Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

X-linked adrenoleukodystrophy(X-ALD) is an inherited progressive neurometabolic disorder caused by mutations in the ATP-binding cassette subfamily D member 1(ABCD1) gene. The encoded ALD protein dysfunction leads to the accumulation of very-long-chain fatty acids(VLCFA). X-ALD is classified according to its clinical characteristics into childhood cerebral ALD, adolescent cerebral ALD, adult cerebral ALD, adrenomyeloneuropathy(AMN), pure adrenocortical insufficiency, and an asymptomatic phenotype, all of which can present with a variety of neurologic manifestations. In this study, we retrospectively analyzed the clinical manifestations, laboratory findings, genetic test results, and follow-up data of four patients with X-ALD, and investigated the clinical features and pathogenicity of the identified gene mutations. All four patients initially presented with adrenocortical insufficiency(Addison′s disease) and received glucocorticoid replacement therapy. Subsequently, all developed neurologic signs and symptoms with rapid progression. The final diagnosis was confirmed based on elevated VLCFA levels, brain magnetic resonance imaging(MRI) findings, and genetic analysis. Notably, a deletion mutation in Exon 10 of the ABCD1 gene was identified in one case for the first time. We report four cases of X-ALD presenting with adrenocortical insufficiency as the initial symptom, and briefly review the relevant literature to analyze the relationship between linical phenotypes and genetic loci, aiming to provide a reference for early diagnosis and treatment of the disease, and to reduce the risk of misdiagnosis and missed diagnosis.

Objective To investigate the effect of oxymatrine on the brain damage of rats with acute carbon monoxide(CO)poisoning through the sirtuin 1(SIRT1)/forkhead box protein O1(FOXO1)signaling pathway.Methods SD rats were used to establish an acute CO poisoning rat model,after intervention with low,medium,and high doses of oxymatrine and edaravone,the cognitive function of the rats was tested using shuttle box experiments to screen for the optimal dosage of oxymatrine.Construct a rat model of acute CO poisoning againand randomly divide it into five groups:control group,model group,oxymatrine group,edaravone group,EX527(SIRT1 inhibitor)group,and oxymatrine+EX527 group,the model group and drug intervention groupinhaled CO gas to construct acute CO poisoning rat model.After drug intervention,the shuttle box experiment was used to detect the cognitive function in rats,the step-through latency(STL)and the total time spent in the dark chamber(TDC)of each group were compared;fluorescent probe was performed to measure the mitochondrial membrane potential of rat brain tissue;TUNEL staining was performed to detect the apoptosis rate of hippocampal neurons in the rat brain;the kit was performed to determine the levels of serum inflammatory factors and the oxidative stress factor;immunoblotting and immunoprecipitation experimentswas performed to determine the expression of SIRT1/FOXO1 pathway protein.Results Compared with the control group,the STL,brain mitochondrial membrane potential,serum SOD level,and brain tissue SIRT1 protein expression in the model group were significantly reduced(P＜0.05),and the TDC,neuron apoptosis rate,serum ROS,PGE2,TNF-α,IL-18 and MDA levels,and brain tissue acely-FOXO1/FOXO1 were significantly increased(P＜0.05).Compared with the model group and the oxymatrine+EX527 group,the STL,brain mitochondrial membrane potential,serum SOD level,and brain tissue SIRT1 protein expression were all increased in the oxymatrine group(P＜0.05),and the TDC,neuron apoptosis rate,serum ROS,PGE2,TNF-α,IL-18 and MDA levels,and brain tissue acely-FOXO1/FOXO1 were all decreased(P＜0.05);the trend of changes in various indicators in the EX527 group is opposite to that of the oxymatrine group(P＜0.05).There was no significant change in the levels of various indicators between the edaravone group and the high-dose oxymatrine group(P＞0.05).Conclusion Oxymatrine can activate SIRT1/FOXO1 signal to reduce inflammation and oxidative stress in rats,inhibit hippocampal neuronal apoptosis,repair brain mitochondrial function,enhance cognitive ability of rats,and improve brain damage of acute CO poisoning rats.

Objective To investigate the effect of oxymatrine on the brain damage of rats with acute carbon monoxide(CO)poisoning through the sirtuin 1(SIRT1)/forkhead box protein O1(FOXO1)signaling pathway.Methods SD rats were used to establish an acute CO poisoning rat model,after intervention with low,medium,and high doses of oxymatrine and edaravone,the cognitive function of the rats was tested using shuttle box experiments to screen for the optimal dosage of oxymatrine.Construct a rat model of acute CO poisoning againand randomly divide it into five groups:control group,model group,oxymatrine group,edaravone group,EX527(SIRT1 inhibitor)group,and oxymatrine+EX527 group,the model group and drug intervention groupinhaled CO gas to construct acute CO poisoning rat model.After drug intervention,the shuttle box experiment was used to detect the cognitive function in rats,the step-through latency(STL)and the total time spent in the dark chamber(TDC)of each group were compared;fluorescent probe was performed to measure the mitochondrial membrane potential of rat brain tissue;TUNEL staining was performed to detect the apoptosis rate of hippocampal neurons in the rat brain;the kit was performed to determine the levels of serum inflammatory factors and the oxidative stress factor;immunoblotting and immunoprecipitation experimentswas performed to determine the expression of SIRT1/FOXO1 pathway protein.Results Compared with the control group,the STL,brain mitochondrial membrane potential,serum SOD level,and brain tissue SIRT1 protein expression in the model group were significantly reduced(P＜0.05),and the TDC,neuron apoptosis rate,serum ROS,PGE2,TNF-α,IL-18 and MDA levels,and brain tissue acely-FOXO1/FOXO1 were significantly increased(P＜0.05).Compared with the model group and the oxymatrine+EX527 group,the STL,brain mitochondrial membrane potential,serum SOD level,and brain tissue SIRT1 protein expression were all increased in the oxymatrine group(P＜0.05),and the TDC,neuron apoptosis rate,serum ROS,PGE2,TNF-α,IL-18 and MDA levels,and brain tissue acely-FOXO1/FOXO1 were all decreased(P＜0.05);the trend of changes in various indicators in the EX527 group is opposite to that of the oxymatrine group(P＜0.05).There was no significant change in the levels of various indicators between the edaravone group and the high-dose oxymatrine group(P＞0.05).Conclusion Oxymatrine can activate SIRT1/FOXO1 signal to reduce inflammation and oxidative stress in rats,inhibit hippocampal neuronal apoptosis,repair brain mitochondrial function,enhance cognitive ability of rats,and improve brain damage of acute CO poisoning rats.

X-linked adrenoleukodystrophy(X-ALD) is an inherited progressive neurometabolic disorder caused by mutations in the ATP-binding cassette subfamily D member 1(ABCD1) gene. The encoded ALD protein dysfunction leads to the accumulation of very-long-chain fatty acids(VLCFA). X-ALD is classified according to its clinical characteristics into childhood cerebral ALD, adolescent cerebral ALD, adult cerebral ALD, adrenomyeloneuropathy(AMN), pure adrenocortical insufficiency, and an asymptomatic phenotype, all of which can present with a variety of neurologic manifestations. In this study, we retrospectively analyzed the clinical manifestations, laboratory findings, genetic test results, and follow-up data of four patients with X-ALD, and investigated the clinical features and pathogenicity of the identified gene mutations. All four patients initially presented with adrenocortical insufficiency(Addison′s disease) and received glucocorticoid replacement therapy. Subsequently, all developed neurologic signs and symptoms with rapid progression. The final diagnosis was confirmed based on elevated VLCFA levels, brain magnetic resonance imaging(MRI) findings, and genetic analysis. Notably, a deletion mutation in Exon 10 of the ABCD1 gene was identified in one case for the first time. We report four cases of X-ALD presenting with adrenocortical insufficiency as the initial symptom, and briefly review the relevant literature to analyze the relationship between linical phenotypes and genetic loci, aiming to provide a reference for early diagnosis and treatment of the disease, and to reduce the risk of misdiagnosis and missed diagnosis.

Objective To explore effect of Wenyang Qudu formula on serum inflammatory factors and immune index in patients with severe infections.Methods A total of 86 severe infection patients admitted to the Third People's Hospital of Henan Province from January to December 2023 were selected as the research subjects.According to the patient file order,odd numbers were the study group,and even numbers were the control group,with 43 cases in each group.The control group was treated with cefoperazone sulbactam sodium,while the study group was treated with Wenyang Qudu formula in addition to the control group[drug composition:Prepared aconite(first decocted)30 g,Poria cocos 30 g,White peony 15 g,Red peony 15 g,Stir fried atractylodes macrocephala 30 g,Dried ginger 9 g,Roasted licorice 9 g,Cassia twig 15 g,Semen lepidii 15 g,Dragon's bone 15 g,Raw oyster 15 g,Codonopsis pilosula 12 g,Angelica sinensis 12 g,Asarum 3 g,Schisandra chinensis 6 g,and Jujube 12 g].Brew in water,and took one dose daily,once in the morning and once in the evening,for a continuous period of 7 days.The differences in the scores of traditional Chinese medicine symptoms such as fever,dyspnea,frequent urination,urgency,and degree of sputum production,serum levels of interleukin-10(IL-10),C-reactive protein(CRP),eosinophils(EOS),and immune function indicators[immunoglobulin E(IgE),CD3+,CD4+,CD8+,CD4+/CD8+]were compared between two groups after treatment,and observed the occurrence of adverse reactions.Results After treatment,the traditional Chinese medicine symptom scores(fever,dyspnea,frequent urination and urgency,degree of sputum production),as well as IL-10,CRP,EOS levels,IgE,and CD8+ were significantly reduced in both groups compared to before treatment,CD3+,CD4+,and CD4+/CD8+ were significantly increased compared to before treatment.In addition,the study group had significantly lower scores of fever,dyspnea,frequent urination and urgency,degree of sputum production,IL-10,CRP,EOS levels,IgE,and CD8+ compared to the control group(fever score:1.36±0.30 vs.2.57±0.46,dyspnea score:1.22±0.31 vs.2.26±0.75,urinary frequency and urgency score:1.30±0.39 vs.2.33±0.82,degree of sputum production:1.19±0.77 vs.2.51±0.85,IL-10(ng/L):9.03±1.67 vs.10.51±2.40,CRP(mg/L):4.68±1.33 vs.7.82±2.53,EOS(×109/L):0.30±0.04 vs.0.46±0.10,IgE(mg/L):104.62±10.73 vs.135.68±14.64,CD8+:0.228±0.016 vs.0.258±0.020,all P<0.05],the levels of CD3+,CD4+,and CD4+/CD8+ were significantly higher than those in the control group(CD3+:0.636±0.044 vs.0.567±0.055,CD4+:0.537±0.054 vs.0.397±0.045,CD4+/CD8+:1.76±0.51 vs.0.55±0.39,all P<0.05].After treatment,it was discovered that the study group had not experienced any adverse reactions,while the control group had 1 case of nausea and vomiting and 1 case of chest tightness.There was no statistically significant difference in the incidence of adverse reactions between the study group and the control group[0(0/43)vs.0.05%(2/43),P>0.05].Conclusion The Wenyang Qudu formula can reduce the serum factor levels of IL-10,CRP,and EOS in critically infected patients,and improve immune function with good safety.

OBJECTIVE To explore the specific application and evaluation effect of objective structured clinical examination(OSCE)-guided scenario-based practical teaching mode in training clinical pharmacists. METHODS Fifty-six trainees who participated in the clinical pharmacist training program in the Second Xiangya Hospital of Central South University from October 2020 to September 2022 were selected as the research objects. OSCE-guided teaching was conducted, and the application effect of OSCE-guided teaching mode in clinical pharmacist training was explored and analyzed by using theoretical examination results and OSCE assessment results as evaluation indicators. RESULTS Through comparative analysis, it was found that the OSCE-guided teaching mode not only enabled students to better grasp the theoretical knowledge points required by the training outline, but also improved their clinical thinking ability, problem-solving ability, and communication and coordination skills to varying degrees. CONCLUSION For clinical pharmacist trainees, the OSCE teaching mode is conducive to the comprehensive improvement of clinical pharmacist skills and is suitable for cultivating clinical pharmacists who are capable of independently carrying out clinical pharmacy services in the new situation.

Objective:To evaluate the predictive value of proximal ureteral diameter (D1)to distal ureteral diameter (D2)ratio (DDR) for impacted stones in the middle and upper ureter.Methods:The clinical data of 173 patients with middle and upper ureteral calculi admitted to the Third Hospital of Shanxi Medical University from January 2014 to November 2021 were retrospectively analyzed. There were 75 males and 98 females, with the median age of 56.0 (51.0, 62.0) years old and median body mass index of 26.1 (24.8, 27.2) kg/m 2. The imaging data of the patients were analyzed. The impacted stones were defined as the inability of the contrast agent to pass through the site of obstruction when intravenous urography or CT urography was performed, resulting in the inability of the ureter to visualize normally in parts below the site of obstruction. D1 was defined as the proximal ureteral diameter at the lower pole of the kidney on horizontal CT images. D2 was defined as the ureteral diameter 3 cm from the calculi. The stone diameter, stone CT value, D1, D2, and DDR were compared between impacted stone group and non-impacted stone group. Univariate logistic regression analysis was used to analyze the different indicators. Random number table was used to divide the training set and validation set according to the ratio of 7∶3. Through least absolute shrinkage and selection operator(LASSO) regression analysis, the independent influencing factors were obtained and the nomogram model was established (Model 1). Receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to verify the predictive efficacy of the model, and the other three effective models (Model 2-4) were constructed by stepwise multivariate logistic regression. The deLong test was used to compare whether there was a significant difference in the AUC between Model 1 and the other three models, and the net benefit of patients was analyzed by clinical decision curve analysis(DCA). Results:In this study, 64 cases (37.0%) were impacted ureteral calculi and 109 cases (63.0%) were non-impacted ureteral calculi, and there were significant differences in diameter[7.8(6.2, 8.8)mm vs. 6.3(5.2, 8.1)mm] , CT value[878.5(763.8, 940.5)HU vs.764.0 (613.0, 854.0) HU], D1[11.1(8.9, 14.9) mm vs. 9.1(7.1, 10.8) mm], D2[4.1(3.1, 4.9) mm vs. 5.0(4.1, 5.9) mm] and DDR[3.1(2.3, 3.9) vs. 1.8(1.4, 2.4)] between the two groups( P < 0.05). The results of univariate logistic regression analysis showed that stone diameter ( OR = 1.333, P < 0.001), CT value ( OR = 1.002, P=0.002), D1 ( OR = 1.146, P<0.001), D2 ( OR = 0.652, P < 0.001) and DDR ( OR = 2.995, P<0.001) were the influencing factors of impacted stones. The training set and validation set included 122 cases and 51 cases, respectively, without significant differences in their image characteristics and outcomes ( P > 0.05). The results of LASSO regression analysis showed that λ corresponding to the simplest result in the optimal range was 0.0908, and three variables were included at this time, and the influencing factors of impacted stones were stone diameter (coefficient 0.0700, OR = 1.073), CT value (coefficient 0.0003, OR = 1.001) and DDR (coefficient 0.5960, OR = 1.815). Moreover, Model 1 was established. According to the model fitting results, ROC curves were plotted, and the AUC of Model 1 was 0.862, and the AUCs of Model 2-4 were 0.859, 0.762, and 0.793, respectively. After deLong test, there was no significant difference between Model 1 and Model 2 ( Z = 0.248, P = 0.804). The AUC of Model 1 was superior to that of Model 3 ( Z = 2.888, P = 0.004) and Model 4 ( Z = 2.321, P = 0.020). The DCA suggested that Model 1 could improve the net benefit rate by up to approximately 21% of patients. Conclusions:DDR is the influencing factor of impacted ureteral calculi, and the model constructed by DDR, stone CT value and stone diameter can effectively predict the probability of impacted ureteral calculi in the middle and upper ureter.

Objective:To investigate the association of muscle mass loss with atherosclerosis in elderly patients with type 2 diabetes mellitus(T2DM).Methods:A total of 322 patients with T2DM aged≥60 years old were divided into muscle mass loss group( n=152) and non-muscle mass loss group( n=170) according to their appendicular skeletal muscle mass index(ASMI). All participants underwent physical examination, dual-energy X-ray absorptiometry check, carotid and lower extremity ultrasound, as well as laboratory tests. Results:Among 322 patients, 49(15.22%) patients were suffered from sarcopenia and 152(47.2%) patients with reduced muscle mass. The carotid and lower extremity atherosclerosis grades in the muscle mass loss group were significantly higher than those in the non-muscle mass loss group( P<0.05), with lower body mass index(BMI), T-score, ASMI, uric acid, and homeostasis model assessment of insulin resistance index( P<0.05). Multivariate logistic regression analysis showed that carotid atherosclerosis and lower extremity atherosclerosis were risk factors for muscle mass loss while BMI and 25-(OH)D 3 were protective factors for muscle mass loss. There existed a consistency in carotid atherosclerosis grade and lower extremity atherosclerosis grade of elderly patients with T2DM( P<0.01). Conclusion:Atherosclerosis has a predictive value for early sarcopenia in elderly patients with T2DM.