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Percutaneous coronary intervention (PCI) is currently the main method for treating coronary artery stenosis, but the incidence of restenosis after PCI is relatively high. Restenosis, the narrowing of blood vessels by more than 50% of the normal diameter after PCI, severely compromises the therapeutic efficacy. Therefore, preventing postinterventional restenosis is important. Vascular restenosis is mainly associated with endothelial injury, the inflammatory response, the proliferation and migration of vascular smooth muscle cells (VSMCs), excessive deposition of extracellular matrix (ECM) and intimal hyperplasia (IH) and is usually prevented by administering antiproliferative or anti-inflammatory drugs through drug-eluting stents (DESs); however, DESs can lead to uncontrolled drug release. In addition, as extracorporeal implants, they can cause inflammation and thrombosis, resulting in suboptimal treatment. Therefore, there is an urgent need for a drug carrier with controlled drug release and high biocompatibility for in vivo drug delivery to prevent restenosis. The development of nanotechnology has enabled the preparation of nanoparticle drug carriers with low toxicity, high drug loading, high biocompatibility, precise targeting, controlled drug release and excellent intracellular delivery ability. This review summarizes the advantages of nanoparticle drug carriers for treating vascular restenosis, as well as how nanoparticles have improved targeting, slowed the release of therapeutic agents, and prolonged circulation in vivo to prevent vascular restenosis more effectively. The overall purpose of this review is to present an overview of nanoparticle therapy for vascular restenosis. We expect these findings to provide insight into nanoparticle-based therapeutic approaches for vascular restenosis.

β-nicotinamide mononucleotide (NMN) is a naturally occurring biologically active nucleotide widely present in organisms and an inherent substance in the human body. As a critical intermediate in synthesizing coenzyme I (NAD+), it widely participates in multiple biochemical reactions in the human body and is closely related to immunity, metabolism, and other factors. In recent years, NMN has rapidly developed and made significant progress in medicine, food, and healthcare. However, there is currently a lack of comprehensive reports on the research progress of NMN, as well as exploration and analysis of the current research achievements and progress of NMN. Therefore, this review is based on retrieving relevant research on NMN from multiple databases at home and abroad, with the retrieval time from database establishment to 20 May 2024. Subsequently, literature search, reading, key information extraction, organization, and summarization were conducted with the aim of providing a comprehensive and in-depth analysis of the characteristics, metabolic pathways, pharmacological effects, progress in human clinical trials, and wide applications of NMN in drug development and food applications. Furthermore, it offers personal insights into NMN’s potential future developments and advancements to present the current development state and existing challenges comprehensively. Ultimately, this review aims to provide guidance and serve as a reference for the future application, innovation, and progression of NMN research.

BackgroundSress early in life has been linked to visceral hyperalgesia and associated functional gastrointestinal disorders. In a mouse model of visceral hyperalgesia, we investigated whether the EphB2 receptor and its EphrinB2 ligand in spinal cord contribute to dysregulation of glia-neuron interactions.MethodsAn established mouse model of stress due to maternal separation (MS). Pups were separated from their mothers for 14 days during early development, then analyzed several weeks later in terms of visceral sensitivity based on the abdominal withdrawal reflex score and in terms of expression of c-fos, EphrinB2, EphB2, and phosphorylated MAP kinases (ERK, p38, JNK).ResultsVisceral hyperalgesia due to MS upregulated EphB2, EphrinB2 and c-fos in the spinal cord, and c-fos levels positively correlated with those of EphB2 and EphrinB2. Spinal astrocytes, microglia, and neurons showed upregulation of EphB2, EphrinB2 and phosphorylated MAP kinases. Blocking EphrinB2/EphB2 signaling in MS mice reduced visceral sensitivity, activation of neurons and glia, and phosphorylation of NMDA receptor. Activating EphrinB2/EphB2 signaling in unstressed mice induced visceral hyperalgesia, upregulation of c-fos, and activation of NMDA receptor similar to maternal separation.ConclusionThe stress of MS during early development may lead to visceral hyperalgesia by upregulating EphrinB2/EphB2 in the spinal cord and thereby altering neuron-glia interactions.

Organoids are in vitro 3D models that maintain their own tissue structure and function. They largely overcome the limitations of traditional tumor models and have become a powerful research tool in the field of oncology in recent years. Gynecological malignancies are major diseases that seriously threaten the life and health of women and urgently require the establishment of models with a high degree of similarity to human tumors for clinical studies to formulate individualized treatments. Currently, organoids are widely studied in exploring the mechanisms of gynecological tumor development as a means of drug screening and individualized medicine. Ovarian, endometrial, and cervical cancers as common gynecological malignancies have high morbidity and mortality rates among other gynecological tumors. Therefore, this study reviews the application of modelling, drug efficacy assessment, and drug response prediction for ovarian, endometrial, and cervical cancers, thereby clarifying the mechanisms of tumorigenesis and development, and providing precise treatment options for gynecological oncology patients.

Eucommia ulmoides (EU) is a precious tree species native to China originating during the ice age. This species has important economic value and comprehensive development potential, particularly in medicinal applications. The medicinal parts of EU are its bark (Eucommiae cortex) and leaves (Eucommiae folium) which have been successively used as a traditional Chinese medicine to treat diseases since the first century BC. During the last 2 decades, as natural polysaccharides have become of increasing interest in pharmacology, biomedicine, cosmetic and food applications, more and more scholars have begun to study polysaccharides derived from EU as well. EU polysaccharides have been found to have a variety of biological functions both in vivo and in vitro, including immunomodulatory, antioxidant, anti-inflammatory, anticomplementary, antifatigue, and hepatoprotective activities. This review aims to summarize these recent advances in extraction, purification, structural characteristics, pharmacological activities and applications in different fields of EU bark and leaf polysaccharides. It was found that both Eucommiae folium polysaccharides and Eucommiae cortex polysaccharides were suitable for medicinal use. Eucommiae folium may potentially be used to substitute for Eucommiae cortex in terms of immunomodulation and antioxidant activities. This study serves as a valuable reference for improving the comprehensive utilization of EU polysaccharides and further promoting the application of EU polysaccharides.

Approximately 80% of all malignant brain tumors are gliomas, which are primary brain tumors. The most prevalent subtype of glioma, glioblastoma multiforme (GBM), is also the most deadly. Chemotherapy, immunotherapy, surgery, and conventional pharmacotherapy are currently available therapeutic options for GBM; unfortunately, these approaches only prolong the patient’s life by 5 years at most. Despite numerous intensive therapeutic options, GBM is considered incurable. Accumulating preclinical data indicate that overt antitumoral effects can be induced by pharmacologically activating endocannabinoid receptors on glioma cells by modifying important intracellular signaling cascades. The complex mechanism underlying the endocannabinoid receptor-evoked antitumoral activity in experimental models of glioma may inhibit the ability of cancer cells to invade, proliferate, and exhibit stem cell-like characteristics, along with altering other aspects of the complex tumor microenvironment. The exact biological function of the endocannabinoid system in the development and spread of gliomas, however, is remains unclear and appears to rely heavily on context. Previous studies have revealed that endocannabinoid receptors are present in the tumor microenvironment, suggesting that these receptors could be novel targets for the treatment of GBM. Additionally, endocannabinoids have demonstrated anticancer effects through signaling pathways linked to the classic features of cancer. Thus, the pharmacology of endocannabinoids in the glioblastoma microenvironment is the main topic of this review, which may promote the development of future GBM therapies.

Background:Ticagrelor is a commonly used antiplatelet agent, but due to the stringent criteria for trial population inclusion and the limited sample size, its safety profile has not been fully elucidated.Method:We utilized OpenVigil 2.1 to query the FDA Adverse Event Reporting System database and retrieved reports by the generic name “ticagrelor” published between 1 October 2010 and 31 March 2023. Adverse drug events (ADEs) were classified and described according to the preferred terms and system organ classes in the Medical Dictionary of Regulatory Activity. Proportional reporting ratio (PRR), reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) were used to detect signals.Results:The number of ADE reports with ticagrelor as the primary suspect drug was 12,909. The top three ADEs were dyspnea [1824 reports, ROR 7.34, PRR 6.45, information component (IC) 2.68], chest pain (458 reports, ROR 5.43, PRR 5.27, IC 2.39), and vascular stent thrombosis (406 reports, ROR 409.53, PRR 396.68, IC 8.02). The highest ROR, 630.24, was found for “vascular stent occlusion”. Cardiac arrest (137 reports, ROR 3.41, PRR 3.39, IC 1.75), atrial fibrillation (99 reports, ROR 2.05, PRR 2.04, IC 1.03), asphyxia (101 reports, ROR 23.60, PRR 23.43, IC 4.51), and rhabdomyolysis (57 reports, ROR 2.75, PRR 2.75, IC 1.45) were suspected new adverse events of ticagrelor.Conclusion:The FAERS database produced potential signals associated with ticagrelor that have not been recorded in the package inserts, such as cardiac arrest, atrial fibrillation, asphyxia, and rhabdomyolysis. Further clinical surveillance is needed to quantify and validate potential hazards associated with ticagrelor-related adverse events.

This work aimed to explore the mechanisms underlying the interaction of the active furanocoumarins in P. corylifolia on tofacitinib both in vivo and in vitro. The concentration of tofacitinib and its metabolite M8 was determined using UPLC-MS/MS. The peak area ratio of M8 to tofacitinib was calculated to compare the inhibitory ability of furanocoumarin contained in the traditional Chinese medicine P. corylifolia in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4 (rCYP3A4). We found that bergapten and isopsoralen exhibited more significant inhibitory activity in RLMs than other furanocoumarins. Bergapten and isopsoralen were selected to investigate tofacitinib drug interactions in vitro and in vivo. Thirty rats were randomly allocated into 5 groups (n = 6): control (0.5% CMC-Na), low-dose bergapten (20 mg/kg), high-dose bergapten (50 mg/kg), low-dose isopsoralen (20 mg/kg) and ketoconazole. 10 mg/kg of tofacitinib was orally intervented to each rat and the concentration level of tofacitinib in the rats were determined by UPLC-MS/MS. More imporrantly, the results showed that bergapten and isopsoralen significantly inhibited the metabolism of tofacitinib metabolism. The AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and Cmax of tofacitinib increased in varying degrees compared with the control group (all p < 0.05), but CLz/F decreased in varying degrees (p < 0.05) in the different dose bergapten group and isopsoralen group. Bergapten, isopsoralen and tofacitinib exhibit similar binding capacities with CYP3A4 by AutoDock 4.2 software, confirming that they compete for tofacitinib metabolism. P. corylifolia may considerably impact the metabolism of tofacitinib, which can provide essential information for the accurate therapeutic application of tofacitinib.

Backgroud: The co-administration of Chinese patent medicine with calcium channel blockers (CCBs) is a prevalent practice in China for treating essential hypertension (EH). However, robust evidence supporting the efficacy and safety of tailored combinations of different Chinese patent medicines with CCBs, according to individual patient conditions, is still limited. This study sought to elucidate the efficacy and safety of these combinations using a systematic review and network meta-analysis.Materials and methods: Relevant studies were sourced from established databases, incorporating randomized controlled trials published up to 1 February 2023. The ROB2 tool from the Cochrane Collaborative Network was employed to independently assess and cross-verify the quality of the included literature. A network meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 and PRISMA-Network Meta-Analyses (PRISMA-NMA) guidelines. A Bayesian network meta-analysis was utilized to gauge the efficacy and safety of distinct integrations of Chinese patent medicine and CCBs. Primary outcomes were interpreted using a paired fixed-effect meta-analysis. Publication bias was appraised through Egger’s test and represented with funnel plots. All statistical analyses were executed within the R statistical framework.Results: Following rigorous selection, data extraction, and bias evaluation, 36 articles were incorporated. Tianma Gouteng Granule, when combined with CCBs, displayed superior efficacy in reducing systolic blood pressure (SBP). In terms of diastolic blood pressure (DBP) reduction, Songling Xuemaikang Capsule combined with CCBs emerged as the most effective. Regarding enhancement of antihypertensive effective rates, Qinggan Jiangya Capsule paired with CCBs demonstrated optimal results. For diminishing Traditional Chinese Medicine syndrome scores, the Qiangli Dingxuan Tablet and CCBs combination proved most beneficial. When aiming to reduce total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels, Tianma Gouteng Granule and CCBs showcased superior results. In contrast, the combination of Songling Xuemaikang Capsule and CCBs was more effective in reducing LDL-C, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6).Conclusion: This study underscores variability in outcomes from combining Chinese patent medicine and CCBs for hypertension, emphasizing the importance of personalized medicinal combinations, especially Tianma Gouteng Granule and Songling Xuemaikang Capsule. The results offer robust evidence to inform clinical guidelines for essential hypertention and significantly aid clinician in seleting appropriate Chinese patent medicines for treatment.

Introduction: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease characterized by excessive deposition of extracellular matrix. Cannabidiol, a natural component extracted from plant cannabis, has been shown to have therapeutic effects on lung diseases, but its exact mechanism of action is unknown, hindering its therapeutic effectiveness.Methods: To establish a pulmonary fibrosis model, combined with UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing, to explore cannabidiol’s mechanism in treating pulmonary fibrosis. The rats were randomly divided into the control group, pulmonary fibrosis model group, prednisone treatment group, and cannabidiol low, medium, and high dose groups. The expression levels of HYP, SOD, and MDA in lung tissue and the expression levels of TNF-α, IL-1β, and IL-6 in serum were detected. Intestinal microbiota was detected using UPLC-QTOF/MS analysis of metabolomic properties and 16S rDNA sequencing.Results: Pathological studies and biochemical indexes showed that cannabidiol treatment could significantly alleviate IPF symptoms, significantly reduce the levels of TNF-α, IL-1β, IL-6, MDA, and HYP, and increase the expression level of SOD (p < 0.05). CBD-H can regulate Lachnospiraceae_NK4A136_group, Pseudomonas, Clostridia_UCG-014, Collinsella, Prevotella, [Eubacterium]_coprostanoligenes_group, Fusobacterium, Ruminococcus, and Streptococcus, it can restore intestinal microbiota function and reverse fecal metabolism trend. It also plays the role of fibrosis through the metabolism of linoleic acid, glycerol, linolenic acid, and sphingolipid.Discussion: Cannabidiol reverses intestinal microbiota imbalance and attenuates pulmonary fibrosis in rats through anti-inflammatory, antioxidant, and anti-fibrotic effects. This study lays the foundation for future research on the pathological mechanisms of IPF and the development of new drug candidates.

Background: Adenoidal hypertrophy (AH) is one of the most common causes of upper airway obstruction in children. Drug and surgical treatment are the typical treatment of AH. The study on the inflammatory mechanism of AH in children provides a new idea for preoperative intervention and non-surgical treatment with anti-inflammatory drugs such as montelukast sodium (a cysteine leukotriene receptor antagonist). The aim of this study is to evaluate the effect of montelukast sodium on adenoidal lymphoid tissue pathology in children with AH under light microscope.Objective: To study whether there is any change in pathology of the adenoidal lymphoid tissue under the light microscope compared with the control group in children with moderate to severe simple AH treated with montelukast sodium for 1 month before operation.Materials and methods: Twenty patients (8 males, 12 females, 3–8 years old) with moderate to severe AH who were prepared for surgical treatment were selected. All the patients were examined by Nasopharyngeal CT and hemocyte analysis before operation. 20 subjects were randomly divided into two groups: One group was given montelukast chewable tablets 5 mg/d, qn, for 4 weeks; The control group was given placebo 5 mg/d, qn, for 4 weeks. After 4 weeks, the adenoids were removed and examined histopathology.Results: Compared with the control group, the number of lymphocytes in the blood cell analysis of the study group was significantly reduced, with a statistically significant difference (p < 0.05). And the number of germinal centers in adenoid tissue of the study group was relatively reduced, no small cyst was found in the epithelium, and the degree of inflammatory cell infiltration was reduced, with a statistically significant difference (p < 0.05).Conclusion: Montelukast can reduce the number of reactive cells, the number of lymphocytes in blood cells and blood vessels in adenoid lymphoid tissue, which can provide a new idea for preoperative intervention and non-surgical treatment of adenoid hypertrophy in children. However, this is only a pilot study and a longer treatment period is needed to assess the long-term effects of montelukast sodium on adenoid lymphoid tissue.Clinical Trial Registration: www.Chictr.org.cn, identifier ChiCTR2300075040.

Macitentan was approved by the United States Food and Drug Administration (FDA) in 2013 for the treatment of pulmonary arterial hypertension (PAH). Bergapten is a furanocoumarin that is abundant in Umbelliferae and Rutaceae plants and is widely used in many Chinese medicine prescriptions. Considering the possible combination of these two compounds, this study is aimed to investigate the effects of bergapten on the pharmacokinetics of macitentan both in vitro and in vivo. Rat liver microsomes (RLMs), human liver microsomes (HLMs), and recombinant human CYP3A4 (rCYP3A4) were used to investigate the inhibitory effects and mechanisms of bergapten on macitentan in vitro. In addition, pharmacokinetic parameters were also studied in vivo. Rats were randomly divided into two groups (six rats per group), with or without bergapten (10 mg/kg), and pretreated for 7 days. An oral dose of 20 mg/kg macitentan was administered to each group 30 min after bergapten or 0.5% CMC-Na administration on day 7. Blood was collected from the tail veins, and the plasma concentrations of macitentan and its metabolites were assessed by ultra-performance liquid chromatography - tandem mass spectrometer (UPLC-MS/MS). Finally, we analyzed the binding force of the enzyme and two small ligands by in silico molecular docking to verify the inhibitory effects of bergapten on macitentan. The in vitro results revealed that the IC50 values for RLMs, HLMs, and rCYP3A4 were 3.84, 17.82 and 12.81 μM, respectively. In vivo pharmacokinetic experiments showed that the AUC(0-t), AUC(0-∞), and Cmax of macitentan in the experimental group (20,263.67 μg/L*h, 20,378.31 μg/L*h and 2,999.69 μg/L, respectively) increased significantly compared with the control group (7,873.97 μg/L*h, 7,897.83 μg/L*h and 1,339.44 μg/L, respectively), while the CLz/F (1.07 L/h/kg) of macitentan and the metabolite-parent ratio (MR) displayed a significant decrease. Bergapten competitively inhibited macitentan metabolism in vitro and altered its pharmacokinetic characteristics in vivo. Further molecular docking analysis was also consistent with the experimental results. This study provides a reference for the combined use of bergapten and macitentan in clinical practice.

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment.Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented.Results: In the treatment process, ceftazidime–avibactam (CAZ–AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ–AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L.Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h.Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived.Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation.

Objective: To investigate the efficacy and safety of chemotherapy in treating Ph+ ALL based on flumatinib.Methods: The clinical data of 29 patients with Ph+ ALL receiving flumatinib-based chemotherapy in Sichuan Provincial People’s Hospital from January 2020 to January 2023 were collected for analysis, with the concentrations of TKI in the peripheral blood, bone marrow, and cerebrospinal fluid of some patients monitored, Cytological experiments on SUP-B15 were conducted in a Ph+ ALL cell line.Results: A total of 29 patients were enrolled, showing the induced CR, 3-month CR, and 6-month CR rates of 96.3%, 87.5%, and 86.7%, respectively after flumatinib-based chemotherapy. The negative conversion ratio of MRD was 82.6%, 91.3%, and 95.6% in 1, 2, and 3 months after treatment, respectively, with 4.3% of patients failing the conversion in 3 months after treatment. The rates of MMR were 73.9%, 87.5%, and 93.3% in 1, 3, and 6 months after treatment, and CMR of 52.2%, 62.5%, and 73.3%, respectively. Among the 29 patients, 11 (37.9%) received transplant and the continuous flumatinib for 1 year after transplantation. The deep remission was maintained in all patients up to the time of follow-up, with the median follow-up of 12 months (1–33 months), progression-free survival (PFS) of 11 months (1–33 months), and median overall survival (OS) of 12 months (1–33 months). The adverse reactions mainly referred to myelosuppression, liver insufficiency and infection that were generally tolerable. In terms of blood concentration, the concentration of flumatinib was ordered as bone marrow > serum > cerebrospinal fluid in Ph+ ALL bone marrow. In contrast, the concentration of dasatinib and imatinib was ordered as serum > bone marrow > cerebrospinal fluid. At the same time, flumatinib has a high probability to cross the blood-brain barrier, while the concentration of cerebrospinal fluid in the patients using Dasatinib was lower compared to the lower limit of detection in this study. Compared with Imatinib and Dasatinib, flumatinib exerted the most potent inhibitory effect on Ph+ ALL cell lines according to pharmacodynamic analysis of SUP-B15 cells.Conclusion: Flumatinib combined with chemotherapy could achieve good efficacy and safety in treating Ph+ ALL, with flumatinib in a high probability of crossing the blood-brain barrier. Flumatinib could be a superior choice to Dasatinib and Imatinib in cell experiments.

Major depressive disorder (MDD) is a psychiatric disorder with increasing prevalence worldwide. It is a leading cause of disability and suicide, severely affecting physical and mental health. However, the study of depression remains at an exploratory stage in terms of diagnostics and treatment due to the complexity of its pathogenesis. MicroRNAs are endogenous short-stranded non-coding RNAs capable of binding to the 3’untranslated region of mRNAs. Because of their ability to repress translation process of genes and are found at high levels in brain tissues, investigation of their role in depression has gradually increased recently. This article summarizes recent research progress on the relationship between microRNAs and depression. The microRNAs play a regulatory role in the pathophysiology of depression, involving dysregulation of monoamines, abnormalities in neuroplasticity and neurogenesis, hyperactivity of the HPA axis, and dysregulation of inflammatory responses. These microRNAs might provide new clue for the diagnosis and treatment of MDD, and the development of antidepressant drugs.

Cinobufacini injection (CI), an aqueous extract of Cutis Bufonis, is clinically used for cancer therapy in China, but its molecular mechanism for the treatment of osteosarcoma (OS) remains unclear. We constructed U2OS ectopic subcutaneous tumor model to verify the anti-OS effect of CI in vivo. Meanwhile, cell proliferation of U2OS and MG63 cells was monitored in vitro using the CCK-8 assay, colony formation and morphological changes. Cell cycle arrest and apoptosis were detected by flow cytometry and western blot, which showed that CI significantly inhibited proliferation, induced cell cycle arrest and apoptosis in human OS cells. The further RNA-seq results identified that the Hippo signaling pathway was involved in the anti-OS effect of CI. YAP/TAZ are two major components of the Hippo pathway in breast cancer and are positively regulated by prolyl isomerase PIN1, we assessed their role in OS using both clinicopathological sections and western blots. CI also inhibited PIN1 enzyme activity in a dose-dependent manner, which resulted in impaired PIN1, YAP, and TAZ expression in vitro and in vivo. Additionally, 15 potential compounds of CI were found to occupy the PIN1 kinase domain and inhibit its activity. In summary, CI plays an anti-OS role by down-regulating the PIN1-YAP/TAZ pathway.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally.Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data.Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment.Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment.Clinical Trial Registration:https://chinadrugtrials.org.cn, identifier: CTR20171377.

Objectives: This present study aimed to infer the association between aspirin exposure prior to ICU admission and the clinical outcomes of patients with Sepsis-associated acute respiratory failure (S-ARF).Methods: We obtained data from the Medical Information Mart for Intensive Care IV 2.0. Patients were divided into pre-ICU aspirin exposure group and Non-aspirin exposure group based on whether they took aspirin before ICU admission. The primary outcome is 28-day mortality. Augmented inverse propensity weighted was used to explore the average treatment effect (ATE) of the pre-ICU aspirin exposure. A generalized additive mixed model was used to analyze the longitudinal data of neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), oxygenation index (P/F), dynamic lung compliance (Cdyn), mechanical power (MP), and mechanical power normalized to predicted body weight (WMP) in the two groups. A multiple mediation model was constructed to explore the possible mediators between pre-ICU aspirin exposure and outcomes of patients with S-ARF.Results: A total of 2090 S-ARF patients were included in this study. Pre-ICU aspirin exposure decreased 28-day mortality (ATE, −0.1945, 95% confidence interval [CI], −0.2786 to −0.1103, p < 0.001), 60-day mortality (ATE, −0.1781, 95% Cl, −0.2647 to −0.0915, p < 0.001), and hospital mortality (ATE, −0.1502, 95%CI, −0.2340 to −0.0664, p < 0.001). In subgroup analysis, the ATE for 28-day mortality, 60-day mortality, and hospital mortality were not statistically significant in the coronary care unit group, high-dose group (over 100 mg/d), and no invasive mechanical ventilation (IMV) group. After excluding these non-beneficiaries, Cdyn and P/F ratio of the pre-ICU aspirin exposure group increased by 0.31mL/cmH2O (SE, 0.21, p = 0.016), and 0.43 mmHg (SE, 0.24, p = 0.041) every hour compared to that of non-aspirin exposure group after initialing IMV. The time-weighted average of NLR, Cdyn, WMP played a mediating role of 8.6%, 24.7%, and 13% of the total effects of pre-ICU aspirin exposure and 28-day mortality, respectively.Conclusion: Pre-ICU aspirin exposure was associated with decreased 28-day mortality, 60-day mortality, and hospital mortality in S-ARF patients except those admitted to CCU, and those took a high-dose aspirin or did not receive IMV. The protective effect of aspirin may be mediated by a low dynamic level of NLR and a high dynamic level of Cdyn and WMP. The findings should be interpreted cautiously, given the sample size and potential for residual confounding.

Objective: Leonurine is a bioactive alkaloid compound extracted from Leonurus japonicus Houtt, which potentially has immunomodulatory effects. The immunomodulatory effect and mechanism of leonurine on monocyte derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients were investigated for the first time.Methods: Peripheral blood from HDs and MM patients was isolated for peripheral blood mononuclear cells (PBMCs). The generation of moDCs was conducted by the incubation of monocytes from PBMCs in the medium consisting of RPMI 1640 medium, 2 mmol/L L-glutamine, 5% human serum, 800 U/mL GM-CSF, 500 U/mL IL-4, 100 U/mL penicillin and 0.1 mg/mL streptomycin. During the incubation of 7 days, the cells were administrated with 1 μM leonurine or 1 × PBS as the control group. On the 8th day, cells were harvested. The expression of maturation associated surface markers CD40, CD83, and HLA-DR on moDCs was analyzed by flow cytometry. Moreover, moDCs with or without 1 μM leonurine administration were evaluated by LC-MS/MS for metabolomics which was further analyzed for the potential mechanism of leonurine on moDCs.Results: The proportion of moDCs in the harvested cells was significantly higher in the HD group (n = 14) than in the MM patient group (n = 11) (p = 0.000). Leonurine significantly enhanced the median fluorescence intensity of CD83, HLA-DR and CD40 expression on HD-moDCs (n = 14; p = 0.042, p = 0.013, p = 0.084) as well as MM paitent-moDCs (n = 11; p = 0.020, p = 0.006, p = 0.025). The metabolomics data showed that in moDCs (HD, n = 15), 18 metabolites in the pathway of arachidonic acid metabolism showed significant differences between the leonurine group and the control group (VIP all >1 and P all

Myocardial infarction (MI) is a highly prevalent and lethal disease worldwide. Prevention and timely recovery are critical for the control of the recurrence and heart failure in MI survivors. The present study was designed to investigate the cardioprotective activity of the herbal medicine formula Baoyuan Decoction (BYD) and identify the active compounds and molecular targets. The ethanolic BYD extract (BYDE) was prepared by water extraction and ethanol precipitation of four herbal medicines, Astragali Radix, Ginseng Radix et Rhizoma, Cinnamomi Cortex, and Glycyrrhizae Radix et Rhizoma. Initially, BYDE was validated for the cardioprotective effectiveness in a mouse model of ischemia injury and rat cardiomyocyte H9C2 cells. As results, BYDE effectively reduced infarct size from 56% to 37% and preserved cardiac functions in mouse MI model while protected H9C2 cells against oxygen glucose deprivation. Subsequent network pharmacology analysis revealed that 122 bioactive ingredients, including flavonoids and saponins from the UPLC-MS/MS profile of BYDE, might target 37 MI-related proteins, including inflammatory and apoptotic mediators (e.g., TNF, NFKB1, CASPs, TNFRSF1A, CXCL12, BCL2A1). Pathway enrichment analysis suggested that BYDE might control the cardiac inflammation via targeting the tumor necrosis factor-alpha (TNF-α)/nuclear factor-κB (NF-κB) pathway while the selected targets were also implicated in IL-17 signaling pathway, lipid and atherosclerosis. Consequently, adenosine, ginsenoside Rh2, isoliquiritigenin, and licochalcone A were selected to generate the four-compound mixture AGILe and validated for the inhibitory effects on the TNF-α/NF-κB pathway. The results of the present study suggested that the mixture AGILe might be a potential cardioprotective remedy against MI.

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography–high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

Aim: Peritoneal dialysis is a common renal replacement method for end-stage renal disease. Long-term peritoneal dialysis leads to peritoneal dialysis-related peritoneal fibrosis, which leads to a cessation of treatment. Calpain is a protein belonging to calcium-dependent endopeptidase family and plays an important role in extracellular matrix remodeling. Here, we evaluated the effect of calpain in peritoneal dialysis-related peritoneal fibrosis.Methods: We established two animal models of peritoneal fibrosis and inhibited the activity of Calpain, and then collected peritoneal tissue to evaluate the progress of fibrosis and the changes of Calpain and β-catenin. We obtained Rat peritoneal mesothelial cells and Human peritoneal mesothelial cell line and stimulated with TGF-β to produce extracellular matrix. Next we inhibited Calpain activity or reduced Calpain9 expression, and then assessed changes in extracellular matrix and β-catenin.Results: Inhibition of calpain activity attenuated chlorhexidine glucose and peritoneal dialysis-induced peritoneal thickening and β-catenin expression in mice. In addition, compared with the control group, when primary rat peritoneal mesothelial cells or human peritoneal mesothelial cells were treated with transforming growth factor beta, down-regulation of calpain activity inhibited the expression of Fibronectin and Collagen I, and increased the expression of E-cadherin. These changes could be adjusted after silencing calpain9. Finally, calpain9 deficiency was associated with down-regulation of Fibronectin and β-catenin in human peritoneal mesothelial cells.Conclusion: Our results suggest that calpain9 may be a key molecule in mediating peritoneal dialysis-related peritoneal fibrosis.

Objective: To investigate the role and mechanisms of action of nafamostat mesylate (NM) in rhabdomyolysis-induced acute kidney injury (RIAKI).Methods: RIAKI rats were assigned into control group (CN), RIAKI group (RM), and NM intervention group (NM). Inflammatory cytokines and proenkephalin a 119–159 (PENKID) were assessed. Cell apoptosis and glutathione peroxidase-4 (GPX4) were detected using TUNEL assay and immunohistochemical staining. Mitochondrial membrane potential (MMP) was detected by JC-1 dye. The expression of genes and metabolites after NM intervention was profiled using transcriptomic and metabolomic analysis. The differentially expressed genes (DEGs) were validated using qPCR. The KEGG and conjoint analysis of transcriptome and metabolome were used to analyze the enriched pathways and differential metabolites. The transcription factors were identified based on the animal TFDB 3.0 database.Results: Serum creatinine, blood urea nitrogen, and PENKID were remarkably higher in the RM group and lower in the NM group compared to the CN group. Pro-inflammatory cytokines increased in the RM group and notably decreased following NM treatment compared to the CN group. Tubular pathological damages were markedly attenuated and renal cell apoptosis was reduced significantly in the NM group compared to the RM group. The expression of GPX4 was lower in the RM group compared to the CN group, and it increased significantly after NM treatment. A total of 294 DEGs were identified in the RM group compared with the NM group, of which 192 signaling pathways were enriched, and glutathione metabolism, IL-17 signaling, and ferroptosis-related pathways were the top-ranking pathways. The transcriptional levels of Anpep, Gclc, Ggt1, Mgst2, Cxcl13, Rgn, and Akr1c1 were significantly different between the NM and RM group. Gclc was the key gene contributing to NM-mediated renal protection in RIAKI. Five hundred and five DEGs were annotated. Compared with the RM group, most of the upregulated DEGs in the NM group belonged to Glutathione metabolism, whereas most of the downregulated DEGs were related to the transcription factor Cytokine-cytokine receptor interaction.Conclusion: NM protects the kidneys against RIAKI, which is mainly associated with NM mediated regulation of glutathione metabolism, inflammatory response, ferroptosis-related pathways, and the related key DEGs. Targeting these DEGs might emerge as a potential molecular therapy for RIAKI.

Background: Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson’s Disease (PD) patients with end-of-dose motor fluctuations.Objective: This study aimed to compare the short-term (

The high accumulation and poor penetration of nanocarriers in tumor is a contradiction of nanomedicine, which reduces the efficacy of chemotherapy. Due to the positive effect of hyperthermia on in vivo drug diffusion, we designed a magnetothermally sensitive micelle (MTM) by integrating magnetic targeting (MT), magnetic hyperthermia (MH), and magnetothermally responsive drug release to facilitate simultaneous drug accumulation and penetration in tumor. Accordingly, we synthesized a cyanine7-modified thermosensitive polymer with phase transition at 42.3°C, and utilized it to prepare drug-loaded MTMs by encapsulating superparamagnetic MnFe2O4 nanoparticles and doxorubicin (DOX). The obtained DOX–MTM had not only high contents of DOX (9.1%) and MnFe2O4 (38.7%), but also some advantages such as superparamagnetism, high saturation magnetization, excellent magnetocaloric effect, and magnetothermal-dependent drug release. Therefore, DOX–MTM improved in vitro DOX cytotoxicity by enhancing DOX endocytosis under the assistance of MH. Furthermore, MT and MH enhanced in vivo DOX–MTM accumulation and DOX penetration in tumor, respectively, substantially inhibiting tumor growth (84%) with excellent biosafety. These results indicate the development of an optimized drug delivery system with MH and MH-dependent drug release, introducing a feasible strategy to enhance the application of nanomedicines in tumor chemotherapy.

Hypertension is one of the common causes of pathological cardiac hypertrophy and a major risk for morbidity and mortality of cardiovascular diseases worldwide. Ubiquitin-Specific Protease 7 (USP7), the first identified deubiquitinating enzymes, participated in a variety of biological processes, such as cell proliferation, DNA damage response, tumourigenesis, and apoptosis. However, its role and mechanism in cardiac remodeling remain unclear. Here, our data indicated that USP7 expression was increased during Ang II-induced cardiac hypertrophy and remodeling in mice and humans with heart failure, while the administration of its inhibitor p22077 attenuated cardiac hypertrophy, cardiac fibrosis, inflammation, and oxidase stress. Mechanistically, the administration of p22077 inhibited the multiple signaling pathways, including AKT/ERK, TGF-β/SMAD2/Collagen I/Collagen III, NF-κB/NLRP3, and NAPDH oxidases (NOX2 and NOX4). Taken together, these findings demonstrate that USP7 may be a new therapeutic target for hypertrophic remodeling and HF.

Background: Euodiae Fructus, a well-known herbal medicine, is widely used in Asia and has also gained in popularity in Western countries over the last decades. It has known side effects, which have been observed in clinical settings, but few studies have reported on its cardiotoxicity.Methods: In the present study, experiments using techniques of untargeted metabolomics clarify the hazardous effects of Euodiae Fructus on cardiac function and metabolism in rats in situations of overdosage and unsuitable syndrome differentiation. In vitro assays are conducted to observe the toxic effects of evodiamine and rutaecarpine, two main chemical constituents of Euodiae Fructus, in H9c2 and neonatal rat cardiomyocytes (NRCMs), with their signaling mechanisms analyzed accordingly.Results: The cardiac cytotoxicity of evodiamine and rutaecarpine in in vivo experiments is associated with remarkable alterations in lactate dehydrogenase, creatine kinase, and mitochondrial membrane potential; also with increased intensity of calcium fluorescence, decreased protein expression of the cGMP-PKG pathway in H9c2 cells, and frequency of spontaneous beat in NRCMs. Additionally, the results in rats with Yin deficiency receiving a high-dosage of Euodiae Fructus suggest obvious cardiac physiological dysfunction, abnormal electrocardiogram, pathological injuries, and decreased expression of PKG protein. At the level of endogenous metabolites, the cardiac side effects of overdose and irrational usage of Euodiae Fructus relate to 34 differential metabolites and 10 metabolic pathways involving among others, the purine metabolism, the glycerophospholipid metabolism, the glycerolipid metabolism, and the sphingolipid metabolism.Conclusion: These findings shed new light on the cardiotoxicity induced by Euodiae Fructus, which might be associated with overdose and unsuitable syndrome differentiation, that comes from modulating the cGMP-PKG pathway and disturbing the metabolic pathways of purine, lipid, and amino acid. Continuing research is needed to ensure pharmacovigilance for the safe administration of Chinese herbs in the future.

Cardiovascular diseases are the leading cause of global mortality, in which myocardial infarction accounts for 46% of total deaths. Although good progress has been achieved in medication and interventional techniques, a proven method to repair the damaged myocardium has not yet been determined. Stem cell therapy for damaged myocardial repair has evolved into a promising treatment for ischemic heart disease. However, low retention and poor survival of the injected stem cells are the major obstacles to achieving the intended therapeutic effects. Chinese botanical and other natural drug substances are a rich source of effective treatment for various diseases. As such, numerous studies have revealed the role of Chinese medicine in stem cell therapy for myocardial infarction treatment, including promoting proliferation, survival, migration, angiogenesis, and differentiation of stem cells. Here, we discuss the potential and limitations of stem cell therapy, as well as the regulatory mechanism of Chinese medicines underlying stem cell therapy. We focus on the evidence from pre-clinical trials and clinical practices, and based on traditional Chinese medicine theories, we further summarize the mechanisms of Chinese medicine treatment in stem cell therapy by the commonly used prescriptions. Despite the pre-clinical evidence showing that traditional Chinese medicine is helpful in stem cell therapy, there are still some limitations of traditional Chinese medicine therapy. We also systematically assess the detailed experimental design and reliability of included pharmacological research in our review. Strictly controlled animal models with multi-perspective pharmacokinetic profiles and high-grade clinical evidence with multi-disciplinary efforts are highly demanded in the future.

Tibetan medicine is one of the oldest traditional medicine systems in the world. Taking the Ruyi Zhenbao tablet (RYZB) as an example, which is a widely used classic oral Tibetan medicine, this article discusses the pharmacokinetics of single administration and long-term treatment and analyzed its metabolic properties and tissue distribution in vivo. After single administration, blood samples were collected before administration and at different time points after administration in different groups of rats. In the study of long-term treatment effects, blood samples were collected from the animals in each group on days 1, 15, and 30 and on day 15 after withdrawal. The results showed that after a single administration, the dose change had no significant effect on the T1/2 and Tmax of agarotetrol, isoliquiritigenin, and piperine (p > 0.05). There was a certain correlation between the increase in AUC0-t and the Cmax of agarotetrol, isoliquiritigenin, piperine, and the increase in dosage, with a dose range of 0.225–0.900 g/kg. There were no significant differences in Cmax and AUC0-t of ferulic acid at different doses (p > 0.05). Meanwhile, there was no significant sex-based difference in the pharmacokinetic parameters of these four components in rats. After long-term administration, the distribution agarotetrol in various tissues of rats was kidney > liver > heart > brain; the tissue distribution in low- and medium-dose groups of isoliquiritigenin was liver > kidney > heart > brain, and in the high-dose group, kidney > liver > heart > brain. The tissue distribution of piperine in each dose group was liver > kidney > heart > brain, and that of ferulic acid in each dose group was kidney > liver > heart > brain. Through the establishment of the previously developed methodology, the pharmacokinetic properties of RYZB were analyzed after a single administration and long-term administration. Our findings confirmed this approach for the exploration and establishment of a pharmacokinetic evaluation of Tibetan medicine, to support its guiding role in clinical application, but also to accelerate research into Tibetan medicine theory and medicine and to provide a solid foundation for the translation of Tibetan medicine throughout the world.

Background: This study aims to investigate the needs of child caregivers for popular science about safe medication for children, to deeply explore the characteristics of child caregivers’ demand for safe medication and the shortcomings of current popular science work, and then to seek better coping strategies to ensure children’s safe medication.Methods: A questionnaire was designed based on Lasswell’s “5W” communication model to investigate the needs of child caregivers in terms of content, channels, and forms of popular healthcare science on the safe usage of children’s medication.Results: The primary ways caregivers receive popular healthcare science education concerning safe medication usage knowledge are through medical institutions, notification by medical staff, and personal media. The caregivers of children have a high demand for the presentation of text, pictures, and videos in three forms of popular healthcare science content. Caregivers placed significant importance on the popularization of safe medication usage for children. The survey results showed that the top 3 ways for caregivers to think that the quality of popular healthcare science content was “very good” came from medical institutions, medical staff notifications, and personal media, effectively increasing popular healthcare information accuracy. The intelligibility and pertinence of content expression are urgently needed within the caregiver population.Conclusion: Caregivers are very concerned about the popular science of safe medication for children, and are willing to learn about relevant content. Guided by the demand, we should actively disseminate accurate and easy-to-understand popular science about safe medication for children to caregivers through online or offline channels so as to promote safe medication for children.

It has been reported that drug-drug interactions (DDIs) can affect the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of azole antifungal drugs (ketoconazole, fluconazole, and itraconazole) on pyrotinib’s pharmacokinetics, DDIs between pyrotinib and three azoles were studied with Sprague-Dawley (SD) rat liver microsomes in vitro. Additionally, in vivo pyrotinib metabolic experiment was also performed. Twenty-four male SD rats were randomly divided into four groups: the ketoconazole (40 mg/kg), fluconazole (40 mg/kg), itraconazole (40 mg/kg), and the control group. UPLC-MS/MS was used for the determination of Pyrotinib’s plasma concentration in rats. In vitro experiments showed that IC50 values of ketoconazole, fluconazole and itraconazole were 0.06, 11.55, and 0.27 μM, respectively, indicating that these drugs might reduce the clearance rate of pyrotinib at different degrees. In rat studies, coadministration of pyrotinib with ketoconazole or fluconazole could dramatically increase the Cmax and AUC(0-t) values and decrease the clearance rate of pyrotinib, especially for ketoconazole. However, coadministration with itraconazole had no impact on the pharmacokinetic characters of pyrotinib. These data indicated that ketoconazole and fluconazole could significantly decrease the metabolism of pyrotinib both in vitro and in vivo. More attentions should be paid when pyrotinib is combined with azole antifungal drugs in clinic although further investigation is still required in future.

Low back pain is thought to be mainly caused by intervertebral disc degeneration (IVDD), and there is a lack of effective treatments. Cellular senescence and matrix degradation are important factors that cause disc degeneration. Mitochondrial dysfunction induced by oxidative stress is an important mechanism of cellular senescence and matrix degradation in the nucleus pulposus (NP), and mitophagy can effectively remove damaged mitochondria, restore mitochondrial homeostasis, and mitigate the damage caused by oxidative stress. Optineurin (OPTN) is a selective mitophagy receptor, and its role in intervertebral disc degeneration remains unclear. Here, we aimed to explore the effect of OPTN on H2O2-induced nucleus pulposus cell (NPCs) senescence and matrix degradation in a rat model of disc degeneration. Western blot analysis showed that OPTN expression was reduced in degenerative human and rat nucleus pulposus tissues and increased in H2O2-induced senescent NPCs. OPTN overexpression significantly inhibited H2O2-induced senescence and increased matrix-associated protein expression in NPCs, but OPTN knockdown showed the opposite effect. As previous reports have suggested that mitophagy significantly reduces mitochondrial damage and reactive oxygen species (ROS) caused by oxidative stress, and we used the mitophagy agonist CCCP, the mitophagy inhibitor cyclosporin A (CsA), and the mitochondrial ROS (mtROS) scavenger mitoTEMPO and confirmed that OPTN attenuated NPCs senescence and matrix degeneration caused by oxidative stress by promoting mitophagy to scavenge damaged mitochondria and excess reactive oxygen species, thereby slowing the progression of IVDD. In conclusion, our research suggests that OPTN is involved in IVDD and exerts beneficial effects against IVDD.

Aims: To develop, optimize, and validate a novel model using alanine aminotransferase (ALT) and total bilirubin (TB) dynamic evolution patterns in predicting acute liver failure (ALF) in drug-induced liver injury (DILI) patients.Methods: The demographics, clinical data, liver biopsy, and outcomes of DILI patients were collected from two hospitals. According to the dynamic evolution of ALT and TB after DILI onset, the enrolled patients were divided into ALT-mono-peak, TB-mono-peak, double-overlap-peak, and double-separate-peak (DSP) patterns and compared. Logistic regression was used to develop this predictive model in both discovery and validation cohorts.Results: The proportion of ALF was significantly higher in patients with the DSP pattern than in the ALT-mono-peak pattern and DOP pattern (10.0 vs. 0.0% vs. 1.8%,p < 0.05). The area under receiver operating characteristic curve (AUROC) of the DSP pattern model was 0.720 (95% CI: 0.682–0.756) in the discovery cohort and 0.828 (95% CI: 0.788–0.864) in the validation cohort in predicting ALF, being further improved by combining with international normalized ratio (INR) and alkaline phosphatase (ALP) (AUROC in the discovery cohort: 0.899; validation cohort: 0.958). Histopathologically, patients with the DSP pattern exhibited a predominantly cholestatic hepatitis pattern (75.0%, p < 0.05) with a higher degree of necrosis (29.2%, p = 0.084).Conclusion: DILI patients with the DSP pattern are more likely to progress to ALF. The predictive potency of the model for ALF can be improved by incorporating INR and ALP. This novel model allows for better identification of high-risk DILI patients, enabling timely measures to be instituted for better outcome.

The Huashi Baidu Formula (HSBDF), a key Chinese medical drug, has a remarkable clinical efficacy in treating acute lung injury (ALI), and it has been officially approved by the National Medical Products Administration of China for drug clinical trials. Nevertheless, the regulated mechanisms of HSBDF and its active compounds in plasma against ALI were rarely studied. Based on these considerations, the key anti-inflammatory compounds of HSBDF were screened by molecular docking and binding free energy. The key compounds were further identified in plasma by LC/MS. Network pharmacology was employed to identify the potential regulatory mechanism of the key compounds in plasma. Next, the network pharmacological prediction was validated by a series of experimental assays, including CCK-8, EdU staining, test of TNF-α, IL-6, MDA, and T-SOD, and flow cytometry, to identify active compounds. Molecular dynamic simulation and binding interaction patterns were used to evaluate the stability and affinity between active compounds and target. Finally, the active compounds were subjected to predict pharmacokinetic properties. Molecular docking revealed that HSBDF had potential effects of inhibiting inflammation by acting on IL-6R and TNF-α. Piceatannol, emodin, aloe-emodin, rhein, physcion, luteolin, and quercetin were key compounds that may ameliorate ALI, and among which, there were five compounds (emodin, aloe-emodin, rhein, luteolin, and quercetin) in plasma. Network pharmacology results suggested that five key compounds in plasma likely inhibited ALI by regulating inflammation and oxidative damage. Test performed in vitro suggested that HSBDF (0.03125 mg/ml), quercetin (1.5625 μM), emodin (3.125 μM), and rhein (1.5625 μM) have anti-inflammatory function against oxidative damage and decrease apoptosis in an inflammatory environment by LPS-stimulation. In addition, active compounds (quercetin, emodin, and rhein) had good development prospects, fine affinity, and stable conformations with the target protein. In summary, this study suggested that HSBDF and its key active components in plasma (quercetin, emodin, and rhein) can decrease levels of pro-inflammatory factors (IL-6 and TNF-α), decrease expression of MDA, increase expression of T-SOD, and decrease cell apoptosis in an inflammatory environment. These data suggest that HSBDF has significant effect on anti-inflammation and anti-oxidative stress and also can decrease cell apoptosis in treating ALI. These findings provided an important strategy for developing new agents and facilitated clinical use of HSBDF against ALI.

Renal tubulointerstitial fibrosis (TIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, is the typical pathological alteration in diabetic nephropathy. Gentiopicroside (GPS), a natural compound with anti-inflammatory activity, has been demonstrated to alleviate glomerulosclerosis, whereas whether GPS inhibits TIF via regulating inflammation remains unclear. In this study, diabetic db/db mice and high glucose (HG)-stimulated renal tubular epithelial cells (NRK-52E) were applied to explore the effects and mechanisms of GPS on TIF. The results in vivo showed that GPS effectively improves glycolipid metabolism disorder, renal dysfunction, and TIF. In particular, GPS treatment reversed the abnormal expressions of EMT marker proteins including elevated α-smooth muscle actin and vimentin and decreased E-cadherin in the kidney of db/db mice. Moreover, GPS treatment also inhibited protein expressions of angiotensinⅡ type 1 receptor (AT1R) and CK2α and the activation of the NF-κB pathway. Importantly, the aforementioned effects of GPS acted in vivo were further observed in vitro in HG-stimulated NRK-52E cells, which were independent of its effects on glucose and lipid-lowering activity but were reversed by AT1R over-expression. Together, our results indicate that GPS that directly inhibits the CK2/NF-κB inflammatory signaling pathway via AT1R may also contribute to the amelioration of TIF in diabetes.

Network pharmacology, as a novel way using bioinformatics to explore drug targets and interactions in cancer, broadens our understanding of drug action, thereby facilitating drug discovery. Here, we utilized network pharmacology to explore the role and mechanism by which cinobufotalin functions in colon adenocarcinoma (COAD). We found that cinobufotalin represses the growth and proliferation of colon cancer cells, and integrated public databases for targets reported to be associated with COAD, together with those predicted to be targets of cinobufotalin. Targets overlapped between COAD-associated proteins and cinobufotalin target proteins were used to filter candidate targets of cinobufotalin in COAD. The following proteins were thought to occupy a key position in COAD-cinobufotalin target networks: SRC, PIK3R1, MAPK1, PIK3CA, HSP90AA1, CTNNB1, GRB2, RHO1, PTPN11, and EGFR. The networks regulated by cinobufotalin were involved mainly in extracellular signal stimulation and transduction, including MAPK signaling pathway, PI3K-AKT signaling pathway, and JAK-STAT signaling pathway. Besides, transcriptome sequencing results also indicated that cinobufotalin inhibits the response of colon cancer cells to extracellular stimulation and promotes cell apoptosis. Molecular docking results showed that cinobufotalin matches in the pocket of the top candidate cinobufotalin target proteins (SRC, PIK3R1, MAPK1 and PIK3CA). These findings demonstrate cinobufotalin can be developed as potential anti-cancer therapeutics.

Aims: The objective of this study was to assess the efficacy and potential mechanisms of Chinese herbal medicine (CHM) for treating coronary heart disease (CHD) patients with anxiety or depression.Methods: A systematic literature search was performed. Screening studies, extracting data, and assessing article quality were carried out independently by two researchers. The active ingredients of CHM for the treatment of CHD with anxiety or depression were analyzed by the network pharmacology, and the main potential mechanisms were summarized by the database of Web of Science.Results: A total of 32 studies were included. The results showed that compared with the blank control groups, CHM was more beneficial in treating anxiety or depression in patients with CHD [anxiety: OR = 3.22, 95% CI (1.94, 5.35), p < 0.00001, I2 = 0%; depression: OR = 3.27, 95% CI (1.67, 6.40), p = 0.0005, I2 = 0%], and the efficacy of CHM was not inferior to that of Western medicine (WM) [anxiety: OR = 1.58, 95%CI (0.39, 6.35), p = 0.52, I2 = 67%; depression: OR = 1.97, 95%CI (0.73, 5.28), p = 0.18, I2 = 33%,]. Additionally, CHM also showed a significant advantage in improving angina stability (AS) in CHD patients with anxiety or depression compared with blank groups [anxiety: SMD = 0.55, 95%CI (0.32, 0.79), p < 0.00001, I2 = 0%; depression: p = 0.004] and WM groups [anxiety: SMD = 1.14, 95%CI (0.80, 1.47), p < 0.00001, I2 = 0%; depression: SMD = 12.15, 95%CI (6.07, 18.23), p < 0.0001, I2 = 0%]. Angina frequency (AF) and electrocardiogram (ECG) analysis after using CHM demonstrated similar trends. Based on the network pharmacology, quercetin, kaempferol, luteolin, beta-sitosterol, puerarin, stigmasterol, isorhamnetin, baicalein, tanshinone IIa, and nobiletin were most closely and simultaneously related to the pathological targets of CHD, anxiety, and depression. The main underlying mechanisms might involve anti-damage/apoptosis, anti-inflammation, antioxidative stress, and maintaining neurotransmitter homeostasis.Conclusion: CHM exhibited an obvious efficacy in treating CHD patients with anxiety or depression, especially for improving the symptom of angina pectoris. The most active compounds of CHM could simultaneously act on the pathological targets of CHD, anxiety, and depression. Multiple effective components and multiple targets were the advantages of CHM compared with WM.

Huang Qin Decoction (HQD), is used for the treatment of diabetic liver injury (DLI) and in this study, its mechanisms were evaluated by metabonomics and system pharmacology. To study the anti-DLI effects of HQD. The 48 male db/db mice were fed adaptively for one week, and a random blood glucose test was performed twice. The db/db mice with a blood glucose level of more than 11.1mol/l were separated into four groups: the model group, the active control group, the high-dose HQD group the low-dose HQD group, the control group consisted of db/m mice. Using the UHPLC/Q-TOF-MS metabolomics approach, 18 metabolites were found to be profoundly altered in the model group, and the levels of these biomarkers were significantly recovered after treatment with HQD. 8 signaling pathways related to HQD, including the Sphingolipid metabolism, Taurine and hypotaurine metabolism, Phenylalanine metabolism, Glutathione metabolism and Glycerophospholipid metabolism, etc. were explored. In addition, the system pharmacology paradigm revealed that HQD contains 141 active ingredients and is related to 265 genes, and 1404 disease genes are related to DLI. The construction of the HQD composition-target-DLI network identified a total of 161 intersection genes. We identified 10 key genes, which is partially compatible with the results of metabolomics. The integrated approach metabolomics and network pharmacology revealed that additional detailed investigation focused on five major targets, including CAT, PTGS2, MAPK3, AKT1, and MAPK8, and their essential metabolites (sphinganine, sphingosine, Glutahione, Oxidized gutahione, Dihydrolipoamide) and pathway (glycerol phospholipid metabolism and tryptophan metabolism). The significant affinity of the primary target for the HQD was confirmed by molecular docking. The results demonstrate that the combination of metabolomics and network pharmacology could be used to reflect the effects of HQD on the biological network and metabolic state of DLI and to evaluate the drug efficacy of HQD and its related mechanisms.

Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions’ function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC), which is characterized by the total absence of human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) expression. Cinobufacini injection (CI) is the aqueous extract from the dry skin of Bufo gargarizans, which is broadly used for the treatment of malignant tumors. However, the potential mechanism of CI against TNBC has not been fully revealed. In this study, we found that CI inhibited the proliferation of MDA-MB-231 and 4T1 cells in a time- and dose-dependent manner. RNA-seq data showed that downregulated and upregulated genes were mainly enriched in biological processes related to tumor cell proliferation, including cell cycle arrest and regulation of apoptosis signaling pathways. Indeed, after CI treatment, the protein level of CDK1 and Bcl-2/Bax decreased, indicating that CI induced the cell cycle of MDA-MB-231 arrest in the G2/M phase and increased the rate of apoptosis. Meanwhile, CI significantly inhibited the growth of tumor in vivo, and RNA-seq data showed that the TAZ signaling pathway played a vital role after CI treatment. Both immunohistochemistry and Western blot analysis confirmed the downregulation of Pin1 and TAZ, caused by CI treatment. Furthermore, the bioinformatics analysis indicated that Pin1 and TAZ were indeed elevated in TNBC patients, with poor staging, classification, and patient survival rate. In conclusion, CI effectively inhibited the proliferation of TNBC in vitro and in vivo and induced their apoptosis and cycle arrest through the Pin1–TAZ pathway.

Shenerjiangzhi formulation (SEJZ) is a new traditional Chinese medicine formulation (patent number: CN110680850A). SEJZ contains Eleutherococcus senticosus (Rupr. and Maxim.), Maxim (Araliaceae; E. senticosus radix and rhizome), Lonicera japonica Thunb (Caprifoliaceae; Lonicera japonica branch, stem), Crataegus pinnatifida Bunge (Rosaceae; Crataegus pinnatifida fruit), and Auricularia auricula. SEJZ has been designed to treat hyperlipidemia. Despite the therapeutic benefits of SEJZ, its underlying mechanism of action is not known. We explored the efficacy of SEJZ against hyperlipidemia by integrating network pharmacology and 16S rRNA gene sequencing and elucidated its mechanism of action. First, SEJZ targets were found through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and from the literature. Hyperlipidemia-related therapeutic targets were obtained from GeneCards, Online Mendelian Inheritance in Man, and DrugBank databases. Then, Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape were applied for the analyses and construction of a protein–protein interaction (PPI) network. The Kyoto Encyclopedia of Genes and Genomes database was employed to identify signaling pathways that were enriched. Second, the therapeutic effects of SEJZ against hyperlipidemia induced by consumption of a high-fat diet in rats were evaluated by measuring body weight changes and biochemical tests. SEJZ treatment was found to alleviate obesity and hyperlipidemia in rats. Finally, 16S rRNA gene sequencing showed that SEJZ could significantly increase the abundance of short-chain fatty acid-producing bacteria, restore the intestinal barrier, and maintain intestinal-flora homeostasis. Using PICRUSt2, six metabolic pathways were found to be consistent with the results of network pharmacology: “African trypanosomiasis”, “amoebiasis”, “arginine and proline metabolism”, “calcium signaling pathway”, “NOD-like receptor signaling pathway”, and “tryptophan metabolism”. These pathways might represent how SEJZ works against hyperlipidemia. Moreover, the “African trypanosomiasis pathway” had the highest association with core genes. These results aid understanding of how SEJZ works against dyslipidemia and provide a reference for further studies.

Background: Polymyxin B has become the last choice for patient with carbapenem-resistant bacterial infection. However, the optimal dosing of polymyxin B in critically ill children receiving continuous renal replacement therapy (CRRT) remains unclear.Case Presentation: Two cases of critically ill pediatric patients (7 years old) with acute kidney injury requiring continuous renal replacement (CRRT) received polymyxin B treatment due to carbapenem-resistant organism bloodstream infections. Therapeutic drug monitoring (TDM) of polymyxin B was carried out by liquid chromatography tandem mass spectrometry (LC-MS/MS). The average steady-state plasma concentration (Css,avg) of 2–4 mg/L was set as the target level. Initial polymyxin B dose was 1 mg/kg every 12 h, and the Css,avg at 4–5th dosing were 1.76 and 1.06 mg/L for patient 1 and patient 2, respectively. TDM-guided polymyxin B dose was escalated to 2 mg/kg every 12 h for both patients, resulting in the Css,avg of 2.60 and 1.73 mg/L, and the infection was controlled subsequently. Css,avg of polymyxin B with the same dosing regimens and infusion length were different during CRRT and after termination of CRRT for both patients (2.60 mg/L vs. 4.94 mg/L with 2 mg/kg every 12 h in 2 h infusion for patient 1; and 1.73 mg/L vs. 3.53 mg/L with 2 mg/kg every 12 h in 2 h infusion for patient 2). The estimation of drug exposure (estimated by AUCss,12h at the same dose) during CRRT and cessation of CRRT showed that 45% and 51% of polymyxin B was cleared during CRRT.Conclusion: Our study showed high clearance of polymyxin B through CRRT, and supplanted dosing of polymyxin B is necessary in pediatric patients undergoing CRRT.

Bidens plants are annuals or perennials of Asteraceae and usually used as medicinal materials in China. They are difficult to identify by using traditional identification methods because they have similar morphologies and chemical components. Universal DNA barcodes also cannot identify Bidens species effectively. This situation seriously hinders the development of medicinal Bidens plants. Therefore, developing an accurate and effective method for identifying medicinal Bidens plants is urgently needed. The present study aims to use phylogenomic approaches based on organelle genomes to address the confusing relationships of medicinal Bidens plants. Illumina sequencing was used to sequence 12 chloroplast and eight mitochondrial genomes of five species and one variety of Bidens. The complete organelle genomes were assembled, annotated and analysed. Phylogenetic trees were constructed on the basis of the organelle genomes and highly variable regions. The organelle genomes of these Bidens species had a conserved gene content and codon usage. The 12 chloroplast genomes of the Bidens species were 150,489 bp to 151,635 bp in length. The lengths of the eight mitochondrial genomes varied from each other. Bioinformatics analysis revealed the presence of 50–71 simple sequence repeats and 46–181 long repeats in the organelle genomes. By combining the results of mVISTA and nucleotide diversity analyses, seven candidate highly variable regions in the chloroplast genomes were screened for species identification and relationship studies. Comparison with the complete mitochondrial genomes and common protein-coding genes shared by each organelle genome revealed that the complete chloroplast genomes had the highest discriminatory power for Bidens species and thus could be used as a super barcode to authenticate Bidens species accurately. In addition, the screened highly variable region trnS-GGA-rps4 could be also used as a potential specific barcode to identify Bidens species.

Drug–drug interactions play a vital role in drug research. However, they may also cause adverse reactions in patients, with serious consequences. Manual detection of drug–drug interactions is time-consuming and expensive, so it is urgent to use computer methods to solve the problem. There are two ways for computers to identify drug interactions: one is to identify known drug interactions, and the other is to predict unknown drug interactions. In this paper, we review the research progress of machine learning in predicting unknown drug interactions. Among these methods, the literature-based method is special because it combines the extraction method of DDI and the prediction method of DDI. We first introduce the common databases, then briefly describe each method, and summarize the advantages and disadvantages of some prediction models. Finally, we discuss the challenges and prospects of machine learning methods in predicting drug interactions. This review aims to provide useful guidance for interested researchers to further promote bioinformatics algorithms to predict DDI.

Background: Therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) testing are widely used as approaches to improve individualized (personalized) pharmacotherapy. Little is known about TDM and PGx testing services in China. This study is aimed to describe the TDM and PGx testing services in northern China, and to lay the foundation for improving these services.Methods: We developed an electronic survey using online software and disseminated it to 32 public hospitals in northern China from May to July 2019. The data were analyzed using the Statistical Package for Social Sciences (SPSS) program (Ver.27.0).Results: We collected 29 of the 32 questionnaires (90.6% response rate) from public hospitals in seven provinces of northern China. Twenty-two public hospitals (76%) utilized TDM; immune suppressants, antiepileptic drugs and anti-infective drugs were the main drugs monitored. The hospitals that did not provide TDM service were traditional Chinese medicine hospitals and hospitals with a smaller number of hospital beds. Seventeen public hospitals (58.6%) had PGx testing programs. The hospitals that did not offer PGx testing service had a smaller number of hospital beds and had fewer daily outpatients.Conclusion: TDM is available in the vast majority of public hospitals in northern China, although mainly in tertiary hospitals. PGx testing, a newer approach, is less widely available. We recommend that more hospitals be encouraged to provide TDM and PGx testing services and more efforts be directed toward quality control, delivery of results and counseling of patients based on those results.

Psoriasis is a chronic inflammatory disease characterized by erythematous scaly plaques, accompanied by systemic damage that leads to the development of multiple comorbidities. In particular, the association between psoriasis and cardiometabolic comorbidities, including cardiovascular diseases (CVDs), obesity, diabetes mellitus, and metabolic syndrome, has been verified in a considerable number of clinical trials. Moreover, the increased risk of cardiometabolic comorbidities positively correlates with psoriasis severity. Biologic therapy targeting inflammatory pathways or cytokines substantially improves the life quality of psoriasis patients and may affect cardiometabolic comorbidities by reducing their incidences. In this review, we focus on exploring the association between cardiometabolic comorbidities and psoriasis, and emphasize the benefits and precautions of biologic therapy in the management of psoriasis with cardiometabolic comorbidities. The pathogenic mechanisms of cardiometabolic comorbidities in psoriasis patients involve common genetic factors, lipid metabolism, insulin resistance, and shared inflammatory pathways such as tumor necrosis factor-α and interleukin-23/Th-17 pathways.