi Gubiao formulas. The C48/80 model exhibited increased vasoactive substances(histamine, PGs, and LTE4), which was suitable for the efficacy study and evaluation of TCM for warming the lung, dispersing cold, drying dampness, and resolving phlegm. The study provides a theoretical basis for model selection for the efficacy evaluation of TCM in the treatment of pneumonia.
Animals ; Disease Models, Animal ; Mice ; Pneumonia/genetics* ; Medicine, Chinese Traditional ; Male ; Humans ; Cytokines/immunology* ; Female ; Lipopolysaccharides/adverse effects* ; Lung/drug effects* ; Drugs, Chinese Herbal ; Ovalbumin ; Mice, Inbred BALB C

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors (NETs). Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue (denoted as ¹⁷⁷Lu-EB-TATE) is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs. This study aimed to enhance the in vivo stability, pharmacokinetics, and pharmacodynamics of ¹⁷⁷Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain, resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical, ¹⁷⁷Lu-LNC1010, for PRRT. In preclinical studies, ¹⁷⁷Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts. Thereafter, we presented the first-in-human dose escalation study of ¹⁷⁷Lu-LNC1010 in patients with advanced/metastatic NETs. ¹⁷⁷Lu-LNC1010 was well-tolerated by all patients, with minor adverse effects, and exhibited significant uptake and prolonged retention in tumor lesions, with higher tumor radiation doses than those of ¹⁷⁷Lu-EB-TATE. Preliminary PRRT efficacy results showed an 83% disease control rate and a 42% overall response rate after two ¹⁷⁷Lu-LNC1010 treatment cycles. These encouraging findings warrant further investigations through multicenter, prospective, and randomized controlled trials.

ObjectiveThis study aimed to investigate the effects of 4-week high-intensity interval training (HIIT) on synaptic plasticity in the prefrontal cortex (PFC) of rats exposed to chronic unpredictable mild stress (CUMS), and to explore its potential mechanisms. MethodsA total of 48 male Sprague-Dawley rats were randomly divided into 4 groups: control (C), model (M), control plus HIIT (HC), and model plus HIIT (HM). Rats in groups M and HM underwent 8 weeks of CUMS to establish depression-like behaviors, while groups HC and HM received HIIT intervention beginning from the 5th week for 4 consecutive weeks. The HIIT protocol consisted of repeated intervals of 3 min at high speed (85%-90% maximal training speed, S_max) alternated with one minute at low speed (50%-55% S_max), with 3 to 5 sets per session, conducted 5 d per week. Behavioral assessments and tail-vein blood lactate levels were measured at the end of the 4th and 8th weeks. After the intervention, rat PFC tissues were collected for Golgi staining to analyze synaptic morphology. Enzyme-linked immunosorbent assays (ELISA) were employed to detect brain-derived neurotrophic factor (BDNF), monocarboxylate transporter 1 (MCT1), lactate, and glutamate levels in the PFC, as well as serotonin (5-HT) levels in serum. Additionally, Western blot analysis was conducted to quantify the expression of synaptic plasticity-related proteins, including c-Fos, activity-regulated cytoskeleton-associated protein (Arc), and N-methyl-D-aspartate receptor 1 (NMDAR1). ResultsCompared to the control group (C), the CUMS-exposed rats (group M) exhibited significant reductions in sucrose preference rates, number of grid crossings, frequency of upright postures, and entries into and duration spent in open arms of the elevated plus maze, indicating marked depressive-like behaviors. Additionally, the group M showed significantly reduced dendritic spine density in the PFC, along with elevated levels of c-Fos, Arc, NMDAR1 protein expression, and increased concentrations of lactate and glutamate. Conversely, BDNF and MCT1 contents in the PFC and 5-HT levels in serum were significantly decreased. Following HIIT intervention, rats in the group HM displayed considerable improvement in behavioral indicators compared with the group M, accompanied by significant elevations in PFC MCT1 and lactate concentrations. Furthermore, HIIT notably normalized the expression levels of c-Fos, Arc, NMDAR1, as well as glutamate and BDNF contents in the PFC. Synaptic spine density also exhibited significant recovery. ConclusionFour weeks of HIIT intervention may alleviate depressive-like behaviors in CUMS rats by increasing lactate levels and reducing glutamate concentration in the PFC, thereby downregulating the overexpression of NMDAR, attenuating excitotoxicity, and enhancing synaptic plasticity.

ObjectiveFunctional near-infrared spectroscopy (fNIRS), a novel non-invasive technique for monitoring cerebral activity, can be integrated with upper limb rehabilitation robots to facilitate the real-time assessment of neurological rehabilitation outcomes. The rehabilitation robot is designed with 3 training modes: passive, active, and resistance. Among these, the resistance mode has been demonstrated to yield superior rehabilitative outcomes for patients with a certain level of muscle strength. The control modes in the resistance mode can be categorized into dynamic and static control. However, the effects of different control modes in the resistance mode on the motor function of patients with upper limb hemiplegia in stroke remain unclear. Furthermore, the effects of force, an important parameter of different control modes, on the activation of brain regions have rarely been reported. This study investigates the effects of dynamic and static resistance modes under varying resistance levels on cerebral functional alterations during motor rehabilitation in post-stroke patients. MethodsA cohort of 20 stroke patients with upper limb dysfunction was enrolled in the study, completing preparatory adaptive training followed by 3 intensity-level tasks across 2 motor paradigms. The bilateral prefrontal cortices (PFC), bilateral primary motor cortices (M1), bilateral primary somatosensory cortices (S1), and bilateral premotor and supplementary motor cortices (PM) were examined in both the resting and motor training states. The lateralization index (LI), phase locking value (PLV), network metrics were employed to examine cortical activation patterns and topological properties of brain connectivity. ResultsThe data indicated that both dynamic and static modes resulted in significantly greater activation of the contralateral M1 area and the ipsilateral PM area when compared to the resting state. The static patterns demonstrated a more pronounced activation in the contralateral M1 in comparison to the dynamic patterns. The results of brain network analysis revealed significant differences between the dynamic and resting states in the contralateral PFC area and contralateral M1 area (F=4.709, P=0.038), as well as in the contralateral PM area and ipsilateral M1 area (F=4.218, P=0.049). Moreover, the findings indicated a positive correlation between the activation of the M1 region and the increase in force in the dynamic mode, which was reversed in the static mode. ConclusionBoth dynamic and static resistance training modes have been demonstrated to activate the corresponding brain functional regions. Dynamic resistance modes elicit greater oxygen changes and connectivity to the region of interest (ROI) than static resistance modes. Furthermore, the effects of increasing force differ between the two modes. In patients who have suffered a stroke, dynamic modes may have a more pronounced effect on the activation of exercise-related functional brain regions.

As an important endocrine organ of human body,adipose tissue secrets a large amount of endocrine fac-tors that regulate a variety of physiological functions,and role of adiponectin in cardiovascular system is especially important.At the cellular and molecular level,adiponectin possesses profound anti-inflammatory,anti-oxidative and anti-apoptotic effects,which can reduce various pathogenic factors of cardiovascular diseases(CVD).In ad-vanced stage of CVD,the expression of adiponectin in adipose tissue as well as its circulating level compensatively increased.Therefore,adiponectin has a protective effect on the cardiovascular system,and increased adiponectin level may suggest severe CVD.In this review article,we systematically introduced the role of adiponectin in CVD and discussed its application prospects as a clinical biomarker.

Objective:To observe the effect of sodium cantharidate assisted bevacizumab in the treatment of advanced non-small cell lung cancer patients.Methods:A total of 120 patients with advanced lung adenocarcinoma from January 2021 to December 2023 were divided into two groups,namely the experimental group and the matched group,each consisting of 60 cases.All patients were treated with AP(cisplatin+pemetrexed)chemotherapy,and bevacizumab(7.5 mg/kg)was administered intravenously at the same time as chemotherapy in the matched group,while sodium bengalate(0.5 mg)was added intravenously in the experimental group on the basis of the matched group,and the patients in the two groups were compared with each other in terms of the clinical efficacy of the two groups in a cycle of 21 d,and the changes in the indicators of the immune function,symptoms and scores of adverse reactions were also compared before and after the 4 consecutive cycles of treatment.After 4 consecutive cycles of treatment,we compared the clinical efficacy,immune function indexes,symptoms,and the incidence of adverse reactions.Results:There was no difference in disease control rate(P＞0.05),and the objective response rate was higher than the matched group(P＜0.05);Pretherapy,tthe levels of natural killer(NK)cells,CD4+/CD8+,immunoglobulin(Ig)G and IgA were different between the test and matched group(P＞0.05).Post-treatment,the levels of NK cells,CD4+/CD8+,IgG,and IgA in the experimental group increased,while there was no significant change in the matched group.The experimental group was higher than the matched group(P＜0.05);Pretherapy,there was no difference in VAS and BFI scores between the experimental group and the matched group(P＞0.05).Post-treatment,the scores of the Simplified Fatigue Scale(BFI)and Visual Analog Scale(VAS)in both groups decreased,and the experimental group was lower than the matched group(P＜0.05);The incidence of grade Ⅰ-Ⅱ gastrointestinal reactions,liver and kidney dysfunction,bone marrow suppression,leukopenia,and grade Ⅲ-Ⅳ bone marrow suppression in the experimental group were all lower than those in the matched group(P＜0.05).Conclusion:Sodium cantharidate assisted bevacizumab therapy has a significant effect on non-small cell lung cancer.Compared with single chemotherapy combined with bevacizumab,it can improve the objective remission rate of patients,improve their immune function level,alleviate pain and cancer-related fatigue symptoms,and assist in reducing the incidence of adverse reactions caused by bevacizumab and chemotherapy.

Objective To investigate the effect of arbutin(Arb)on osteogenic differentiation of human periodontal ligament stem cells(hPDLSCs)under inflammatory conditions and the mechanism of NF-κB signaling pathway in this process.Methods The effects of Arb on the proliferation and osteogenic differentiation of hPDLSCs were analyzed by CCK-8,alkaline phosphatase staining,Alizarin Red staining,and Western blot.After establishing an inflammatory model using lipopolysaccharide(LPS),the effect of Arb on the ex-pression levels of inflammatory factors in hPDLSCs was analyzed by RT-qPCR.The effect of Arb on osteogenic differentiation of hP-DLSCs was analyzed,and the effect of Arb on the NF-κB pathway was analyzed by Western blot.After adding the NF-κB signaling pathway activator PMA to the culture system,whether the effect of Arb on hPDLSCs changed was analyzed.Results 100 nmol/L Arb did not affect the proliferation of hPDLSCs,but significantly promoted cell osteogenic differentiation and inhibited the expression of in-flammatory factors under LPS stimulation.Arb reduced the activation effect of LPS on the NF-κB signaling pathway and the inhibitory effect on cell osteogenic differentiation,while the efficacy of Arb was partially eliminated by PMA.Conclusion Arb alleviates the in-hibitory effect of LPS on osteogenic differentiation of hPDLSCs by inhibiting NF-κB signaling.

Aim To explore the relevant mechanisms of isoliquiritigenin(ISL)in inhibiting the proliferation and migration of vascular smooth muscle cells(VSMCs)by regulating the GRB2/ERK signaling pathway.Methods Human primary vascular smooth muscle cells(hVSMCs)were cultured,and stimulated with different concentrations of ISL and fixed concen-trations of growth factors PDGF-BB and EGF,respec-tively.Subsequently,the effect of overexpressing GRB2 on the efficacy of ISL was observed.CCK-8 assay was used to detect cell proliferation;BrdU assay was used to detect DNA synthesis;Western blot was used to de-tect the expression levels of OPN,ICAM-1,VCAM-1,GRB2,ERK1/2,and p-ERK1/2;wound healing assay was used to detect cell migration;transwell assay was used to detect cell invasion.Results Compared with the blank control group and the ISL 20 mg·L-1 group,the PDGF-BB group and the EGF group showed increased cell viability and DNA synthesis,decreased cell migration distance,and increased number of inva-sive cells.Additionally,the expression levels of GRB2 and p-ERK1/2 increased.Compared with the PDGF-BB 40 μg·L-1group or the EGF 10 mg·L-1 group,the ISL drug intervention group showed decreased cell viability and DNA synthesis,increased migration dis-tance of cells,decreased number of invasive cells,and decreased expression levels of GRB2 and p-ERK1/2.Compared with the ISL 20 mg·L-1+PDGF-BB and ISL 20 mg·L-1+EGF groups,the groups with ISL+PDGF-BB+pcDNA-GRB2 group and ISL+EGF+pcDNA-GRB2 group showed increased expression lev-els of GRB2,p-ERK1/2,OPN,ICAM-1,and VCAM-1,increased cell viability and DNA synthesis,decreased migration distance,and increased number of invasive cells.Compared with the ISL+PDGF-BB+pcDNA-GRB2 group and the ISL+EGF+pcDNA-GRB2 group,the pcDNA-GRB2+PDGF-BB group or the pcDNA-GRB2+EGF group showed increased expres-sion levels of GRB2,p-ERK1/2,OPN,ICAM-1,and VCAM-1,increased cell viability and DNA synthesis,decreased migration distance,and increased number of invasive cells.Conclusions Isoliquiritigenin inhibits the proliferation and migration of vascular smooth mus-cle cells by regulating the GRB2/ERK signaling path-way.