OBJECTIVE To explore the effects of limonin on renal lesions， glucose metabolism， inflammation， and oxidative stress in gestational diabetic rats and its possible mechanisms. METHODS The model of gestational diabetic rats was established by intraperitoneal injection of streptozotocin. The diabetic rats were divided into the model group （intragastrical administration and tail vein injection of equal volume of normal saline）， limonin low-， medium-， and high-dose groups （intragastrical administration of limonin， at doses of 12.5， 25.0 and 50.0 mg/kg， and equal volume of normal saline into the tail vein）， and combination group [intragastrical administration of limonin 50.0 mg/kg + tail vein injection of c-Jun N-terminal kinase （JNK） activator Anisomycin 2 mg/kg ]， with 12 rats in each group. In addition， 12 pregnant rats were selected as the control group （intragastrical administration and tail vein injection of equal volume of normal saline）. They were given relevant medicine， once a day， for 14 consecutive days. After the last administration， fasting blood glucose （FBG）， the levels of fasting insulin （FINS）， interleukin-1β （IL-1β）， IL-6， and tumor necrosis factor-α （TNF-α） in the serum were detected； the levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione peroxidase （GSH-Px）， blood urea nitrogen （BUN）， and creatinine （Cr） in the renal tissue were detected； the pathological changes of renal tissue were observed； the expressions of proteins related to the JNK/nuclear factor-κB （NF-κB） signaling pathway in the renal tissue were detected. RESULTS Compared with control group， in model group， the rats showed pathological injuries in the kidney tissue， such as glomerular atrophy， edema of renal tubular epithelial cells； the levels of FBG， FINS， IL-1β， IL-6， TNF-α， MDA， BUN and Cr， HOMA-IR， as well as the phosphorylation levels of JNK and NF-κB 0453-6602005。E-mail：mcvi45@163.com p65 proteins were increased significantly （P＜0.05）， while the levels of SOD and GSH-Px were decreased significantly （P＜0.05）. Compared with model group， in each dose group of limonin， the degree of renal tissue lesions in rats was alleviated， and the above-mentioned indicators were significantly improved （P＜0.05）， showing an obvious dose-effect relationship （P＜0.05）. Compared with high-dose limonin group， in the combination group， the degree of renal tissue lesions in rats was relatively aggravated， and the changes in the above-mentioned indicators were significantly reversed （P＜0.05）. CONCLUSIONS Limonin has a certain improvement effect on renal lesions， glucose metabolism， inflammation， and oxidative stress in pregnant rats with gestational diabetes. Its mechanism may be related to the inhibition of the JNK/NF-κB signaling pathway.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Uremic pruritus (UP) is a common complication in patients with end-stage renal disease, which seriously reduces the quality of life of patients. Compared with the internal treatment of TCM, the external treatment of TCM for UP is simpler and more effective, and can avoid the first pass effect caused by oral drugs and may cause liver and kidney damage. The treatment methods mainly include external washing of TCM, medicated bath, fumigation, wet compress, enema, scraping, acupuncture, auricular point sticking, acupoint application, acupoint iontophoresis, autologous blood acupoint injection and so on. At present, most studies are based on the conventional treatment of Western medicine, and the addition of external treatment of TCM can improve the efficacy, and has certain advantages in improving itching symptoms, inflammatory indicators, sleep quality, anxiety and depression. Some studies have selected parathyroid hormone, blood phosphorus, CRP, IL-6, histamine, SCr, BUN, β2-microglobulin and other indicators to evaluate the efficacy. The results suggest that external treatment of TCM can improve the micro-inflammatory state of patients and protect renal function, but further mechanism research is needed. The existing research has the following problems: the clinical efficacy evaluation scale is not uniform, and it is difficult to compare and summarize horizontally; the relief of pruritus symptoms is based on the scale evaluation, which is subjective; the course of treatment is short, and the long-term efficacy and safety can not be evaluated; some studies do not specify the patients' syndrome type, which is difficult to reflect the advantages of TCM syndrome differentiation and treatment, and needed to be improved in the future.

Objective:To evaluate the efficacy of oral midazolam solution for preoperative sedation in the pediatric outpatients undergoing root canal treatment under general anesthesia.Methods:One hundred and forty-seven pediatric patients of either sex, aged 2-7 yr, weighing 10-30 kg, of American Society of Anesthesiologists Physical Status classificationⅠ or Ⅱ, were divided into 3 groups ( n=49 each) using a random number table method: oral midazolam solution group (OM group), midazolam injection group (M group), and dexmedetomidine group (D group). In OM group, patients received oral midazolam solution at a dose of 0.5 mg/kg along with a placebo (an equivalent amount of normal saline based on body weight) administered via nasal drops. In M group, patients were given oral midazolam injection at a dose of 0.5 mg/kg along with a placebo via nasal drops. In D group, patients were administered a placebo orally along with dexmedetomidine at a dose of 2 μg/kg via nasal drops. The Induction Compliance Checklist (ICC) scores upon entering the operating room, sedation success rates (ICC score ≤ 3), drug acceptance scores, mask acceptance scores, and separation anxiety scores were recorded. The emergence time, time of stay in postanesthesia care unit (PACU), and occurrence of adverse events such as bradycardia, hypotension, hypoxemia, and laryngospasm during surgery and in PACU were recorded. Results:A total of 143 pediatric patients were finally included in the study, with 48 cases in OM group, 48 cases in M group and 47 cases in D group. Compared with M and D groups, the ICC scores upon entry to the operating room were significantly decreased, the sedation success rates were increased, drug acceptance scores were increased, separation anxiety scores were decreased, and mask acceptance scores were decreased in OM group ( P<0.05). Compared with D group, the ICC scores upon entry to the operating room were significantly decreased, the sedation success rates were increased, and mask acceptance scores were decreased in M group ( P<0.05). There were no statistically significant differences in the emergence time, time of stay in PACU, and incidence of adverse events during surgery and in PACU among the three groups ( P>0.05). Conclusions:Oral midazolam solution provides good effect with less adverse reactions when used for preoperative sedation in the pediatric outpatients undergoing root canal treatment under general anesthesia.

At present,precise radiotherapy has been widely used through the development with many years,but the existing technique still is limited by the limitation of tolerance dose of normal tissues,which cannot achieve the optimal goal of treating tumor.Flash radiotherapy(Flash-RT)is one kind of radiotherapy technique that uses the beam with ultra-high dose rate(UHDR)to conduct irradiation,which can furthest treat tumors while significantly reduce radiation injury of normal tissues.But until now,the biological mechanism,key physical parameters and triggering mechanism of Flash-RT are still unclear,and its principle and clinical translational application are still in the stage of research.This review clarified the technological advance and clinical translational application of Flash-RT research through summarized the relevant research of Flash-RT.

Objective:To investigate the impacts of hirudin(HRD)on neuronal apoptosis and inflammatory response in rats with cerebral infarction by regulating Ras homolog gene family member A(RhoA)/Rho-associated coiled-coil-forming protein kinase(ROCK)signaling pathway.Methods:SD rats were grouped into Ct group,Model group,low-dose HRD group(HRD-L group,13.33 mg/kg),high-dose HRD group(HRD-H group,26.66 mg/kg),positive control Nimodipine group(NMDP group,40 mg/kg),U-46619(RhoA agonist,0.03 mg/kg)group and HRD-H+U-46619 group(26.66 mg/kg+0.03 mg/kg),with 24 rats per group.Except for the Ct group,rats in other groups constructed the rat model of cerebral infarction by the modified suture method.The rats in the Ct group only exposed the blood vessels without incision and suture insertion.After 1 hour of successful modeling,drug treatment was car-ried out,once a day for 4 weeks.Zea-Longa method was applied to evaluate the neurological function of rats;dry and wet weight meth-od was applied to detect the water content of rat brain tissue;2,3,5-triphenyltetrazolium chloride(TTC)staining was applied to deter-mine the volume of cerebral infarction in rats;TUNEL staining was applied to detect the apoptosis of neurons in the CA1 region of the hippocampus of rats.The levels of TNF-α,IL-1β and IL-6 in rat hippocampus were detected by ELISA;the protein expressions of cleaved-Caspase-3 Cleaved-Caspase-3,Bcl-2-associated X protein(Bax),RhoA,ROCK1 and ROCK2 in rat hippocampus were de-tected by Western blot.Results:Compared with Ct group,the neurological function scores,brain tissue water content,cerebral in-farction volume percentage,neuron apoptosis rate,levels of TNF-α,IL-1β,IL-6,the protein expressions of Cleaved-Caspase-3,Bax,RhoA,ROCK1 and ROCK2 increased in the Model group(P<0.05).Compared with Model group,the neurological function scores,brain tissue water content,cerebral infarction volume percentage,neuron apoptosis rate,levels of TNF-α,IL-1β,IL-6,the protein expressions of Cleaved-Caspase-3,Bax,RhoA,ROCK1 and ROCK2 decreased in HRD-L group,HRD-H group,NMDP group,however,the corresponding index changes in the U-46619 group showed an opposite trend(P<0.05).Compared with HRD-H group,the neurological function scores,brain tissue water content,cerebral infarction volume percentage,neuron apoptosis rate,levels of TNF-α,IL-1β,IL-6,the protein expressions of Cleaved-Caspase-3,Bax,RhoA,ROCK1 and ROCK2 were increased in the HRD-H+U-46619 group(P<0.05).Conclusion:HRD may inhibit neuronal apoptosis and inflammatory response in rats with cerebral infarction by inhibiting RhoA/ROCK signaling pathway.

Objective:To evaluate the effect of gender factor on efficacy of remimazolam combined with alfentanil in the patients undergoing gastrointestinal endoscopy.Methods:Two hundred patients, aged 18-64 yr, with body mass index of 18-30 kg/m 2, of American Society of Anesthesiologists Physical Status classificationⅠor Ⅱ, scheduled for elective gastrointestinal endoscopy, were divided into 2 groups ( n=100 each) according to gender: male group (group M) and female group (group F). Remimazolam 0.2-0.3 mg/kg and alfentanil 5-7 μg/kg were intravenously injected, remimazolam 0.5-0.7 mg·kg -1·h -1 was continuously infused during operation to maintain the modified observer′s assessment of alert/sedation score<3 points, and alfentanil 2 μg/kg was administered when necessary. The consumption of remimazolam and alfentanil, examination time, recovery time and time of post-anesthesia care unit stay were recorded. The satisfaction scores of examination physicians and patients were recorded. The occurrence of adverse reactions such as injection pain, intraoperative body movement, respiratory depression, hypotension, bradycardia and hiccups and postoperative dizziness, nausea, vomiting, fatigue, abdominal pain and abdominal distension were recorded. Results:There was no significant difference in the consumption of remimazolam and alfentanil, examination time, recovery time, satisfaction scores of examination physicians and patients between the two groups ( P>0.05). There was no significant difference in the incidence of respiratory depression, hypotension, bradycardia, injection pain, body movement, hiccups, abdominal pain, abdominal distension, and fatigue between the two groups ( P>0.05). Compared with group M, the time of post-anesthesia care unit stay was significantly prolonged, and the incidence of postoperative dizziness, nausea and vomiting was increased in group F ( P<0.05). Conclusions:Remimazolam combined with alfentanil provides better efficacy in male patients than in female patients undergoing gastrointestinal endoscopy.

OBJECTIVE: To investigate whether Omicron BA.1 breakthrough infection after receiving the SARS-CoV-2 vaccine could create a strong immunity barrier. METHODS: Blood samples were collected at two different time points from 124 Omicron BA.1 breakthrough infected patients and 124 controls matched for age, gender, and vaccination profile. Live virus-neutralizing antibodies against five SARS-CoV-2 variants, including WT, Gamma, Beta, Delta, and Omicron BA.1, and T-lymphocyte lymphocyte counts in both groups were measured and statistically analyzed. RESULTS: The neutralizing antibody titers against five different variants of SARS-CoV-2 were significantly increased in the vaccinated population infected with the Omicron BA.1 variant at 3 months after infection, but mainly increased the antibody level against the WT strain, and the antibody against the Omicron strain was the lowest. The neutralizing antibody level decreased rapidly 6 months after infection. The T-lymphocyte cell counts of patients with mild and moderate disease recovered at 3 months and completely returned to the normal state at 6 months. CONCLUSION Omicron BA.1 breakthrough infection mainly evoked humoral immune memory in the original strain after vaccination and hardly produced neutralizing antibodies specific to Omicron BA.1. Neutralizing antibodies against the different strains declined rapidly and showed features similar to those of influenza. Thus, T-lymphocytes may play an important role in recovery.
Humans ; Antibodies, Neutralizing ; Prospective Studies ; SARS-CoV-2 ; Breakthrough Infections ; COVID-19 Vaccines ; COVID-19 ; T-Lymphocytes ; China/epidemiology* ; Antibodies, Viral

OBJECTIVE: To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will. (EEOD) on a three-dimensional (3D) human malignant glioma (MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will. (OD). METHODS: The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology, and the action mechanism of Chinese medicine (CM) on human MG cells was investigated through network pharmacology analysis. First, the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Then, cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments, and two-dimensional (2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays. The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach. RESULTS: Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS. EEOD suppressed the viability of MG cells, promoted their apoptosis, and inhibited their migratory and invasive potentials (all P<0.05). Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK, EGFR, MYC, GSK3B, and other targets. The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization. CONCLUSIONS ]EEOD could inhibit the invasion of human MG cells, and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization.

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.
Child ; Adult ; Humans ; Antimalarials/pharmacology* ; Cardiovascular Diseases/drug therapy* ; Artemisinins/pharmacology* ; Quinolines ; Malaria, Cerebral/drug therapy* ; Heart Failure/drug therapy* ; Arrhythmias, Cardiac/drug therapy*