OBJECTIVE To investigate the potential of low-frequency, low-power ultrasound to enhance the transdermal absorption and efficacy of ketoprofen gel. METHODS Ketoprofen gel was used as a model drug to compare the in vitro transdermal permeation of ultrasound treated group and untreated group. Additionally, a rat model of collagen-induced inflammation provided a basis for evaluating pharmacodynamic differences. Pharmacokinetic studies further elucidated the effects of ultrasound on ketoprofen gel's penetration process. RESULTS Ultrasound treatment enhanced the cumulative transdermal permeation of ketoprofen gel by 3.5-fold over 24 hours compared to untreated. Significant pharmacokinetic improvements in AUC0-t from (4289.02±763.58)ng·h·mL−1 to (11301.10±3386.30)ng·h·mL−1 and a reduction in Tmax from (6.0±1.4)h to (3.0±2.0)h. Ultrasound notably improved the gel's anti-inflammatory effects in the rat model, effectively and rapidly reducing inflammation-induced swelling. CONCLUSION Low-frequency, low-power ultrasound can significantly improve the amount and rate of transdermal absorption of ketoprofen gel and enhance its pharmacological potency, from the aspects of skin permeation tests, pharmacodynamic evaluation, and pharmacokinetic studies, which is an effective penetration enhancer for transdermal administration of ketoprofen gel.

Stroke is a cerebrovascular disease characterized by high rates of disability,recurrence and mortal-ity.It results primarily from cerebrovascular rupture or transient/permanent occlusion.Due to the complex pathological mechanism of stroke and the lack of early-stage biomarkers,effective treatment options remain limited.Circular RNAs(circRNAs)are stable and conserved endogenous long noncoding RNA that regulate the pathological process of stroke,in-cluding oxidative stress,inflammation,apoptosis and autophagy.In addition,the regulatory roles of circRNAs in stroke include ceRNA,DNA methylation and histone modification.This review provides a comprehensive overview of circRNA biogenesis,major functions and characteristics.Furthermore,it presents the latest research findings on circRNAs in the context of stroke pathology,with the aim of providing new insights and potential approaches for unraveling the underlying mechanism,diagnosis and treatment of such diseases.

Objective:To analyze the influencing factors of clozapine plasma concentration in patients with mental disorders after oral administration, so as to provide reference for individualized treatment.Methods:Retrospective analysis was made on 221 inpatient reports of Clozapine blood concentration monitoring in the Therapeutic Drug Monitoring Laboratory (TDM) of the Pharmacy Department of the Chaohu Hospital Affiliated to Anhui Medical University from January to October 2021, and information such as patient gender, age, body mass index (BMI), smoking history, clozapine dose, combined drug use and blood concentration monitoring results were collected; Single factor analysis of variance and binary logistic regression were used to analyze the monitoring results of clozapine blood concentration in patients with mental disorders and its influencing factors.Results:Among 221 monitoring reports, 74 cases (normal concentration group) had clozapine plasma concentration within the effective plasma concentration range (350-600 ng/ml), 103 cases (low concentration group) were lower than the effective plasma concentration range (<350 ng/ml), and 44 cases (high concentration group) were higher than the effective plasma concentration range (>600 ng/ml). The results of single factor analysis of variance showed that there were statistically significant differences in daily dose of clozapine, standard dose, smoking history, course of disease, and abnormal liver function of patients in different blood concentration groups of clozapine (all P<0.05). The most frequently used antipsychotic drugs in 221 patients with clozapine were sodium valproate, amisulpride, aripiprazole and lithium carbonate in turn. The proportion of clozapine combined with ≥2 antipsychotics in the normal concentration group was higher than that in the low concentration group and the high concentration group, and the difference was statistically significant ( P<0.05). The results of binary logistic regression analysis showed that the combination of one antipsychotic drug and ≥ two antipsychotic drugs might help the blood concentration of clozapine in patients with mental disorders reach the target concentration (350-600 ng/ml), and the combination of two drugs was more beneficial [ OR(95% CI): 1.795(0.753-4.282)], with a statistically significant difference ( P<0.05). Conclusions:Clozapine plasma concentration varies greatly among individuals, and the therapeutic window is narrow. It is necessary to adjust the dosage in combination with the basic information and clinical information of patients, and regularly monitor the plasma concentration, so as to achieve the safety and effectiveness of individualized drug use.

Objective:To investigate the role of cholinergic anti-inflammatory pathway in the regulation of peptide transporter 1 (PepT1) expression in small intestinal epithelium of septic rats by Ghrelin.Methods:One hundred adult male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, sepsis+vagotomy group, sepsis+Ghrelin group, and sepsis+vagotomy+Ghrelin group, with 20 rats in each group. In the sham operation group, the cecum was separated after laparotomy, without ligation and perforation. In the sepsis group, the rats received cecal ligation puncture (CLP). In the sepsis+vagotomy group, the rats received CLP and vagotomy after laparotomy. In the sepsis+Ghrelin group, 100 μmol/L Ghrelin was intravenously injected after CLP immediately. The rats in the sepsis+vagotomy+Ghrelin group received CLP and vagotomy at the same time, then the Ghrelin was intravenously injected immediately with the same dose as the sepsis+Ghrelin group. Ten rats in each group were taken to observe their survival within 7 days. The remaining 10 rats were sacrificed 20 hours after the operation to obtain venous blood and small intestinal tissue. The condition of the abdominal intestine was observed. The injury of intestinal epithelial cells was observed with transmission electron microscopy. The contents of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in serum and small intestinal tissue were detected by enzyme-linked immunosorbent assay (ELISA). The brush border membrane vesicle (BBMV) was prepared, the levels of mRNA and protein expression of PepT1 in the small intestinal epithelium were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blotting.Results:All rats in the sham operation group survived at 7 days after operation. The 7-day cumulative survival rate of rats in the sepsis group was significantly lower than that in the sham operation group (20% vs. 100%, P < 0.05). The cumulative survival rate of rats after Ghrelin intervention was improved (compared with sepsis group: 40% vs. 20%, P < 0.05), but the protective effect of Ghrelin was weakened after vagotomy (compared with sepsis+Ghrelin group: 10% vs. 40%, P < 0.05). Compared with the sham operation group, in the sepsis group, the small intestine and cecum were dull red, the intestinal tubules were swollen and filled with gas, the intestinal epithelial cells were seriously injured under transmission electron microscopy, the levels of TNF-α and IL-1β in serum and small intestinal were significantly increased, and the expression levels of PepT1 mRNA and protein in the small intestinal epithelium were significantly decreased. It indicated that the sepsis rat model was successfully prepared. After vagotomy, the intestinal swelling and gas accumulation became worse in septic rats, leading to the death of all rats. Compared with the sepsis group, the abdominal situation in the sepsis+Ghrelin group was improved, the injury of intestinal epithelial cells was alleviated, the serum and small intestinal TNF-α and IL-1β were significantly decreased [serum TNF-α (ng/L): 253.27±23.32 vs. 287.90±19.48, small intestinal TNF-α (ng/L): 95.27±11.47 vs. 153.89±18.15, serum IL-1β (ng/L): 39.16±4.47 vs. 54.26±7.27, small intestinal IL-1β (ng/L): 28.47±4.13 vs. 42.26±2.59, all P < 0.05], and the expressions of PepT1 mRNA and protein in the small intestinal epithelium were significantly increased [PepT1 mRNA (2 -ΔΔCt): 0.66±0.05 vs. 0.53±0.06, PepT1 protein (PepT1/GAPDH): 0.80±0.04 vs. 0.60±0.05, both P < 0.05]. Compared with the sepsis+Ghrelin group, after vagotomy in the sepsis+vagotomy+Ghrelin group, the effect of Ghrelin on reducing the release of inflammatory factors in sepsis rats was significantly reduced [serum TNF-α (ng/L): 276.58±19.88 vs. 253.27±23.32, small intestinal TNF-α (ng/L): 144.28±12.99 vs. 95.27±11.47, serum IL-1β (ng/L): 48.15±3.21 vs. 39.16±4.47, small intestinal IL-1β (ng/L): 38.75±4.49 vs. 28.47±4.13, all P < 0.05], the up-regulated effect on the expression of PepT1 in small intestinal epithelium was lost [PepT1 mRNA (2 -ΔΔCt): 0.58±0.03 vs. 0.66±0.05, PepT1 protein (PepT1/GAPDH): 0.70±0.02 vs. 0.80±0.04, both P < 0.05], and the injury of small intestinal epithelial cells was worse. Conclusion:Ghrelin plays a protective role in sepsis by promoting cholinergic neurons to inhibit the release of inflammatory factors, thereby promoting the transcription and translation of PepT1.

Objective:To investigate the role of LncRNA-TUG1 in the injury of intestinal epithelial cells induced by lipopolysaccharide (LPS).Methods:LPS was used to treat HIEC-6 human intestinal epithelial cells for 24 h to construct a sepsis injury model. Whole transcriptome RNA sequencing was used to analyze the expression changes of mRNA, microRNA and lncRNA in HIEC-6 cells after LPS treatment. Real-time fluorescence quantitative (qRT-PCR) and Western blot was performed to detect the expression changes of lncRNA-TUG1, microRNA-132-3p (miR-132-3p), SIRT1 mRNA and SIRT1 protein in HIEC-6 cells after LPS treatment. The expression levels of LncRNA-TUG1, miR-132-3p and SIRT1 were artificially changed by in vitro transfection. qRT-PCR and Western blot were used to confirm the regulatory effect of lncRNA-TUG1 on microRNA-132-3p and SIRT1. CCK-8 and flow cytometry were used to analyze the effects of LncRNA-TUG1, miR-132-3p and SIRT1 on the proliferation and apoptosis of HIEC-6 cells. The dual luciferase report analysis was used to verify the targeting relationship between LncRNA-TUG1, miR-132-3p and SIRT1. Statistical analysis was performed using SPSS 17.0, and differences between the two groups were compared using independent sample t test. Results:RNA sequencing results showed that the expressions of lncRNA-TUG1 and SIRT1 were decreased in HIEC-6 cells after LPS treatment ( t=3.26, P<0.05 and t=2.55, P<0.05), but the expression of miR-132-3p was increased ( t=4.12, P<0.05). In vitro cell experiments, the expression of lncRNA-TUG1 and SIRT1 were decreased in HIEC-6 cells treated with LPS ( t=5.69, P<0.05 and t=5.712, P<0.05), while the expression of miR-132-3p was increased ( t=3.88, P<0.05). Overexpression of lncRNA-TUG1 increased the proliferation rate ( t=6.55, P<0.05) and decreased the apoptosis rate ( t=3.94, P<0.05) of LPS-treated cells. Upregulation of lncRNA-TUG1 decreased the expression of miR-132-3p ( t=4.66, P<0.05), and increased the mRNA and protein levels of SIRT1 ( t=3.91, P<0.05). Transfection of miR-132-3P mimic could inhibit the mRNA ( t=4.08, P<0.05) and protein levels of SIRT1. In LPS-treated cells, the cells co-transfected with miR-132-3pmimic and siRNA-SIRT1 had a lower proliferation rate ( t=4.55, P<0.05 and t=5.67, P<0.05) and a higher apoptosis rate ( t=3.90, P<0.05 and t=4.22, P<0.05) than those transfected with only pcDNA3.1-lncRNA-TUG. Conclusions:lncRNA-TUG1 may act as a ceRNA to regulate miR-132-3p/SIRT1, therefore alleviating HIEC-6 cell injury caused by LPS. Intervention of lncRNA-TUG1/miR-132-3p/SIRT1 regulatory pathway may become a potential strategy to prevent sepsis-induced intestinal mucosal damage.

objective:To investigate the tolerability of early enteral nutrition (EN), and to further explore the association of early EN with clinical outcome in critically ill patients with hemodynamic instability.Methods:The adult patients from Zhejiang Provincial People’s Hospital with an expected admission to ICU for at least 24 h were consecutively recruited from May 2014 to May 2016, and all clinical, laboratory, and survival data were prospectively collected. The AGI grade was daily assessed on the first week of ICU admission. Enteral nutrition (EN) started after 6 h of hemodynamic stability (MAP ≥ 65 mmHg) when the patients took vasoactive medication. The patients were divided into three groups based on the timing of EN initiation: early EN group (EN initiation within 48 h of ICU admission), late EN group (EN initiation at more than 48 h of ICU admission), and no initiation of enteral feeding within 7 days of ICU admission.Results:Of 201 patients enrolled, the mean age was 65.3 ± 16.4 years, APACHE II score was 22.4 ± 6.85, and 191 patients (95.0%) took mechanical ventilation. There were no differences in high gastric residual volume, diarrhea, and gastrointestinal (GI) bleeding between the early EN group and late EN group ( P>0.05). Whereas, patients in the no initiation of EN within 7 days of ICU admission had a lower prevalence of gastric residual volume (16.7% vs. 33.3%, P=0.05), but higher prevalence of GI bleeding (47.2% vs. 26.1%, P=0.02). Compared with those in the late EN group and in no initiation of EN within 7 days of ICU admission, patients in the early EN group had lower 28- (30.4% vs. 47.9% vs. 55.6%, P=0.01) and 60-day mortality rates (38.0% vs. 53.4% vs. 63.9%, P=0.017). Multivariate Cox regression analysis showed that the timing of EN initiation on the admission to ICU (early EN vs. late EN, χ 2≥5.83, P<0.05; early EN vs. no initiation of EN, χ 2≥7.90, P<0.01), serum creatinine ( χ 2=5.06, P<0.05), plasma albumin ( χ 2≥6.41, P<0.01), AGI grade ( χ 2≥8.15, P<0.01), and APACHE II score ( χ 2≥9.62, P<0.01) were independent predictors for 28- and 60-day mortality. Conclusions:Early EN on admission to ICU could be tolerated, and is significantly associated with lower risk of 28- and 60-day mortality in critically ill patients with vasoactive medication to maintain hemodynamic stability.

Objective:To investigate the related risk factors for the prognosis of hospital-acquired carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections in elderly patients with critical illness.Methods:Clinical data of elderly patients with nosocomial CRKP bloodstream infection in intensive care unit (ICU) from Jan. 2010 to Dec. 2016 were retrospectively analyzed. Patients were divided into the death and survival groups according to the prognosis. Clinical characteristics were compared between the two groups. Influencing factors for the prognosis of nosocomial CRKP bloodstream infections in elderly ICU patients were screened by multivariate Logistic regression analysis.Results:A total of 119 elderly ICU patients with nosocomial CRKP bloodstream infection were enrolled. The overall ICU mortality rate was 62.2% (74/119 patients), among which the ICU mortality was lower in patients treated with tigecycline than without tigecycline treatment (50.0% or 25/50 vs. 71.0% or 49/69, χ2=4.770, P=0.029). And the ICU mortality was lower in patients with combination therapy than with mono-therapy (54.9% or 39/71 vs. 72.9% or 35/48, χ2=3.940, P=0.047). Multivariate Logistic regression analysis revealed that the administration of vasoactive drugs ( OR=25.545, 95% CI: 9.743-52.242, P=0.001), and the resistance to tigecycline ( OR=8.990, 95% CI: 0.957-24.488, P=0.049) were independent risk factors for ICU mortality. While the early initiated appropriate antibiotics treatment, which was defined as using at least one susceptible antibiotic within 48 hours ( OR=0.081, 95% CI: 0.014-0.463, P=0.005), and appropriate antibiotics and adequate duration ( OR=0.785, 95% CI: 0.631-0.977, P=0.030), were protective factors for the good outcome. Conclusions:Nosocomial CRKP bloodstream infection in elderly ICU patients leads a high ICU mortality rate. The early initiated appropriate antibiotics treatment and optimum antibiotics duration could reduce the risk for death.

Objective: To explore the effects of a complex made from lily,glutinous rice,black bean,red jujube,whey protein powder and spirulina on tumor growth and immune function in C57BL/6 tumor-bearing mice,so as to provide evidence for nutrition intervention on tumor sufferers. Methods: Twenty-four C57BL/6 male tumor-bearing mice were divided into three dose groups and a control group. The mice in the low,medium and high dose group was fed with 8 g/kgbw,20 g/kgbw and 40 g/kgbw complex,respectively;the mice in the control group was fed with 0.5% CMC-Na. All mice were intragastrically administered for seven days,and the weight gain,tumor volume,tumor weight,tumor inhibition rate,thymus index,spleen index,T lymphocyte proliferation,NK cell killing rate and interleukin-2 expression were measured. Results: The tumor weights of the mice in the three dose groups wereall less than that in the control group（P<0.05）. The numbers of CD3+ T cells in the three dose groups were more than that in the control group（P<0.05）. The tumor inhibition rates of the low,medium and high dose groupwere 32.46%,45.14% and 48.03%,respectively. The optical density,NK cell killing rates,IL-2 expression of spleen cells and the number of T lymphocyte subsets were dose-dependent（P<0.05）. Compared with the control group,the mice in the medium and high dose group had higher thymus indexes,NK cell killing rates,IL-2 expression of spleen cells,CD4+T cell levels and CD4+ to CD8+ ratios,but lower tumor volumes and CD8+ T cell levels（P<0.05）;the mice in the high dose group had higher optical density（P<0.05）. Conclusion This nutritional complex may play an anti-tumor role by regulating the immune function of tumor-bearing mice.

OBJECTIVE： To investigate the improvement effects of Qishenlian eczema cream on the atopic dermatitis （AD） model guinea pigs， and to investigate its possible mechanism. METHODS： Female guinea pigs were randomly divided into normal control group， model control group， matrix control group （Qishenlian eczema cream matrix， 1 g/kg）， Qishenlian eczema cream low-dose， medium-dose and high-dose groups （0.5， 1， 2 g/kg） and Hydrocortisone butyrate cream group （0.5 g/kg）， with 10 guinea pigs in each group. Using ovalbumin as antigen， the skin allergy of guinea pigs was stimulated to induce AD model. Forty-eight hours after the last excitation， guinea pigs were smeared with normal saline in normal control group and model control group， while those were smeared with Qishenlian eczema cream matrix in matrix control group， and administration groups were treated with relevant medicine， twice a day， for consecutive 14 d. The scores of erythema， edema and scratch before and after administration were recorded in each group. The morphological characteristics of skin were observed by HE staining. TUNEL method was used to detect the apoptosis of keratinocytes in skin tissue. The level of IFN-γ in skin lesions was detected by ELISA. RESULTS： Compared with normal control group， inflammatory cell infiltration， hyperkeratosis of epidermis and thickening of spinous layer were observed in skin tissue of guinea pigs in model control group and matrix control group； the scores of erythema， edema and scratch and their total score， the level of IFN-γ in skin tissue were increased significantly； the apoptosis number of keratinocytes was decreased significantly （P＜0.01）. Compared with model control group and matrix control group， above symptoms of medication groups were relieved to different extents； the scores of erythema， edema and scratch and their total score after medication in medication groups， the level of IFN-γ in skin tissue in Qishenlian eczema cream medium-dose and high-dose groups and Hydrocortisone butyrate cream group were decreased significantly， and above scores in medication groups were significantly lower than before medication （P＜0.05 or P＜0.01）； the apoptosis number of keratinocytes was increased significantly in medication groups （P＜0.05 or P＜0.01）. CONCLUSIONS： Qishenlian eczema cream has certain improvement effect on AD model guinea pigs， the mechanism of which may be associated with promoting the keratinocyte apoptosis， reducing the level of INF-γ in skin tissue.

Objective To explore the prognostic values of telomerase reverse transcriptase promoter (TERTp) mutation and 1p/19q co-deletion in newly-diagnosed O6-methylguanine-DNA methyltransferase (MGMT) promoter un-methylated/isocitrate dehydrogenase (IDH) wild-type glioblastoma multiform (GBM). Methods A total of 82 patients pathologically newly-diagnosed MGMT promoter un-methylated/IDH wild-type GBM, admitted to our hospitals from March 2016 to November 2018, were included in this study. TERTp mutations (TERTp wild-type and TERTp mutation [C228 mutation and C250 mutation]) in GBM specimens were detected by PCR sequencing, 1p/19q co-deletion in GBM specimens was detected by fluorescence in situ hybridization (FISH), and clinical data, adverse reactions and prognoses of patients with different molecular typing were compared. Results There were 33 patients in the TERTp wild type group with mean age of 48 years, and 49 patients in the TERTp mutation group with mean age of 59 years; the difference of age was significant (P<0.05); there were no statistical differences in gender distribution, Karnofsky performance status (KPS) scores, tumor sites and surgical resection degrees between the two groups (P>0.05). There were 8 patients with 1p/19q co-deletion and 74 patients without 1p/19q co-deletion; no significant differences in above clinical parameters were noted between the two groups. There were no statistically significant differences in the incidences of bone marrow suppression, digestive tract response and fatigue, disease progression rate, or survival rate between patients from TERTp wild type group and TERTp mutation group, and between patients with 1p/19q co-deletion and patients without 1p/19q co-deletion (P>0.05). No significant differences in above clinical parameters, disease progression rate, and survival rate were noted between patients with C228 mutation and C250 mutation (P>0.05). Conclusion TERTp typing and 1p/19q co-deletion status do not have prognostic value in newly-diagnosed MGMT un-methylated/IDH wild-type GBM patients; patients with TERTp mutations have older age than wild-type patients; patients with C250 mutation trend to have higher survival rate than those with C228 mutation.