Impact and implications of national centralized drug procurement in China.

The national centralized drug procurement (NCDP) policy, known as the "4 + 7" policy in China, has transformed pharmaceutical procurement and access by leveraging healthcare institutions' collective buying power to reduce drug prices substantially. This policy has profoundly impacted drug pricing mechanisms, healthcare expenditures, market dynamics, and the quality of available drugs. This commentary evaluates the efficacy, challenges, and broader implications of the NCDP, summarizes the current state of post-marketing monitoring of selected generic drugs for centralized procurement, and presents relevant considerations.

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

OBJECTIVE: We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4 years old after liver transplantation and to develop individualized tacrolimus dosing software. METHODS: A total of 663 blood concentrations from 85 patients aged 4.57 months to 3.97 years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. RESULTS: A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). CONCLUSIONS: A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Neurobrucellosis: laboratory features, clinical characteristics, antibiotic treatment, and clinical outcomes of 21 patients.

BACKGROUND: Neurobrucellosis (NB) is a rare and serious complication of brucellosis. Its clinical manifestations vary, with no obvious specificity. At present, there is no clear clinical diagnosis or treatment for reference. In this study, we retrospectively analyzed the clinical data for 21 patients with NB to provide reference data for its further study. METHODS: We analyzed the epidemiological and clinical manifestations, laboratory tests, imaging examinations, cerebrospinal fluid, and treatment plans of 21 patients diagnosed with NB in the Department of Neurology, Xuanwu Hospital, Capital Medical University Beijing, China. RESULTS: The ages of the patients ranged from 15 to 60 years old (mean age 40.1 ± 13.33 years), the male: female ratio was 4.25:1. Thirteen patients had a history of animal (sheep, cattle) contact, three had no history of animal contact, and the contact status of four was unknown. Brucella can invade various systems of the body and show multi-system symptoms, the main general manifestations were fever (66.67%), fatigue (57.14%) and functional urination or defecation disturbance (42.86%). The main nervous system manifestations were limb weakness (52.38%) and hearing loss (47.62%).The main positive signs of the nervous system included positive pathological signs (71.43%), sensory abnormalities (52.38%), limb paralysis (42.86%). Nervous system lesions mainly included spinal cord damage (66.67%), cranial nerve involvement (61.90%), central demyelination (28.57%) and meningitis (28.57%). In patients with cranial nerve involvement, 69.23% of auditory nerve, 15.38% of optic nerve and 15.38% of oculomotor nerve were involved. The blood of eight patients was cultured for Brucella, and three (37.5%) cultures were positive and five (63.5%) negative. The cerebrospinal fluid (CSF) of eight patients was cultured for Brucella, and two (25.00%) cultures were positive and six (75.00%) negative. Nineteen of the patients underwent a serum agglutination test (SAT), 18 (94.74%) of whom were positive and one (5.26%) of whom were negative. A biochemical analysis of the CSF was performed in 21 patients, and the results were all abnormal. Nineteen patients underwent magnetic resonance imaging (MRI). Twenty-one patients were treated with doxycycline and/or rifampicin, combined with ceftriaxone, quinolone, aminoglycoside, or minocycline. After hospitalization, 15 patients improved (71.43%), two patients did not recover, and the status of four patients was unknown. CONCLUSIONS: The clinical manifestations, CSF parameters, and neurological imaging data for patients with NB show no significant specificity or correlations. When patients with unexplained neurological symptoms accompanied by fever, fatigue, and other systemic manifestations in a brucellosis epidemic area or with a history of contact with cattle, sheep, animals, or raw food are encountered in clinical practice, the possibility of NB should be considered. Treatment is based on the principles of an early, combined, and long course of treatment, and the general prognosis is good.

MiR-1281 is involved in depression disorder and the antidepressant effects of Kai-Xin-San by targeting ADCY1 and DVL1.

Kai-Xin-San (KXS) is a Chinese medicine formulation that is commonly used to treat depression caused by dual deficiencies in the heart and spleen. Recent studies indicated that miRNAs were involved in the pathophysiology of depression. However, there have been few studies on the mechanism underlying the miRNAs directly mediating antidepressant at clinical level, especially in nature drugs and TCM compound. In this study, we identified circulating miRNAs defferentially expressed among the depression patients (DPs), DPs who underwent 8weeks of KXS treatment and health controls (HCs). A total of 45 miRNAs (17 were up-regulated and 28 were down-regulated) were significantly differentially expressed among three groups. Subsequently, qRT-PCR was used to verify 10 differentially expressed candidate miRNAs in more serum samples, and the results showed that 6 miRNAs (miR-1281, miR-365a-3p, miR-2861, miR-16-5p, miR-1202 and miR-451a) were consistent with the results of microarray. Among them, miR-1281, was the novel dynamically altered and appeared to be specifically related to depression and antidepressant effects of KXS. MicroRNA-gene-pathway-net analysis showed that miR-1281-regulated genes are mostly key nodes in the classical signaling pathway related to depression. Additionally, our data suggest that ADCY1 and DVL1 were the targets of miR-1281. Thus, based on the discovery of miRNA expression profiles in vivo, our findings suggest a new role for miR-1281 related to depression and demonstrated in vitro that KXS may activate cAMP/PKA/ERK/CREB and Wnt/ß-catenin signal transduction pathways by down-regulating miR-1281 that targets ADCY1 and DVL1 to achieve its role in neuronal cell protection.

Interaction between Chinese medicine and digoxin: Clinical and research update.

Background: Digoxin is one of the most widely and commonly used cardiac drug, which plays an irreplaceable role in treating heart failure and arrhythmia. The 2010 Edition of Pharmacopoeia of the People's Republic of China stipulates that the effective range of digoxin plasma concentration is 0.5-2.0 ng/mL and it is toxic at plasma concentration >2 ng/mL. Its effective plasma drug concentration is close to the toxic concentration, and large individual differences in the effects of the drug have been observed. It is often used in combination with other drugs, but drug interactions have a great impact on the plasma concentration of digoxin and lead to adverse reactions (ADRs), such as poisoning. Most of the reported drug interactions are with Western drugs. However, there are many combinations of traditional Chinese medicine (TCM) and Western drugs, TCM interacting with digoxin comprises monomer components, single medicines, and Chinese patent medicines. Aim of the study: We aimed i) to provide an overview of the TCM formulations affecting the pharmacology of digoxin and their mechanisms of action and ii) to provide a theoretical reference for the safe and rational use of digoxin in combination with TCM in clinical practice and to avoid ADRs. Methods: A literature search of electronic databases, including PubMed, MEDLINE, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WANFANG Data, was performed to search for articles published between 1 January 1960, and 1 August 2022. Search terms used included "digoxin," "traditional Chinese medicine," "Chinese patent medicine," and "adverse reactions" and their combinations. Results: A total of 49 articles were obtained, including clinical reports, pharmacological experiments and in vitro experiments. The mechanisms of action affecting the pharmacology of digoxin are complex. TCM formulations may affect the pharmacology of digoxin in vivo by influencing gastrointestinal motility or gastric juice pH, regulating P-glycoprotein levels, exerting cumulative pharmacological effects, and enhancing the sensitivity of the heart to digoxin. Although studies have shown that some TCM formulations interact with digoxin, they may be influenced by the complexity of the composition and the pharmacological effects of the TCM, the sensitivity of digoxin concentration determination methods, etc. The results of existing studies are controversial and further in-depth studies are required. Conclusion: Combinations of digoxin and TCM formulations are commonly used. This article serves as a reference to understand the interactions between TCM formulations and digoxin to avoid the occurrence of ADRs and improve the efficacy and safety of digoxin.

Traditional Chinese medicine decoctions and Chinese patent medicines for the treatment of depression: Efficacies and mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a major mental disorder and it is currently recognized as the second-leading cause of disability worldwide. However, the therapeutic effect of antidepressants remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely used for centuries, including commonly-used complementary and alternative medical therapies for depression. Recent clinical trials have been carried out to assess the efficacy and safety of TCM, and to explore the mechanisms of action in relation to the treatment of depression. AIM OF THE STUDY: To summarize frequently used TCM decoctions and Chinese patent medicines (CPM) for treating depression, review their clinical therapeutic effects in treating depressive disorders, consider their possible mechanisms, and characterize the relationships between their efficacy and mechanisms. MATERIALS AND METHODS: We performed a computerized literature search using the electronic databases such as PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases, with the keywords "depression", "traditional Chinese medicine decoction", "Chinese patent medicine", "application", "mechanism", and their combinations, from January 1, 2000 to August 8, 2022 (inclusive). RESULTS: A total of 51 papers were identified. We reviewed studies on six each TCM decoctions and CPMs, which demonstrated their significant clinical efficacy for treating depression and examined their mechanisms of action. The anti-depressive effects were related to: 1) increased monoamine neurotransmitter levels, 2) inhibiting hyperactivity of the hypothalamic-pituitary-adrenal axis, 3) regulating hippocampal neurons and neurotrophic factors, 4) regulating immune cytokines, 5) counteracting excitatory amino acid toxicity, and 6) regulating microbe-gut-brain axis function. CONCLUSION: TCM plays an increasingly important role in the management of depression by enhancing the therapeutic effects and alleviating the side effects of antidepressant chemicals.

Epithelial-mesenchymal transition-related long noncoding RNAs in gastric carcinoma.

As an evolutionarily phenotypic conversion program, the epithelial-mesenchymal transition (EMT) has been implicated in tumour deterioration and has facilitated the metastatic ability of cancer cells via enhancing migration and invasion. Gastric cancer (GC) remains a frequently diagnosed non-skin malignancy globally. Most GC-associated mortality can be attributed to metastasis. Recent studies have shown that EMT-related long non-coding RNAs (lncRNAs) play a critical role in GC progression and GC cell motility. In addition, lncRNAs are associated with EMT-related transcription factors and signalling pathways. In the present review, we comprehensively described the EMT-inducing lncRNA molecular mechanisms and functional perspectives of EMT-inducing lncRNAs in GC progression. Taken together, the statements of this review provided a clinical implementation in identifying lncRNAs as potential therapeutic targets for advanced GC.

miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis.

The aim of this study was to verify the biological function of miR-1273h-5p in gastric cancer (GC) and its underlying mechanisms. The differential expression of microRNAs between GC and tumor-adjacent normal tissues was detected using microarrays, miR-1273h-5p, and chemokine (C-X-C motif) ligand 12 (CXCL12) mRNA, and protein levels were evaluated using polymerase chain reaction and Western blotting methods, cell proliferation, apoptosis, migration, and invasion were determined by CCK-8, flow cytometry, and transwell assay. Compared to tumor-adjacent normal tissue and gastric epithelial mucosa cell line cells, miR-1273h-5p was significantly downregulated in tissues and cells of GC. The overexpression of miR-1273h-5p could inhibit cell proliferation, migration, invasion, and promote cell apoptosis; in contrast, inhibition of miR-1273h-5p expression could reverse this process. Moreover, a significant upregulation of CXCL12 was observed when the miR-1273h-5p was downregulated in GC cells. Additionally, miR-1273h-5p significantly reduces tumor volume and weight. Thus, this study suggests that miR-1273h-5p regulates cell proliferation, migration, invasion, and apoptosis during GC progression by directly binding to CXCL12 mRNA 3'-untranslational regions, which may be a novel diagnostic and therapeutic target in GC.

Comparison of the efficacy and safety of levetiracetam and phenytoin in the treatment of established status epilepticus: A systematic review and meta-analysis.

Status epilepticus (SE) is the second most critical neurological illness after cerebrovascular disease. Phenytoin has traditionally been considered the second-line drug of first choice after failure of first-line treatment using benzodiazepines. In recent years, levetiracetam has been proposed as a potential substitute for phenytoin. To comprehensively evaluate the efficacy and safety of levetiracetam and phenytoin in the treatment of patients with established SE, we integrated the data from 11 eligible studies and conducted a systematic review and meta-analysis. The PubMed, Web of Science, Cochrane Library, and Embase databases were searched to identify eligible articles reporting outcomes including clinical seizure cessation within 60 min, clinical recurrence rate within 24 h, good final outcome at discharge, and adverse events (AEs) of treatment with levetiracetam and phenytoin. Our study included a total of 11 trials including a total of 1933 patients. The outcomes showed that the pooled Risk Raito (RR) of clinical seizure cessation within 60 min was 1.08 (95% CI = 1.02-1.14, P = 0.01). The pooled RR of clinical recurrence rate within 24 h was 1.03 (95% CI = 0.66-1.59, P = 0.91). The pooled RR of AEs was 0.83 (95% CI = 0.57-1.21, P = 0.34). The pooled RRs of life-threatening hypotension and acute respiratory depression were 0.29 (95% CI = 0.10-0.81, P = 0.02) and 0.63 (95% CI = 0.40-0.98, P = 0.04), respectively. Levetiracetam might be more effective than phenytoin for the treatment of established SE and is associated with a lower incidence of more serious AEs. Levetiracetam can be used as an alternative to phenytoin for the treatment of benzodiazepine-refractory SE.

Quaternary stratigraphy and paleoenvironmental evolution of the Ningbo Coastal Plain revealed by core Z02.

The Quaternary sediment in the Ningbo Coastal Plain was the deposit due to sea-land interaction, which recorded information of past climate changes. The region is therefore an ideal area to study paleoclimate changes and sedimentary characteristics. We determined the stratigraphic division and paleoenvironmental evolution based on 14C and paleomagnetic dating, along with detailed analyses of lithology, pollen assemblage, foraminifera and ostracodes assemblage, and grain size of sediment in core Z02 located in the southeastern Ningbo Coastal Plain. The results showed that the boundary between the Holocene and Upper Pleistocene in the core Z02 record was at 30.5 m, the boundary between the Upper and Middle Pleistocene was at 82.65 m, and the boundary between the Quaternary and Lower Cretaceous was at 90 m. The Middle Pleistocene section of the core contained few sediments, while the Lower Pleistocene section was completely missed. During the late Pleistocene, the hydrodynamic conditions experienced energy levels of medium to medium low to medium, and sedimentary facies changed from alluvial lake to overbank to river to lake to alluvial lake to lake to overbank. During the Holocene, the hydrodynamic changes experienced energy levels of medium low to low to medium, and the sedimentary facies changed from shoreland to shallow sea to shoreland lake. The Ningbo Coastal Plain had experienced tectonic uplift, weathering and erosion stage in the Early and Middle Pleistocene, from warm and humid to dry in the Late Pleistocene, and from warm and humid to dry and cool in the Holocene, as revealed by the core Z02 record. This study provided useful information in investigating past environmental changes in the subtropical coastal region of eastern China.

Involvement of 5-HT-BDNF signaling axis in mediating synergistic antidepressant-like effects after combined administration of two oligosaccharide esters.

Potential mechanisms of depression involving herbal medicines and their specific compounds include elevated 5-HT level and downstream BDNF pathway. To identify potentially new combined therapeutic strategies, 3,6'-disinapoylsucrose (DISS) and tenuifoliside A (TFSA) have been observed to show antidepressant-like effects and its related 5-HT-BDNF pathway. We have tried to investigate whether combined administration of DISS and TFSA exerted more effective in the treatment of depression, as assessed through tail suspension test (TST) and forced swimming test (FST). In addition, we also analyzed the expression of three important proteins, cyclic adenosine monophosphate (cAMP) response element binding (CREB), brain-derived neurotrophic factor (BDNF), and cAMP-regulated transcriptional coactivators (CRTC1), which have been shown to be involved in the regulation of the neurotrophic factors in the hippocampus. The DISS and TFSA separately, both at a dose of 5 mg/kg each, displayed small effect in the immobility time. However, combined treatment of these two in multiple doses exhibited better effect. Moreover, combined treatment of DISS and TFSA also demonstrated enhanced levels of 5-hydroxytryptamine (5-HT), and stronger increase in the phosphorylation levels of CREB, BDNF, and CRTC1 proteins in the hippocampus. Overall, our results indicated that coadministration of these two oligosaccharide esters at low dose may induce more pronounced antidepressant activity, in comparison with individual treatment even at high dosage. Thus, the antidepressant properties of both these compounds can be attributed to their ability to influence 5-HT and BDNF pathway, and thereby suggesting that this combination strategy can definitely act as alternative therapy for depression disorder with very limited side effects.

Efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in treatment of advanced gastric cancer or gastroesophageal junction cancer: A meta-analysis.

BACKGROUND: Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer (GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis. AIM: To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients. METHODS: PubMed, Web of Science, Cochrane Library ,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) of anti-PD-1/anti-PD-L1 antibody therapy. RESULTS: Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15% (95% confidence interval [CI]: 14%-18%) and 40% (95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54% (95%CI: 45%-64%) and 26% (95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42% (95%CI: 21%-62%) and 11% (95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64% (95%CI: 54%-73%) and 18% (95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients (odds ratio = 2.54, 95%CI: 1.56-4.15). CONCLUSION: Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.

Behavioral and Biochemical Effects of KXS on Postmyocardial Infarction Depression.

BACKGROUND: Depression and coronary heart disease (CHD) often occur together in clinical practice. As a traditional Chinese medicine, Kai-Xin-San (KXS) has been widely used for the treatment of emotion-related disorders. In the present study, we aimed to explore whether KXS had both antidepressive effects and cardioprotective functions in a rat model of myocardial ischemia (MI) with depression. METHODS: A total of 50 SD rats were randomly assigned into five groups as follows: normal control (control group), celiac injection of isopropyl adrenaline (ISO) (MI group), depression (depression group), MI+ depression (model group) and MI+ depression treated with intragastric administration of 370 mg/kg KXS (KXS group). MI was induced by subcutaneous injection of 85 mg/kg ISO. Depression was developed by a 7-week chronic mild stress (CMS) challenge. Behavioral test was conducted before and during the experiment. Echocardiography and biochemical analysis were carried out after 7 weeks of CMS challenge. RESULTS: After 7 weeks of experiment, depression-like behaviors were observed in all the groups except for control and KXS groups, and KXS treatment dramatically increased open-field test scores and sucrose consumption (P < 0.01 vs. model group). Echocardiography and biochemical analysis showed that KXS treatment could improve levels of ejection fraction (EF) and fractional shortening (FS), which were reduced by depression and ISO challenge. Meanwhile, KXS treatment significantly decreased the levels of creation kinase MB (CK-MB) and lactate dehydrogenase (LDH), which were increased in the model group. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), catalase (CAT) were increased, while the malondialdehyde (MDA) activity was significantly decreased in the KXS group. Moreover, KXS treatment reduced the levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in myocardial tissue compared with the model group. CONCLUSIONS: KXS had antidepressant-like activity and offered cardioprotective effects against ISO-induced myocardial infarction with depression.

Anti-depressive effects of Kai-Xin-San on lipid metabolism in depressed patients and CUMS rats using metabolomic analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: In this study, in order to explore potential depressive biomarkers and potential regulatory targets of KXS on depression, we assessed the effects of Kai-Xin-San (KXS) on lipid metabolism in depressed patients (DPs) and rats exposed to chronic and unpredictable mild stress (CUMS). MATERIALS AND METHODS: Serum samples were collected from DPs, DPs with 8 weeks of KXS treatment (KXS) and healthy controls (HCs), and non-targeted lipidomics was used to analyze the effect of KXS on serum lipid metabolites in DPs. Based on UPLC-Q-TOF/MS technology, differential metabolites were validated in a large sample size. The potential regulatory network of KXS was analyzed by bioinformatic analysis, and the expressions of proteins in serum were verified using western boltting analysis. Moreover, effects of KXS on serum lipid and lipid metabolism-related hormone levels in CUMS rats were detected by enzyme-linked immunosorbent assay and enzymatic method. RESULTS: We validated that the levels of six serum lipid metabolites (N-Desmethylcitalopram (HMDB14021), PC(14:1(9Z)/24:0) (HMDB07926), PC(P-18:1(11Z)/20:0) (HMDB11281), PC(O-18:0/20:4(8Z,11Z,14Z,17Z)) (HMDB13420), PC(16:0/P-18:0) (HMDB07995) and PC(16:0/P-18:1(11Z)) (HMDB07996)) between HC/DP groups and between DP/KXS groups were significantly different. Among these six metabolites, HMDB07995, HMDB07996, HMDB13420 and HMDB11281 were highly sensitive and specific for depression and KXS treatment by receiver operating characteristic (ROC) curve analysis. matrix metalloproteinases (MMPs) including MMP2 and MMP9, apolipoproteins (Apo) including APOA1 and APOC1 were up-regulated and apolipoproteins (Apo) including APOB, APOD and APOE, phospholipid transfer protein (PLTP), Paraoxonase 1 (PON1) were down-regulated in DPs, and KXS treatment could reverse these changes. In CUMS rats, KXS could increase the open-field score, sucrose preference and body weight, and reduce immobility time. Furthermore, KXS increased the serum levels of the above-mentioned six metabolites, reduced serum total cholesterol (TCH), triglyceride (TG) and free fatty acid (FFA) levels and increased the serum high-density lipoprotein cholesterol (HDL-C) level in CUMS rats. In addition, leptin and ghrelin were down-regulated by KXS. CONCLUSIONS: The results suggested that KXS exerted antidepressant effects by regulating the signaling pathways involved in lipid metabolism disorders. The lipid metabolites might be potential biomarkers of depression and possible targets for KXS-based treatment of depression.

Identification of protein targets for the antidepressant effects of Kai-Xin-San in Chinese medicine using isobaric tags for relative and absolute quantitation.

Kai-Xin-San consists of Ginseng Radix, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria at a ratio of 3:3:2:2. Kai-Xin-San has been widely used for the treatment of emotional disorders in China. However, no studies have identified the key proteins implicated in response to Kai-Xin-San treatment. In this study, rat models of chronic mild stress were established using different stress methods over 28 days. After 14 days of stress stimulation, rats received daily intragastric administrations of 600 mg/kg Kai-Xin-San. The sucrose preference test was used to determine depression-like behavior in rats, while isobaric tags were used for relative and absolute quantitation-based proteomics to identify altered proteins following Kai-Xin-San treatment. Kai-Xin-San treatment for 2 weeks noticeably improved depression-like behaviors in rats with chronic mild stress. We identified 33 differentially expressed proteins: 7 were upregulated and 26 were downregulated. Functional analysis showed that these differentially expressed proteins participate in synaptic plasticity, neurodevelopment, and neurogenesis. Our results indicate that Kai-Xin-San has an important role in regulating the key node proteins in the synaptic signaling network, and are helpful to better understand the mechanism of the antidepressive effects of Kai-Xin-San and to provide objective theoretical support for its clinical application. The study was approved by the Ethics Committee for Animal Research from the Chinese PLA General Hospital (approval No. X5-2016-07) on March 5, 2016.

LncRNA COL1A1-014 is involved in the progression of gastric cancer via regulating CXCL12-CXCR4 axis.

BACKGROUND: The aberrant expression of long noncoding RNAs (lncRNAs) is found in various types of cancers and also showed its association with the occurrence and development of gastric cancer (GC). We found lncRNA COL1A1-014 was frequently upregulated in GC. METHODS: This study investigated COL1A1-014 for its biological function at both cellular and animal levels, using MTT, flow cytometry, colony formation and transwell assays. The expression levels of COL1A1-014 and other genes were detected by RT-PCR and western blot. Luciferase reporter assay was used to detect the potential binding of miR-1273h-5p to COL1A1-014 and CXCL12. RESULTS: We found that COL1A1-014 was frequently upregulated in GC tissues as well as cells. COL1A1-014 increased cell proliferation, colony forming efficiency, migration ability, invasion ability, and weight and volume of grafted tumors, while reduced cell apoptosis. Overexpression of COL1A1-014 increased the mRNA expression of chemokine (CXCmotif) ligand (CXCL12) and high levels of CXCL12 and CXCR4 proteins in GC cells. The levels of miR-1273h-5p showed an inverse correlation with COL1A1-014 and CXCL12 in GC cells transfected with miR-1273h-5p. The mRNAs of wild-type COL1A1-014 and CXCL12 showed reduction in HEK293 cells transfected with miR-1273h-5p. This suggested that COL1A1-014 functions as an efficient miR-1273h-5p sponge and as a competing endogenous RNA (ceRNA) to regulate CXCL12. The proliferative activity of COL1A1-014 on GC cells was blocked by CXCL12-CXCR4 axis inhibitor AMD-3100. CONCLUSIONS: These findings demonstrated that COL1A1-014 play an important regulatory role in GC development by functioning as a ceRNA in regulating the CXCL12/CXCR4 axis via sponging miR-1273h-5p.

Kai­Xin­San suppresses matrix metalloproteinases and myocardial apoptosis in rats with myocardial infarction and depression.

Depression is often triggered by prolonged exposure to psychosocial stressors and associated with coronary heart disease (CHD). Matrix metalloproteinases (MMPs) are involved in the pathogenesis of various emotional and cardiovascular disorders. The purpose of this study was to investigate whether Kai­Xin­San (KXS), which may terminate the signaling of MMPs, exerts antidepressant­like and cardioprotective effects in a myocardial infarction (MI) plus depression rat model. Rats were randomly assigned to five groups: A normal control (control group), a celisc­injection of isopropyl adrenaline group (ISO group), depression (depression group), an ISO + depression (depression + ISO group), and an ISO + depression group treated with intragastric administration of 1,785 mg/kg KXS (KXS group). Behavioral changes, echocardiography, biochemical index, matrix metalloproteinase (MMP) and apoptosis­related proteins were assessed. Compared with the depression + ISO group, KXS significantly improved stress­induced alterations of behavioral parameters and protected the heart by enlarging the left ventricular (LV) fractional shortening (FS) and LV ejection fraction (EF). Moreover, KXS significantly attenuated ISO + depression­induced MMP­2 and MMP­9 expression at the mRNA and protein level and decreased TIMP in the heart compared to the complex model group. Myocardial apoptosis was significantly attenuated by KXS by regulating the Bcl­2/Bax axis. These results indicated that MI comorbid with depression may damage the MMP balance in the central and peripheral system, and KXS may have a direct anti­depressive and cardio­protective effect by regulating the level of MMPs and associated myocardial apoptosis. It is promising to further explore the clinical potential of KXS for the therapy or prevention of MI plus depression comorbidity disease.

Sanguinarine inhibits the proliferation of BGC-823 gastric cancer cells via regulating miR-96-5p/miR-29c-3p and the MAPK/JNK signaling pathway.

Sanguinarine (SAN), a quaternary benzophenanthridine alkaloid extracted from the root of Papaveraceae plants, has shown antitumour effects in multiple cancer cells. However, the therapeutic effects and the underlying mechanisms of SAN in gastric cancer (GC) remain elusive. In this study, the in vitro proliferation inhibition effect of SAN in GC cells was determined using CCK-8 assay, the in vivo antitumor effect of SAN was evaluated in mice with xenotransplanted tumor. The mechanism underlying the antitumor activity of SAN was explored by gene microarray assay and bioinformatics analysis. The levels of differentially expressed miRNAs and target genes were verified by real-time RT-PCR and immunohistochemistry. SAN inhibited the proliferation of BGC-823 cells in a concentration-dependent manner in vitro and in vivo. The miR-96-5p and miR-29c-3p were significantly upregulated in untreated BGC-823 cells and significantly downregulated in SAN treated cells. The mRNA and protein expression of their target gene MAP4K4 were upregulated in SAN treated xenotransplanted tumors, and pMEK4 and pJNK1 proteins in the MAPK/JNK signaling pathway were also upregulated by SAN. These indicate that SAN may inhibit the proliferation of BGC-823 cells through the inhibition of miR-96-5p and miR-29c-3p expression, and subsequent activation of the MAPK/JNK signaling pathway.

Efficacy of tea polyphenols (TP 50) against radiation-induced hematopoietic and biochemical alterations in beagle dogs.

OBJECTIVE: To investigate the radioprotective effect of tea polyphenols (TP 50) against radiation-induced organ and tissue damage. METHODS: Beagle dogs were exposed to a single acute dose of whole-body γ-radiation (3 Gy) and orally administered TP 50 (80 or 240 mg·kg－1·d－1) for 28 consecutive days. A hemogram was obtained from experimental dogs every other day for 42 d. At the end of the experiment, enzyme activities of the antioxidants superoxide-dismutase andglutathione peroxidase, serum levels of inflamma- tory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6), colony-forming units of bone marrow hematopoietic progenitor cells, andorgan coefficients were measured. RESULTS: Dogs exposed to γ-radiation alone exhibited typical hematopoietic syndrome. In contrast, irradiated dogs that received TP 50 exhibited an improved blood profile with reduced leucopenia, thrombocytopenia (platelet counts), and reticulocyte levels. TP 50 also significantly elevated levels of the endogenous antioxidant enzyme superoxide-dismutase, reduced the increased levels of serum cytokine in response to radiation-induced toxicity, and increased colony-forming units of bone marrow hematopoietic progenitor cells. In addition, TP 50 repaired radiation-induced organ damage. CONCLUSION: The current findings suggest that oral administration of TP 50 to beagle dogs effectively alleviated hematopoietic bone marrow dam- age induced by γ-radiation.

Protective Effect of JXT Ethanol Extract on Radiation-Induced Hematopoietic Alteration and Oxidative Stress in the Liver.

This study aims at investigating the radioprotective effect of ethanol extract from Ji-Xue-Teng (JXT, Spatholobus suberectus) on radiation-induced hematopoietic alteration and oxidative stress in the liver. Mice were exposed to a single acute γ-radiation for the whole body at the dose of 6.0 Gy, then subjected to administration of amifostine (45 mg/kg) or JXT (40 g crude drug/kg) once a day for 28 consecutive days, respectively. Bone marrow cells and hemogram including white cells, red cells, platelet counts, and hemoglobin level were examined. The protein expression levels of pJAK2/JAK2, pSTAT5a/STAT5a, pSTAT5b/STAT5b, and Bcl-2 in bone marrow tissue; levels of reactive oxygen species (ROS); and the activity of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum and liver tissue were determined. At the end of the experiment, the effect of JXT on cell viability and G-CSF and G-CSFR levels in NFS-60 cells were tested by CCK-8 assay, ELISA, and flow cytometry. The results showed that the mice exposed to γ-radiation alone exhibited a typical hematopoietic syndrome. In contrast, at the end of the 28-day experiment, irradiated mice subjected to oral administration of JXT showed an obvious improvement on blood profile with reduced leucopenia, thrombocytopenia (platelet counts), RBC, and hemoglobin levels, as well as bone marrow cells. The expression of pJAK2/JAK2, pSTAT5a/STAT5a, and Bcl-2 in bone marrow tissue was increased after JXT treatment. The elevation of ROS was due to radiation-induced toxicity, but JXT significantly reduced the ROS level in serum and liver tissue, elevated endogenous SOD and GSH-PX levels, and reduced the MDA level in the liver. JXT could also increase cell viability and G-CSFR level in NFS-60 cells, which was similar to exogenous G-CSF. Our findings suggested that oral administration of JXT effectively facilitated the recovery of hematopoietic bone marrow damage and oxidative stress of the mice induced by γ-radiation.