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Introduction: Despite the clinical value of Chinese herbal medicine (CHM), restricted comprehension of its toxicity limits the secure and efficacious application. Previous studies primarily focused on exploring specific toxicities within CHM, without providing an overview of CHM’s toxicity. The absence of a quantitative assessment of focal points renders the future research trajectory ambiguous. Therefore, this study aimed to reveal research trends and areas of concern for the past decade.Methods: A cross-sectional study was conducted on publications related to CHM and toxicity over the past decade from Web of Science Core Collection database. The characteristics of the publication included publication year, journal, institution, funding, keywords, and citation counts were recorded. Co-occurrence analysis and trend topic analysis based on bibliometric analysis were conducted on keywords and citations.Results: A total of 3,225 publications were analyzed. Number of annal publications increased over the years, with the highest number observed in 2022 (n = 475). The Journal of Ethnopharmacology published the most publications (n = 425). The most frequently used toxicity classifications in keywords were hepatotoxicity (n = 119) or drug-induced liver injury (n = 48), and nephrotoxicity (n = 40). Co-occurrence analysis revealed relatively loose connections between CHM and toxicity, and their derivatives. Keywords emerging from trend topic analysis for the past 3 years (2019–2022) included ferroptosis, NLRP3 inflammasome, machine learning, network pharmacology, traditional uses, and pharmacology.Conclusion: Concerns about the toxicity of CHM have increased in the past decade. However, there remains insufficient studies that directly explore the intersection of CHM and toxicity. Hepatotoxicity and nephrotoxicity, as the most concerned toxicity classifications associated with CHM, warrant more in-depth investigations. Apoptosis was the most concerned toxicological mechanism. As a recent increase in attention, exploring the mechanisms of ferroptosis in nephrotoxicity and NLRP3 inflammasome in hepatotoxicity could provide valuable insights. Machine learning and network pharmacology are potential methods for future studies.

Background: Captisol®-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium.Objective: We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx®), and phenytoin sodium (intravenous injection only).Methods: In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, n = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug.Results: T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98–1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their Cmax was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2.Conclusion: CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes’s impairment of spatial learning memory.Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines.Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide.Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Background and ethnopharmacological relevance: The morbidity and mortality of cardiovascular diseases (CVDs) are among the highest of all diseases, necessitating the search for effective drugs and the improvement of prognosis for CVD patients. Paeoniflorin (5beta-[(Benzoyloxy)methyl] tetrahydro-5-hydroxy-2-methyl-2,5-methano-1H-3,4-dioxacyclobuta [cd] pentalen-1alpha (2H)-yl-beta-D-glucopyranoside, C23H28O11) is mostly derived from the plants of the family Paeoniaceae (a single genus family) and is known to possess multiple pharmacological properties in the treatment of CVDs, making it a promising agent for the protection of the cardiovascular system.Aim of the study: This review evaluates the pharmacological effects and potential mechanisms of paeoniflorin in the treatment of CVDs, with the aim of advancing its further development and application.Methods: Various relevant literatures were searched in PubMed, ScienceDirect, Google Scholar and Web of Science. All eligible studies were analyzed and summarized in this review.Results: Paeoniflorin is a natural drug with great potential for development, which can protect the cardiovascular system by regulating glucose and lipid metabolism, exerting anti-inflammatory, anti-oxidative stress, and anti-arteriosclerotic activities, improving cardiac function, and inhibiting cardiac remodeling. However, paeoniflorin was found to have low bioavailability, and its toxicology and safety must be further studied and analyzed, and clinical studies related to it must be carried out.Conclusion: Before paeoniflorin can be used as an effective therapeutic drug for CVDs, further in-depth experimental research, clinical trials, and structural modifications or development of new preparations are required.

COVID-19-associated acute kidney injury (COVID-19 AKI) is an independent risk factor for in-hospital mortality and has the potential to progress to chronic kidney disease. Prunella vulgaris L., a traditional Chinese herb that has been used for the treatment of a variety of kidney diseases for centuries, could have the potential to treat this complication. In this study, we studied the potential protective role of Prunella vulgaris in COVID-19 AKI and explored its specific mechanisms applied by network pharmacology and bioinformatics methods. The combination of the protein-protein interaction network and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment -target gene network revealed eight key target genes (VEGFA, ICAM1, IL6, CXCL8, IL1B, CCL2, IL10 and RELA). Molecular docking showed that all these eight gene-encoded proteins could be effectively bound to three major active compounds (quercetin, luteolin and kaempferol), thus becoming potential therapeutic targets. Molecular dynamics simulation also supports the binding stability of RELA-encoded protein with quercetin and luteolin. Together, our data suggest that IL6, VEGFA, and RELA could be the potential drug targets by inhibiting the NF-κB signaling pathway. Our in silico studies shed new insights into P. vulgaris and its ingredients, e.g., quercetin, as potential botanical drugs against COVID-19 AKI, and warrant further studies on efficacy and mechanisms.

Atherosclerosis (AS) is the main cause of cardiovascular disease (CVD) and is characterized by endothelial damage, lipid deposition, and chronic inflammation. Gut microbiota plays an important role in the occurrence and development of AS by regulating host metabolism and immunity. As human mitochondria evolved from primordial bacteria have homologous characteristics, they are attacked by microbial pathogens as target organelles, thus contributing to energy metabolism disorders, oxidative stress, and apoptosis. Therefore, mitochondria may be a key mediator of intestinal microbiota disorders and AS aggravation. Microbial metabolites, such as short-chain fatty acids, trimethylamine, hydrogen sulfide, and bile acids, also affect mitochondrial function, including mtDNA mutation, oxidative stress, and mitophagy, promoting low-grade inflammation. This further damages cellular homeostasis and the balance of innate immunity, aggravating AS. Herbal medicines and their monomers can effectively ameliorate the intestinal flora and their metabolites, improve mitochondrial function, and inhibit atherosclerotic plaques. This review focuses on the interaction between gut microbiota and mitochondria in AS and explores a therapeutic strategy for restoring mitochondrial function and intestinal microbiota disorders using herbal medicines, aiming to provide new insights for the prevention and treatment of AS.

Enterovirus 71 (EV71) is the major cause of severe hand, foot, and mouth disease (HFMD). Compared to other HFMD pathogens, like coxsackievirus A16 (CVA16), EV71 can invade the central nervous system and cause permanent damage. At present, there are no available antivirals against EV71 for clinical treatment. Herein, multiple Chinese botanical drugs were collected, and 47 types of botanical extracts were extracted using aqueous solutions and organic solvents. Based on the cytopathic effect inhibition assay, petroleum ether extract of Tournefortia sibirica L. (PE-TS) demonstrated 97.25% and 94.75% inhibition rates for EV71 infection (at 250 μg/ml) and CVA16 infection (at 125 μg/ml), respectively, with low cytotoxicity. Preliminary mechanistic studies showed that PE-TS inhibits replication of EV71 genomic RNA and synthesis of the EV71 protein. The released extracellular EV71 progeny virus titer decreased by 3.75 lg under PE-TS treatment. Furthermore, using a newborn mouse model, PE-TS treatment protected 70% and 66.7% of mice from lethal dose EV71 intracranial challenge via administration of intraperitoneal injection at 0.4 mg/g and direct lavage at 0.8 mg/g, respectively. The chemical constituents of the PE-TS were analyzed by Gas Chromatography-Mass Spectrometer (GC-MS), and a total of 60 compounds were identified. Compound-target network analysis and molecular docking implied potential bioactive compounds and their protein targets against EV71 associated pathology. The present study identified antiviral effects of PE-TS against EV71/CVA16 infection in vitro and EV71 infection in vivo, providing a potential antiviral botanical drug extract candidate for HFMD drug development.

Background: With the development of fiberoptic bronchoscopy in the diagnosis and treatment of various pulmonary diseases, the anesthesia/sedation requirements are becoming more demanding, posing great challenges for patient safety while ensuring a smooth examination/surgery process. Remimazolam, a brand-new ultra-short-acting anesthetic, may compensate for the shortcomings of current anesthetic/sedation strategies in bronchoscopy.Methods: This study was a prospective, multicenter, randomized, double-blind, parallel positive controlled phase 3 clinical trial. Subjects were randomized to receive 0.2 mg/kg remimazolam besylate or 2 mg/kg propofol during bronchoscopy to evaluate the efficacy and safety of remimazolam.Results: A total of 154 subjects were successfully sedated in both the remimazolam group and the propofol group, with a success rate of 99.4% (95%CI of the adjusted difference −6.7 × 10%–6% to −5.1 × 10%–6%). The sedative effect of remimazolam was noninferior to that of propofol based on the prespecified noninferiority margin of −5%. Compared with the propofol group, the time of loss of consciousness in the remimazolam group (median 61 vs. 48s, p < 0.001), the time from the end of study drug administration to complete awakening (median 17.60 vs. 12.80 min, p < 0.001), the time from the end of bronchoscopy to complete awakening (median 11.00 vs. 7.00 min, p < 0.001), the time from the end of study drug administration to removal of monitoring (median 19.50 vs. 14.50 min, p < 0.001), and the time from the end of bronchoscopy to removal of monitoring (median 12.70 vs. 8.60 min, p < 0.001) were slightly longer. The incidence of Adverse Events in the remimazolam group and the propofol group (74.8% vs. 77.4%, p = 0.59) was not statistically significant, and none of them had Serious Adverse Events. The incidence of hypotension (13.5% vs. 29.7%, p < 0.001), hypotension requiring treatment (1.9% vs. 7.7%, p = 0.017), and injection pain (0.6% vs. 16.8%, p < 0.001) were significantly lower in the remimazolam group than in the propofol group.Conclusion: Moderate sedation with 0.2 mg/kg remimazolam besylate is effective and safe during bronchoscopy. The incidence of hypotension and injection pain was less than with propofol, but the time to loss of consciousness and recovery were slightly longer.Clinical Trial Registration:clinicaltrials.gov, ChiCTR2000039753

Cerebralvascular diseases are the most common high-mortality diseases worldwide. Despite its global prevalence, effective treatments and therapies need to be explored. Given that oxidative stress is an important risk factor involved with cerebral vascular diseases, natural antioxidants and its derivatives can be served as a promising therapeutic strategy. Resveratrol (3, 5, 4′-trihydroxystilbene) is a natural polyphenolic antioxidant found in grape skins, red wine, and berries. As a phytoalexin to protect against oxidative stress, resveratrol has therapeutic value in cerebrovascular diseases mainly by inhibiting excessive reactive oxygen species production, elevating antioxidant enzyme activity, and other antioxidant molecular mechanisms. This review aims to collect novel kinds of literature regarding the protective activities of resveratrol on cerebrovascular diseases, addressing the potential mechanisms underlying the antioxidative activities and mitochondrial protection of resveratrol. We also provide new insights into the chemistry, sources, and bioavailability of resveratrol.

Atherosclerotic cardiovascular diseases (ASCVDs) are the most important diseases that endanger people’s health, leading to high morbidity and mortality worldwide. In addition, various thrombotic events secondary to cardiovascular and cerebrovascular diseases need must be considered seriously. Therefore, the development of novel anti-platelet drugs with high efficiency, and fewer adverse effects has become a research focus for preventing of cardiovascular diseases (CVDs). Blood-activation and stasis-removal from circulation have been widely considered as principles for treating syndromes related to CVDs. Blood-activating Chinese (BAC botanical drugs, as members of traditional Chinese medicine (TCM), have shown to improve hemodynamics and hemorheology, and inhibit thrombosis and atherosclerosis. Modern medical research has identified that a combination of BAC botanical drugs and anti-platelet drugs, such as aspirin or clopidogrel, not only enhances the anti-platelet effects, but also reduces the risk of bleeding and protects the vascular endothelium. The anti-platelet mechanism of Blood-activating Chinese (BAC) botanical drugs and their compounds is not clear; therefore, their potential targets need to be explored. With the continuous development of bioinformatics and “omics” technology, some unconventional applications of BAC botanical drugs have been discovered. In this review, we will focus on the related targets and signaling pathways of anti-atherosclerotic treatments involving a combination of BAC botanical drugs and anti-platelet drugs reported in recent years.

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects.Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25–200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions.Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33–0.50 h and 0.62–0.75 h, respectively, and their mean half-life was 2.5–12.3 h and 49.7–53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC).Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients.Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

Background: The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults.Objective: This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs) safety, tolerability, and immunogenicity of single ascending subcutaneous injections of QX002N in healthy Chinese volunteers.Methods: A total of 65 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled, single ascending dose phase I study (10–320 mg). Ten subjects were allocated to each cohort (containing 8 subjects treated with QX002N and 2 with placebo), except cohort 1 (only 4 subjects treated with QX002N and 1 with placebo). The studies on PKs, PDs, tolerability, and immunogenicity of QX002N were performed.Results: Our study showed that QX002N injection was well tolerated, without deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). Neither more frequency nor high severity of the drug-related adverse reaction was observed with increasing QX002N dose. The TEAEs in all subjects were considered Grades 1–2 (CTCAE 5.0) except for one case of Grade 3 (hypertriglyceridemia). Tmax of QX002N was obtained from 168 to 240 h across the dose range after administration. The Cmax and area under the curve of QX002N increased in proportion to dose, and showed linear PKs. Anti-drug antibody positivity was detected in one (1.9%) subject after drug administration.Conclusion: QX002N was well tolerated in our study. Based on the PKs and safety results of QX002N, 80 mg is recommended as the effective dose for a future phase Ib study.Clinical Trial Registration: https://www.chinadrugtrials.org.cn/, identifier ChiCTR1900023040.

Atherosclerotic thrombotic disease continues to maintain a high morbidity and mortality rate worldwide at present. Aspirin, which is reckoned as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVDs), has been applied in clinics extensively. However, cardiovascular events continue to occur even though people utilize aspirin appropriately. Therefore, the concept of aspirin resistance (AR) was put forward by scholars, which is of great significance for the prediction of the clinical outcome of diseases. The pathogenesis of AR may be incorporated with low patient compliance, insufficient dose, genetic polymorphism, increased platelet transformation, inflammation, and the degenerative changes and calcification of platelets. The improvement of AR in the treatment of ASCVDs has gradually become a research hot spot in recent years. Traditional Chinese medicine (TCM) regards individuals as a whole and treats them from a holistic view, which has been found to have advantages in clinical studies on the treatment of AR. Many kinds of blood-activating TCM have the effect of improving AR. The potential mechanism for the improvement of AR by blood-activating herbs combined with aspirin was explored. The combination of blood-activating herbs and aspirin to improve AR is likely to turn into a hot topic of research in the future.

Purpose: The aim of this study is i) to establish a strategy to estimate the area under the curve of the dosing interval (AUC0–12h) of mycophenolic acid (MPA) in the heart transplant recipients and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure.Methods: This single-center, prospective, open-label, observational study was conducted in 91 adult heart transplant recipients orally taking mycophenolate mofetil dispersible tablets. Samples collected intensively and sparsely were analyzed by the enzyme-multiplied immunoassay technique, and all the data were used in PPK modeling. Potential covariates were tested stepwise. The goodness-of-fit plots, the normalized prediction distribution error, and prediction-corrected visual predictive check were used for model evaluation. Optimal sampling times by ED-optimal strategy and multilinear regression (MLR) were analyzed based on the simulated data by the final PPK model. Moreover, using intensive data from 14 patients, the accuracy of AUC0–12h estimation was evaluated by Passing–Bablok regression analysis and Bland–Alman plots for both the PPK model and MLR equation.Results: A two-compartment model with first-order absorption and elimination with a lag time was chosen as the structure model. Co-medication of proton pump inhibitors (PPIs), estimated glomerular filtration rate (eGFR), and albumin (ALB) were found to significantly affect bioavailability (F), clearance of central compartment (CL/F), and the distribution volume of the central compartment (V2/F), respectively. Co-medication of PPIs decreased F by 27.6%. When eGFR decreased by 30 ml/min/1.73 m2, CL/F decreased by 23.7%. However, the impact of ALB on V2/F was limited to MPA exposure. The final model showed an adequate fitness of the data. The optimal sampling design was pre-dose and 1 and 4 h post-dose for pharmacokinetic estimation. The best-fit linear equation was finally established as follows: AUC0–12h = 3.539 × C0 + 0.288 × C0.5 + 1.349 × C1 + 6.773 × C4.5.Conclusion: A PPK model was established with three covariates in heart transplant patients. Co-medication of PPIs and eGFR had a remarkable impact on AUC0–12h of MPA. A linear equation was also concluded with four time points as an alternative way to estimate AUC0–12h for MPA.

Troxerutin (TRX), a semi-synthetic derivative of the natural bioflavonoid rutin, is a bioactive flavonoid widely abundant in various fruits and vegetables. Known as vitamin P4, TRX has been demonstrated to have several activities including anti-inflammation, anti-oxidants, vasoprotection, and immune support in various studies. Although rutin, the precursor of troxerutin, was reported to have a protective role against bone loss, the function of TRX in skeletal system remains unknown. In the present study, we found that TRX promoted osteogenic differentiation of human mesenchymal stem cells (MSCs) in a concentration-dependent manner by stimulating the alkaline phosphatase (ALP) activity, calcium nodule formation and osteogenic marker genes expression in vitro. The further investigation demonstrated that TRX stimulated the expression of the critical transcription factor β-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/β-catenin signaling. Using a femur fracture rats model, TRX was found to stimulate new bone formation and accelerate the fracture healing in vivo. Collectively, our data demonstrated that TRX could promote osteogenesis in vitro and facilitate the fracture healing in vivo, indicating that TRX may be a promising therapeutic candidate for bone fracture repair.

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer’s disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects.Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples.Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4–12 h), t1/2 of 10–60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (

Atherosclerosis (AS), especially atherosclerotic cardiovascular diseases (ASCVDs), and metabolic diseases (such as diabetes, obesity, dyslipidemia, and nonalcoholic fatty liver disease) are major public health issues worldwide that seriously threaten human health. Exploring effective natural product-based drugs is a promising strategy for the treatment of AS and metabolic diseases. Berberine (BBR), an important isoquinoline alkaloid found in various medicinal plants, has been shown to have multiple pharmacological effects and therapeutic applications. In view of its low bioavailability, increasing evidence indicates that the gut microbiota may serve as a target for the multifunctional effects of BBR. Under the pathological conditions of AS and metabolic diseases, BBR improves intestinal barrier function and reduces inflammation induced by gut microbiota-derived lipopolysaccharide (LPS). Moreover, BBR reverses or induces structural and compositional alterations in the gut microbiota and regulates gut microbe-dependent metabolites as well as related downstream pathways; this improves glucose and lipid metabolism and energy homeostasis. These findings at least partly explain the effect of BBR on AS and metabolic diseases. In this review, we elaborate on the research progress of BBR and its mechanisms of action in the treatment of AS and metabolic diseases from the perspective of gut microbiota, to reveal the potential contribution of gut microbiota to the multifunctional biological effects of BBR.

Loss of endogenous estrogen and dysregulation of the estrogen receptor signaling pathways are associated with an increase in risk for cognitive deficit and depression in women after menopause. Estrogen therapy for menopause increases the risk of breast and ovarian cancers, and stroke. Therefore, it is critical to find an alternate treatment for menopausal women. Osthole (OST), a coumarin, has been reported to have neuroprotective effects. This study examined whether OST improves ovariectomy (OVX)-induced cognitive impairment, and alleviates anxiety- and depression-like behaviors induced by OVX in mice. Adult female C57BL/6J mice were ovariectomized and then treated with OST at a dose of 30 mg/kg for 14 days. At the end of the treatment period, behavioral tests were used to evaluate spatial learning and memory, recognition memory, anxiety- and depression-like behaviors. A cohort of the mice were sacrificed after 14 days of OST treatment and their hippocampi were collected for measurement of the proteins of interest using western blot. OVX-induced alteration in the levels of proteins was accompanied by cognitive deficit, anxiety- and depression-like behaviors. OST treatment improved cognitive deficit, alleviated anxiety- and depression-like behaviors induced by OVX, and reversed OVX-induced alterations in the levels of synaptic proteins and ERα, BDNF, TrKB, p-CREB, p-Akt and Rac1 in the hippocampus. Therefore, reversal of OVX-induced decrease in the levels of hippocampal proteins by OST might contribute to the effects of OST on improving cognitive deficit and alleviating anxiety- and depression-like behaviors induced by OVX.

Objective: To evaluate the tolerance, variability, and pharmacokinetics (PK) of QX001S, a biosimilar for ustekinumab, in healthy Chinese men.Methods: One hundred and seventy-eight healthy men were recruited in this randomized, double-blind, single-dose, two-arm, parallel study, and received 45 mg of QX001S or ustekinumab in a single subcutaneous injection. PK, immunogenicity, and tolerance were evaluated in all participants for a period of 113°days.Results: The similarity between the two drugs was determined by comparing the baseline characteristics for each drug. The PK parameters were similar in the two groups: QX001S (n = 89) and ustekinumab (n = 88). The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of QX001S to the reference (ustekinumab) for the maximum observable serum concentration (Cmax), area under the curve (AUC) from zero to the final quantifiable concentration (AUC0–t), and AUC from zero to infinity (AUC0–∞) were 100.90–118.68%, 98.71–115.26%, and 98.49–115.81%, respectively, which were within the predefined bioequivalence limit of 80.00–125.00%. High inter-subject variability (ranging from 32.0 to 33.5%) was observed. A total of 17 participants (19.1%) in the QX001S group and 36 (40.9%) in the ustekinumab group developed anti-drug antibodies (ADA) after administration. Nevertheless, the ADA did not affect the outcomes of the bioequivalence tests. Adverse reactions were recorded in 38 individuals injected with QX001S and 37 injected with ustekinumab. The most common adverse reactions were upper respiratory infection and elevated alanine aminotransferase.Conclusions: Our study ratified pharmacokinetic biosimilarity between QX001 S and ustekinumab, with high variability between subjects.

Purpose: Cancer is a leading cause of morbidity and mortality worldwide. Off-label (OL) use of antineoplastic drugs to treat malignancies is prevalent. In this study, we quantified and characterized OL use of antineoplastic drugs to treat malignancies in China.Methods: This was a retrospective study using nationwide data collected from 2008 to 2010. Use of antineoplastic drugs was considered OL if they were used for indications not reflected in the package insert published by the National Medical Products Administration at the time of prescription. Descriptive analysis and Spearman rank correlation were used to evaluate the frequency and pattern of OL drug use.Results: In total, 51,382 patients with malignancies, 24 categories of antineoplastic drugs, and 77 types of malignancies treated with OL drugs were included in this study. Twenty commonly used antineoplastic drugs (ICD encoded as L01) were used OL in 10–61% of cases, and four commonly used endocrine therapy antineoplastic drugs (ICD encoded as L02) were used OL in 10–19% of cases. There was a significant negative correlation between the disease constituent ratio and the average OL use rate of antineoplastic drugs for various malignancies. In contrast, there was a significant positive correlation between the average OL use rate of antineoplastic drugs and the number of malignancies treated with OL drugs.Conclusion: This study provided information regarding OL use of antineoplastic drugs for treatment of malignancies, and showed that OL use was prevalent. In addition, uncommon malignancies were more likely to be treated with OL antineoplastic drugs. Furthermore, more commonly used antineoplastic drugs were more likely to be used OL.

Objective: This study explored the bioequivalence of a proposed biosimilar HOT-3010 vs. its reference product (adalimumab) among healthy Chinese male subjects. The study also investigated the tolerance, immunogenicity, and pharmacokinetics (PK).Methods: A randomized, double-blind, two-arm, parallel study was performed to examine the bioequivalence of HOT-3010 (40 mg) with that of adalimumab (Humira®, AbbVie) as a reference drug. The study subjects were followed up for 71 days.Results: PK properties exhibited by HOT-3010 (N = 66) and adalimumab (N = 68) groups were similar. The 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0∞ were observed to be in the range 80–125% on comparing the two groups. For anti-drug antibodies (ADA), the number of subjects found to be positive in the HOT-3010 group and adalimumab group were 29 (43.94%) and 32 (47.06%), whereas 27 (40.91%) and 27 (39.71%) subjects were found to be positive for NAb, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were recorded in 32 subjects each in both the groups, respectively.Conclusion: The PK characteristics and immunogenicity exhibited by HOT-3010 were similar to that of the reference product, adalimumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

Objective: The study aimed to explore the bioequivalence of a proposed biosimilar BAT1806 to its reference products marketed in the EU and US (RoActemra-EU and Actemra-US) among healthy Chinese men. The tolerance, immunogenicity, and pharmacokinetics (PK) of the three drugs were also investigated.Methods: In this randomized, double-blind, single-dose, three-arm, parallel study, a single-dose of 4 mg/kg of the reference products, or the biosimilar was administered to the participants. The participants were followed up for 57 days, and PK, immunogenicity, and tolerance evaluations were completed during this period.Results: The PK parameters were similar in all three groups: BAT1806 (n = 45), RoActemra-EU (n = 42), and Actemra-US (n = 42). The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0–t and AUC0–∞ were 86.90–104.41% for BAT1806 vs. RoActemra-EU, 91.70–106.15% for BAT1806 vs Actemra-US, and 90.04–105.53% for Actemra-US vs RoActemra-EU. For all comparisons, the 90% CIs for the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit of 80.00–125.00%. The intersubject variability ranged from 14.5% to 21.5%, which was considerably low. Among the participants, 19 (42.2%), 10 (23.8%), and 12 (28.6%) from the BAT1806, RoActemra-EU, and Actemra-US groups were, respectively, found to be positive for anti-drug antibodies, while 14 (31.1%), nine (21.4%), and 12 (28.6%) were positive for neutralizing antibodies. Nevertheless, these antibodies did not affect the drug concentrations, and the outcomes in the bioequivalence tests were similar after sensitivity analysis. Treatment-related and treatment-emergent adverse events (TEAEs) were recorded in 27, 34, and 32 participants in the BAT1806, RoActemra-EU, and Actemra-US groups, respectively. The most common treatment-related adverse events observed were a decrease in neutrophil, and white blood cell counts.Conclusion: The PK characteristics of BAT1806 were similar to those of the reference products, RoActemra-EU and Actemra-US. Both BAT1806 and the reference products exhibited low intersubject variability and similar safety profiles.Clinical trial registration number:http://www.chinadrugtrials.org.cn/index.html, CTR20180039; https://clinicaltrials.gov/NCT03606876

As a noted medicinal mushroom, Ganoderma lucidum (G. lucidum) has been reported to have a number of pharmacological effects such as anti-tumor and liver protection. Compared with the common ethanol reflux method, supercritical CO2 extraction has obvious advantages in obtaining antitumor extracts from G. lucidum fruiting body such as short extraction time, low temperature and no solvent residue. However, Using high-pressure supercritical CO2 without entrainer to obtain the antitumor extracts from G. lucidum and studying their anti-hepatoma effect have not been reported. In this study, high-pressure supercritical CO2 extracts obtained under 65, 85, and 105 MPa pressure named as G65, G85, G105 respectively and ethanol reflux extract (GLE) were used to investigate their anti-hepatoma activity and the underlying molecular mechanism. The total triterpenoid content of G85 was significantly higher than that of G65 and GLE, but did not differ significantly from that of G105 by UV and high-performance liquid chromatography. GLE, G65, and G85 could inhibit cell proliferation, arrest cell cycle in G2/M phase, and induce apoptosis in two liver cancer cell lines (QGY7703 and SK-Hep1), of which G85 had the strongest effect. The results showed that the potency of their cytotoxicity of the high-pressure supercritical CO2 extracts on human hepatoma carcinoma cells in vitro was consistent with their total triterpenoid content. G85 exhibited significant anti-hepatoma effect with low toxicity In vivo. Further mechanistic investigation revealed that the anti-tumor effect of these extracts was associated with their inhibition of Ras/Raf/MEK/ERK signaling pathway. Our findings suggest that the high-pressure supercritical CO2 extraction of G. lucidum fruiting body can be used to obtain a triterpenoid-rich anti-tumor agent, which may have potential clinical significance for the treatment of human hepatoma.

ObjectiveThis study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects.MethodsThis is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva® was administered to the subjects, who were followed up for 134 days.ResultsSimilar PK properties as those of Xgeva® were exhibited by QL1206. When compared to QL1206 with Xgeva®, the 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0-∞ were observed to be within 80–125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva® groups, respectively.ConclusionSimilar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva®. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva® were found to be similar.

Atherosclerosis and its associated cardiovascular diseases (CVDs) are serious threats to human health and have been reported to be associated with the gut microbiota. Recently, the role of berberine (BBR) in atherosclerosis and gut microbiota has begun to be appreciated. The purposes of this study were to observe the effects of high or low doses of BBR on atherosclerosis and gut microbiota modulation, and to explore their correlation in ApoE–/– mice fed a high-fat diet. A significant decrease in atherosclerotic lesions was observed after treatment with BBR, with the effect of the high dose being more obvious. Both BBR treatments significantly reduced total cholesterol, APOB100, and very low-density lipoprotein cholesterol levels but levels of high/low-density lipoprotein cholesterol and lipoprotein (a) were only reduced by high-dose BBR. Decreased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6 and increased anti-inflammatory IL-10 and adiponectin levels were observed in the high-dose BBR group, but no decrease in IL-6 or increase in IL-10 was evident using the low-dose of BBR. 16S rRNA sequencing showed that BBR significantly altered the community compositional structure of gut microbiota. Specifically, BBR enriched the abundance of Roseburia, Blautia, Allobaculum, Alistipes, and Turicibacter, and changed the abundance of Bilophila. These microbiota displayed good anti-inflammatory effects related to the production of short-chain fatty acids (SCFAs) and were related to glucolipid metabolism. Alistipes and Roseburia were significantly enriched in high-dose BBR group while Blautia and Allobaculum were more enriched in low-dose, and Turicibacter was enriched in both BBR doses. Metagenomic analysis further showed an elevated potential for lipid and glycan metabolism and synthesis of SCFAs, as well as reduced potential of TMAO production after BBR treatment. The findings demonstrate that both high and low-dose BBR can improve serum lipid and systemic inflammation levels, and alleviate atherosclerosis induced by high-fat diet in ApoE–/– mice. The effects are more pronounced for the high dose. This anti-atherosclerotic effect of BBR may be partly attributed to changes in composition and functions of gut microbiota which may be associated with anti-inflammatory and metabolism of glucose and lipid. Notably, gut microbiota alterations showed different sensitivity to BBR dose.

ObjectiveIn this study, we aim to investigate the effect of different doses of dexmedetomidine as an adjuvant to hyperbaric ropivacaine in spinal anesthesia for cesarean section.MethodsSeventy-five parturients with American Society of Anesthesiologists (ASA) I or II were anesthetized with intrathecal ropivacaine (12.5 mg) alone (R group) or in combination with dexmedetomidine 3 μg (RD3 group) and 5 μg (RD5 group) to undergo a cesarean section. The anesthetic parameters, postoperative analgesia, stress responses and neonates outcomes were monitored.ResultsThe onset time of sensory block to T10, T4, and peak level in the RD3 group and RD5 group were significantly shorter than those in the R group (p < 0.05). The time of the level of sensory block to descend two segments and to T10 in the RD3 group(57.28 ± 16.65 min, 3.87 ± 1.60 h) and RD5 group (71.92 ± 10.10 min, 3.99 ± 1.06 h) were longer than that in the R group (40.64 ± 12.06 min, 1.98 ± 1.01 h) (p < 0.05). The median time of motor blockade to both legs score 3 on the Bromage scale (B3B3) in the RD3 group and RD5 group was shorter than that in the R group (p < 0.001). The time of motor blockade recovery to both legs score 0 on the Bromage scale (B0B0) in the RD5 group (3.6 h) was longer than that in the R group (2 h) or RD3 group (2.2 h) (p < 0.001). Visceral traction response and abdominal muscle relaxation during the operation in the RD3 group and the RD5 group were better than that in the R group. The Visual Analogue Score (VAS) in the 12 h after the operation in the RD3 group (3.30 ± 1.17) and RD5 group (2.80 ± 0.87) was smaller than that in the R group (3.80 ± 1.47) (p < 0.05). The incidence of shivering in the RD3 group and RD5 group was significantly lower than that in the R group (p < 0.05). The postoperative concentrations of c-reactive protein (CRP), interleukin-6 (IL-6) and cortisol in the RD3 and RD5 groups were lower than that in the R group (p < 0.05).Conclusion3 µg intrathecal dexmedetomidine as an adjuvant to ropivacaine improved intraoperative somato-visceral sensory block characteristics and postoperative analgesia, alleviated shivering in parturients, and did not prolong the time of motor block or produce any side effects, which makes this dose appropriate for cesarean delivery.Cinical Trial RegistrationChiCTR, identifier ChiCTR1800014454. Registered 15 January 2018, http://www.chictr.org.cn/edit.aspx?pid=24613&htm=4

Cardiovascular disease (CVD), especially atherosclerosis, is a leading cause of morbidity and mortality globally; it causes a considerable burden on families and caregivers and results in significant financial costs being incurred. Hawthorn has an extensive history of medical use in many countries. In China, the use of hawthorn for the treatment of CVD dates to 659 AD. In addition, according to the theory of traditional Chinese medicine, it acts on tonifying the spleen to promote digestion and activate blood circulation to dissipate blood stasis. This review revealed that the hawthorn extracts possess serum lipid-lowering, anti-oxidative, and cardiovascular protective properties, thus gaining popularity, especially for its anti-atherosclerotic effects. We summarize the four principal mechanisms, including blood lipid-lowering, anti-oxidative, anti-inflammatory, and vascular endothelial protection, thus providing a theoretical basis for further utilization of hawthorn.

Cardiovascular disease (CVD) is the leading cause of death worldwide, especially in developed countries, and atherosclerosis (AS) is the common pathological basis of many cardiovascular diseases (CVDs) such as coronary heart disease (CHD). The role of the gut microbiota in AS has begun to be appreciated in recent years. Trimethylamine N-oxide (TMAO), an important gut microbe-dependent metabolite, is generated from dietary choline, betaine, and L-carnitine. Multiple studies have suggested a correlation between plasma TMAO levels and the risk of AS. However, the mechanism underlying this relationship is still unclear. In this review, we discuss the TMAO-involved mechanisms of atherosclerotic CVD from the perspective of inflammation, inflammation-related immunity, cholesterol metabolism, and atherothrombosis. We also summarize available clinical studies on the role of TMAO in predicting prognostic outcomes, including major adverse cardiovascular events (MACE), in patients presenting with AS. Finally, since TMAO may be a novel therapeutic target for AS, several therapeutic strategies including drugs, dietary, etc. to lower TMAO levels that are currently being explored are also discussed.

Background: Emergence agitation (EA) is a common pediatric complication after sevoflurane anesthesia that can be prevented with dexmedetomidine. However, an inappropriate dose of dexmedetomidine can cause prolonged sedation and cardiovascular complications. Thus, we evaluated the optimal dose (ED95) of dexmedetomidine for preventing EA with sevoflurane and remifentanil anesthesia after pediatric tonsillectomy and adenoidectomy.Methods: We enrolled American Society of Anesthesiologists (ASA) I and II children 3–7 years of age who underwent tonsillectomy with adenoidectomy. During induction, dexmedetomidine was infused for 10 min. Anesthesia was induced with sevoflurane and maintained with sevoflurane and remifentanil, resulting in a bispectral spectrum index (BIS) range from 40 to 60. Extubation time, surgical and anesthetic duration time, and duration time in the postanesthesia care unit (PACU) stay were recorded. EA [measured with Pediatric Anaesthesia Emergence Delirium (PAED) scores] and pain [measured with Face, Legs, Activity, Cry, Consolability (FLACC) scores] were assessed at extubation (E0), 15 min after extubation (E1), and 30 min after extubation (E2). If EA occurred, the next surgical procedure included increased dexmedetomidine by 0.1 μg/kg, and if not, the drug was reduced by 0.1 μg/kg.Results: The 50% effective dose (ED50) of dexmedetomidine for preventing EA after sevoflurane and remifentanil anesthesia for tonsillectomy and adenoidectomy was 0.13 μg/kg, and its 95% confidence interval is 0.09–0.19 μg/kg; ED95 was 0.30 μg/kg, and its 95% confidence interval is 0.21–1.00 μg/kg.Conclusion: Intravenous dexmedetomidine infusion at ED50 (0.13 μg/kg) or ED95 (0.30 μg/kg) during induction for 10 min can prevent half or almost all EA after sevoflurane and remifentanil anesthesia during pediatric tonsillectomy and adenoidectomy.

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

Objective: The aim of this study was to explore the tolerance, variability, and pharmacokinetics (PK) of albumin-bound paclitaxel (QL, HR, ZDTQ) among Chinese breast cancer patients.Methods: Three randomized, open-label, two-period crossover bioequivalence studies were conducted with albumin-bound paclitaxel. Each subject received a single dose of 260 mg/m2 albumin-bound paclitaxel [sponsor 1 (QL, light food), sponsor 2 (HR, fasting), sponsor 3 (ZDTQ, light food); test] or Abraxane® (reference) and was monitored for 72 h. Serum concentrations of total paclitaxel and unbound paclitaxel were measured using liquid chromatography/mass spectrometry (LC/MS), and appropriate pharmacokinetic parameters were determined by non-compartmental methods. Safety assessments included adverse events, hematology and biochemistry tests.Results: The bioequivalence analyses of the QL, HR, and ZDTQ products included 24, 23, and 24 patients, respectively. The mean t1/2 was 20.61–27.31 h for total paclitaxel. Food intake did not affect the pharmacokinetics of paclitaxel. From the comparison of total paclitaxel and unbound paclitaxel, the 90% confidence intervals (CIs) for the ratios of Cmax, AUC0−t, and AUC0−∞ were within 80.00–125.00%. The intra-subject variability ranged from 6.4–11% to 9.85–15.87% for total paclitaxel and unbound paclitaxel, respectively. Almost all subjects in the test and Abraxane® (reference) groups experienced mild or moderate adverse events. No fatal AEs or study drug injection site reactions related to these drugs were observed.Conclusion: Albumin-bound paclitaxel (QL, HR or ZDTQ; test products) showed bioequivalence to Abraxane® (reference) with lower intra-subject variability, which was less than 16% in all cases, and was well-tolerated in Chinese breast cancer patients. Twenty-two patients are enough for an albumin-bound paclitaxel bioequivalence study.

Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects.Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR).Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4–5 h, and the mean elimination half-life (t1/2) was 18–26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result.Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.

Comprehensively understanding pharmacological functions of natural products is a key issue to be addressed for the discovery of new drugs. Unlike some single-target drugs, natural products always exert diverse therapeutic effects through acting on a “network” that consists of multiple targets, making it necessary to develop a systematic approach, e.g., network pharmacology, to reveal pharmacological functions of natural products and infer their mechanisms of action. In this work, to identify the “network target” of a natural product, we perform a functional analysis of matrine, a marketed drug in China extracted from a medical herb Ku-Shen (Radix Sophorae Flavescentis). Here, the network target of matrine was firstly predicted by drugCIPHER, a genome-wide target prediction method. Based on the network target of matrine, we performed a functional gene set enrichment analysis to computationally identify the potential pharmacological functions of matrine, most of which are supported by the literature evidence, including neurotoxicity and neuropharmacological activities of matrine. Furthermore, computational results demonstrated that matrine has the potential for the induction of macropinocytosis and the regulation of ATP metabolism. Our experimental data revealed that the large vesicles induced by matrine are consistent with the typical characteristics of macropinosome. Our verification results also suggested that matrine could decrease cellular ATP level. These findings demonstrated the availability and effectiveness of the network target strategy for identifying the comprehensive pharmacological functions of natural products.