ObjectiveAt present, the most commonly used photosensitizers in photodynamic therapy are still chemical photosensitizers, such as porphyrin and methylene blue, in order to specifically target cellular tissues, and thus poison cells, chemical photosensitizers need to use antibody conjugation or a transgenically encoded tag with affinity for the modified photosensitizing ligand, e.g. FlAsH, ReAsh or Halo Tag. Gene-encoded photosensitizers can directly poison cells by targeting specific cell compartments or organelles. However, currently developed gene-encoded photosensitizers have low reactive oxygen species production and low cytotoxicity, so it is necessary to continue to develop and obtain photosensitizers with higher reactive oxygen species production for the treatment of microbial infections and tumors. MethodsIn this study, we developed a photosensitizer LovPSO2 based on the light-oxygen-voltage (LOV) structural domain of phototropin-1B-like from Oryza sativa japonica. LovPSO2 was expressed in E. coli BL21(DE3) and purified to obtain protein samples, the purified protein samples were added 3 µmol/L singlet oxygen probe of SOSG and 5 µmol/L superoxide anion probe of DHE after fixed to A₄₄₅=0.063±0.003, respectively, then measured every 2 min of singlet oxygen production for 10 min and every 1 min of superoxide anion production for 5 min under blue light irradiation at 445 nm, 70 µmol·m^-2·s^-1. ResultsThe results showed that LovPSO2 could produce a large amount of singlet oxygen under blue light irradiation at 445 nm, 70 µmol·m^-2·s^-1, and its singlet oxygen quantum yield was 0.61, but its superoxide anion yield was low, so in order to improve the superoxide anion yield of LovPSO2, a mutant with a relatively high superoxide anion yield was obtained by further development and design on its basis LovPRO2. The stability of proteins is crucial for research in drug development and drug delivery, among others. Temperature and light are the key factors affecting the production of reactive oxygen species (ROS) by photosensitive proteins and their stability, while the temperature in cell culture and mammals in vivo is about 37°C, and the temperature inside tumor cells is about 42-45°C. Therefore, we further analyzed the photostability of miniSOG, SOPP3, LovPSO2, and LovPRO2 and their thermostability at 37℃ and 45℃. The analysis of proteins thermostability showed that LovPSO2 and LovPRO2 had better thermostability at 37℃ and 45℃, respectively. Analysis of the photostability of the proteins showed that LovPRO2 had better photostability. In addition, to further determine the phototoxic effects of photosensitizers, LovPSO2 and LovPRO2 were expressed in E. coli BL21(DE3) and HeLa cells, respectively. The results showed that LovPSO2 and LovPRO2 had better phototoxicity to E. coli BL21(DE3) under blue light irradiation, and the cellular phototoxicity lethality was as high as 90% after 30 min of continuous light irradiation, but the phototoxicity was weaker in HeLa cells. The reason for this result may be that the intracellular environment exacerbated the photobleaching of FMN encapsulated by LovPSO2 and LovPRO2, respectively, which attenuated the damage of reactive oxygen species to animal cellular tissues, limiting its use as a mechanistic tool to study oxidative stress. ConclusionLovPSO2 and LovPRO2 can be used as antibacterial photosensitizers, which have broader application prospects in the food and medical fields.

Objective To describe and analyze the epidemiological characteristics of scrub typhus in Huai'an, Jiangsu Province from 2006 to 2024 and explore the long-term incidence trend and distribution of high-risk areas, and to formulate targeted prevention and control strategies. Methods The scrub typhus case report data of Huai'an from 2006 to 2024 in the Chinese Disease Prevention and Control Information System were extracted for descriptive analysis. Results A total of 898 cases of scrub typhus were reported in Huai'an, with an average annual incidence rate of 0.96 per 100 000 from 2006 to 2024. There was a turning point in the incidence trend of scrub typhus in 2011. From 2006 to 2011, the annual percentage change (APC) was 47.09% (95% CI: 7.53 - 859.39), and the upward trend was statistically significant (P < 0.05). From 2012 to 2024, the APC was -2.12% (95% CI: -29.09 - 3.75), and the downward trend was not statistically significant. October and November were the high-incidence months, and the total concentration from 2006 to 2024 was 0.93, indicating that scrub typhus had strict seasonality. The circular distribution method estimated that the peak period of the epidemic was from October 11th to November 25th, and the peak day of incidence was November 3rd. Jinhu County was a high-incidence area. The ratio of male to female cases was 1.03. The age group with the highest reported incidence was 40 to < 80 years old. The occupation with the highest proportion was farmers, accounting for 78.03%. Conclusion From 2006 to 2024, scrub typhus in Huai'an shows a peak every 3 - 4 years. Middle-aged and elderly farmers are the key population at risk, and Jinhu County is a key area. In the future, targeted health education should be carried out to effectively control the prevalence of scrub typhus.

Objective To conduct preliminary evaluation of the reliability and safety of pancreatic duct-to-jejunum stent-bridging internal drainage as a supplementary approach to pancreaticojejunostomy in central pancreatectomy.Methods The clinical data of 28 patients who underwent robotic central pancreatectomy performed by our team between January 2021 and November 2024 were retrospectively collected,and and follow-up of postoperative endocrine and exocrine functions was performed.Based on the methods of digestive tract reconstruction adopted,the patients were divided into a conventional pancreaticojejunostomy group and a pancreatic duct-to-jejunum stent-bridging internal drainage group(PancreaticoJejunal-Stent bridge group).The operative time,digestive tract reconstruction time,and short-term complications were compared between the two groups.Results Among patients undergoing robotic central pancreatectomy,the digestive tract reconstruction time was shorter(t=5.168,P<0.001)in the PancreaticoJejunal-Stent bridge group([31.1±6.3]min)than that in the conventional pancreaticojejunostomy group([49.7±8.9]min)(t=5.168,P<0.001).The total operative time was(172.7±64.6)min in the PancreaticoJejunal-Stent bridge group and(200.1±52.7)min in the conventional pancreaticojejunostomy group,showing no statistically significant difference(t=1.215,P=0.235).In the PancreaticoJejunal-Stent bridge group,one patient developed a postoperative biochemical fistula,and 14 patients developed grade B pancreatic fistulas.Among the 14 patients with grade B pancreatic fistulas,1 case was complicated by fistula-related intra-abdominal infection,and 13 cases had drainage tube retention time of more than 21 days.In the conventional pancreaticojejunostomy group,2 patients developed postoperative biochemical fistulas,and 11 patients developed grade B pancreatic fistulas.Among the 11 patients with grade B pancreatic fistulas,1 case was complicated by fistula-related intra-abdominal infection,and 1 case was complicated by fistula-related intra-abdominal bleeding and infection.No postoperative gastroparesis,pancreatitis,or grade C pancreatic fistulas occurred in either group.There were no statistically significant differences between the two groups in overall postoperative complication rate(P=0.522),postoperative pancreatic fistula rate(P=0.583),intra-abdominal infection rate(P=0.583),or bleeding rate(P=0.464).Conclusion Pancreatic duct-to-jejunum stent-bridging internal drainage optimizes the anastomosis between the distal end of the pancreas and the jejunum during central pancreatectomy,shortens digestive tract reconstruction time,and reduces surgical complexity without increasing the risk of short-term severe postoperative complications.This approach is safe and feasible.

As a member of class I histone deacetylase (HDACs), HDAC8 is an important anticancer drug target. Based on our previously developed pharmacophore model for the HDAC8 inhibitor, we designed and synthesized 13 quinoline acid derivatives as new HDAC8 inhibitors. Among them, the compound SDFZ-E2 and SDFZ-E3 exhibited good HDAC8 inhibitory activities and isoform selectivity. In cell experiments, the target compounds SDFZ-E2 and SDFZ-E3 showed better antiproliferation activities than the known HDAC8 selective inhibitor PCI-34051. In addition, the proposed binding mode of SDFZ-E2 was investigated using molecular docking and molecular dynamics simulation. This work is a new attempt to develop HDAC8 selective inhibitor using quinoline as the scaffold, and the active compounds could serve as lead compounds for further structural optimization.

Objective To investigate the hemodynamic effects of enhanced external counterpulsation(EECP)on cerebral arteries with different stenoses.Methods Zero-dimensional/three-dimensional multiscale hemodynamic models of cerebral arteries with different stenoses were constructed.Numerical simulations of the EECP hemodynamics were performed under different counterpulsation modes to quantify several hemodynamic indicators of the cerebral arteries.Among them,the mean time-averaged wall shear stress(TAWSS)downstream of the stenosis was in the range of 4-7 Pa,a low percentage of TAWSS risk area,and high narrow branch flow were considered to inhibit the development of atherosclerosis and create a good hemodynamic environment.Results For cerebral arteries with 50%,60%,70%,and 80%stenosis,the hemodynamic environment was optimal in counterpulsation mode when the moment of cuff deflation was 0.5,0.6,0.7,and 0.7 s within the cardiac cycle.Conclusions For 50%stenotic cerebral arteries,the counterpulsation mode with a deflation moment of 0.5 s should be selected.For 60%stenotic cerebral arteries,the counterpulsation mode with a deflation moment of 0.6 s should be selected.For 70%or 80%stenotic cerebral arteries,the counterpulsation mode with a deflation moment of 0.7 s should be selected.As stenosis of the cerebral arteries increases,the pressure duration should be prolonged.This study provides a theoretical reference for the EECP treatment strategy for patients with ischemic stroke with different stenoses.

Objective To investigate the primary symptoms of the common syndrome types in chronic gastritis through complex system modeling method,thus to provide evidence for the objectivity of the differentiation of traditional Chinese medicine(TCM)syndrome in chronic gastritis.Methods The complex system modeling methods of random forest,mutual information,rough sets,affinity propagation clustering and discriminant analysis were comprehensively used to screen the primary symptoms for the diagnosis of common syndrome types in chronic gastritis,such as syndrome of damp turbidity obstruction in the middle energizer,syndrome of spleen and stomach qi deficiency,syndrome of deficiency-cold in spleen and stomach,syndrome of liver depression and qi stagnation,and syndrome of stagnated heat in liver and stomach.And then the relationship between symptoms and syndromes types,and the relationship between symptoms and symptoms were mined.The diagnostic efficiency of the primary symptoms of chronic gastritis was evaluated by the discriminant analysis interactive validation method and the area under the receiver operating characteristic curve(AUC).Results The specific symptoms positively correlated with the syndrome of damp turbidity obstruction in the middle energizer were greasy coating,tooth-marked tongue,thick coating and enlarged tongue,while red tongue,thin coating and yellow coating were the identification symptoms negatively correlated with the syndrome,and their prediction accuracy was 79.2%with the AUC value being 0.868.The specific symptoms positively correlated with the syndrome of spleen and stomach qi deficiency were weakness,white coating,tooth-marked tongue,pale lip,and loose stools,while the identification symptoms negatively correlated with the syndrome were greasy moss and red tongue,and their prediction accuracy was 75.5%with the AUC value being 0.830.The specific symptoms positively correlated with the syndrome of deficiency-cold in spleen and stomach were cold limbs,preference of warmth in the epigastrium,and thin coating,while no identification symptoms negatively correlated with the syndrome,and their predictive accuracy was 79.2%with the AUC value being 0.836.The specific symptoms positively correlated with the syndrome of liver depression and qi stagnation were symptom aggravation due to emotional factors,distention or pain over hypochondriac region and belching,while the identification symptoms negatively correlated with the syndrome were weakness and greasy coating,and their predictive accuracy was 74.1%with the AUC value being 0.818.The specific symptoms positively correlated with the syndrome of stagnated heat in liver and stomach were red tongue,distention or pain over hypochondriac region and red lips,while the identification symptoms negatively correlated with the syndrome were greasy coating,white coating and thick coating,and their predictive accuracy was 79.9%with the AUC value being 0.845.The specific symptoms positively correlated with the common syndrome types in chronic gastritis mainly involved spleen,stomach and liver,and the disease-nature syndrome elements covered damp turbidity,qi deficiency,blood deficiency,cold dampness,yang deficiency,qi stagnation and heat.Conclusion The primary symptoms for the common syndrome types in chronic gastritis screened out through comprehensive application of complex system modeling methods are basically consistent with TCM theories,clinical practices and previous diagnostic criteria.Tongue and lip manifestations account for the largest proportion of the primary symptoms,indicating that tongue diagnosis and lip diagnosis are of great significance for the diagnosis of TCM syndrome types in chronic gastritis.

Objective To observe the influence of nintedanib ethanesulfonate soft capsules combined with tetrandrine tablets on pulmonary function and dyspnea symptoms in patients with connective tissue disease-related pulmonary interstitial fibrosis.Methods Patients with connective tissue disease-related pulmonary interstitial fibrosis were divided into treatment group and control group by cohort method.The control group was given basic treatment such as glucocorticoids and immunosuppressants according to the patient's condition;the treatment group was given ethanesulfonate nintedanib soft capsules(100 mg,bid)and tetrandrine tablets(40 mg,tid)on the basis of the control group,and the treatment course was 3 months.The clinical efficacy,severity of dyspnea[modified British Medical Research Council Dyspnea Scale(mMRC)and St.George's Respiratory Questionnaire(SGRQ)],pulmonary function indicators,pulmonary fibrosis score,and blood gas analysis indicators were compared between the two groups,and the safety was assessed.Results A total of 42 cases were included in the treatment group and the control group,respectively.The total effective rates of the treatment group and the control group were 92.86％(39 cases/42 cases)and 76.19％(32 cases/42 cases)respectively(P＜0.05).After treatment,the mMRC scores of the treatment group and the control group were(1.43±0.27)and(1.69±0.31)points;the SGRQ scores were(46.51±4.39)and(51.08±4.76)points;the forced expiratory volume in one second(FEV1)values were(64.96±6.55)％and(58.67±5.01)％;the fibrosis scores were(1.12±0.14)and(1.26±0.18)points;the partial pressure of arterial oxygen values were(80.31±7.03)and(75.02±6.94)mmHg.The above indexes of the treatment group were compared with those of the control group,and the differences were statistically significant(all P＜0.05).There were no adverse drug reactions in the treatment group,and the main adverse drug reactions in the control group were gastrointestinal discomfort.The total incidence rates of adverse drug reactions in the treatment group and the control group were 0 and 2.38％,respectively(P＞0.05).Conclusion Compared with basic treatment,nintedanib ethanesulfonate soft capsules combined with tetrandrine tablets can better improve the pulmonary fibrosis degree and dyspnea degree in patients with connective tissue disease-related pulmonary interstitial fibrosis,and delay the decline of pulmonary function of patients.

As a key epigenetic regulator, histone deacetylases (HDACs) play a crucial role in cancer development. Small molecule HDAC inhibitors have been shown to inhibit tumor proliferation and induce apoptosis, attracting significant research attention. In this study, we designed and synthesized a series of novel saccharin derivatives as HDAC inhibitors. Biological experiments demonstrated that the target compound 9a exhibited superior HDACs inhibition activity to vorinostat and demonstrating promising in vitro and in vivo anti-tumor activity against triple-negative breast cancer (TNBC). All animal experiments in this study were performed in strict accordance with the protocols approved by the Ethical Committee of School of Pharmaceutical Sciences in Shandong University (Approval No. 230094). This work represents an initial exploration of developing saccharin-based HDAC inhibitors, and the active compound 9a could serve as a lead compound for further study.

Severe acute pancreatitis (SAP) is a serious disease commonly encountered in the emergency department and can precipitate systemic inflammatory response syndrome and multiple organ dysfunction syndrome with high morbidity and mortality. However, its etiology and pathogenesis are complex and have not been fully elucidated. Clinical studies can provide some data on the etiology, pathophysiology, and outcome associated with the disease. However, research on SAP cannot be carried out in humans directly for ethical considerations. It is very important to establish an appropriate animal model of SAP to elucidate its pathogenesis and seek innovative therapeutic methods. In this paper, we reviewed the latest research progress at home and abroad in animal models of SAP over the past several years.