Pancreatic cancers (PCs) is a common malignant tumor with poor prognosis in the digestive system. Its main treatment methods include surgery, radiotherapy, chemotherapy, and targeted therapy. The early diagnosis rate of hidden onset of PCs is low, and most patients have already lost the opportunity to undergo surgery when diagnosed with PCs. Chemotherapy is still the main treatment for advanced PCs, but the use of chemotherapy drugs in PCs can easily lead to drug resistance. The most significant feature that distinguishes PCs from other tumors is its rich and dense matrix, which not only hinders drug penetration but also impedes the infiltration of immune cells. The above reasons have led to a very low survival rate of PCs patients. Therefore, drug delivery systems are very important in the diagnosis and treatment of PCs. They can improve drug delivery, enhance biological barrier penetration, reduce side effects, and combine multiple treatment methods. Therefore, the treatment prospects of PCs are very broad. Currently, drug delivery systems widely applied in PCs primarily include nanodrug delivery systems, tumor microenvironment-targeted drug delivery system, immunotherapy drug delivery system, gene therapy drug delivery system, and combination therapy drug delivery system that synergize multiple therapeutic modalities. Emerging drug delivery systems (DDSs) have revolutionized PCs treatment by addressing these challenges through multiple mechanisms. Nanoformulations improve drug solubility, prolong circulation time, and reduce systemic toxicity via passive/active targeting. Smart DDSs responsive to PCs-specific stimuli enable extracellular matrix degradation, tumor-associated fibroblasts reprogramming, and vascular normalization to enhance drug accessibility. Last but not least, carrier systems loaded with myeloid-derived suppressor cell inhibitors or T cell activators can reverse immunosuppression and potentiate immunotherapy efficacy. Advanced platforms co-deliver chemotherapeutics with immunomodulators, gene-editing tools, or sonodynamic agents to achieve synergistic antitumor effects. These platforms aim to address critical challenges in PCs treatment, such as enhancing drug bioavailability, overcoming stromal barriers, reprogramming immunosuppressive niches, and achieving multi-mechanistic antitumor effects. This article provides a systematic summary and prospective analysis of the current development status, latest cutting-edge advances, opportunities, and challenges of the above-mentioned drug delivery systems in the field of PCs therapy.

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

Objective To investigate the protective effect of cardamomine(CAR)on anthracycline-induced cardiotoxicity in rats by regulating the pyroptosis mediated by Notch/nuclear factor-κB(NF-κB)signal pathway.Methods The rat model of cardiotoxicity was established by intraperitoneal injection of doxorubicin(DOX).The model rats were randomly divided into DOX group,CAR-L group,CAR-H group and Jagged1 group.Another 10 rats were taken as the control group.The control group and the DOX group were given the same amount of 0.9％NaCl.The CAR-L group and CAR-H group were given 40 and 80 mg·kg-1 CAR by gavage,respectively.The Jagged1 group was given 80 mg·kg-1 CAR+and 25 ng·kg-1 Jagged1 by gavage once a day for 4 weeks.Myocardial injury markers creatine kinase isoenzyme(CK-MB)and troponin Ⅰ(cTn Ⅰ)were detected by kit.The expression of pyroptosis protein Nod-like receptor protein 3(NLRP3)and desquamate D(GSDM-D)were observed by immunohistochemistry.The expression of Notch1 and phosphorylated NF-κB p65(p-NF-κB p65)protein in myocardial tissue was detected by Western blotting.Results The levels of CK-MB in control group,DOX group,CAR-L group,CAR-H group and Jagged1 group were(48.51±5.39),(175.93±13.27),(106.83±9.73),(83.71±8.39)and(126.08±9.74)U·L-1;the levels of cTn Ⅰ were(1.95±0.18),(12.46±1.83),(7.15±0.64),(4.13±0.38)and(8.01±0.78)ng·mL-1;the average optical density of NLRP3 protein were 0.19±0.07,0.36±0.05,0.25±0.05,0.21±0.03 and 0.31±0.06;the average optical density of GSDM-D were 0.18±0.04,0.43±0.06,0.24±0.03,0.19±0.04 and 0.32±0.05.There were significant differences in the above indexes between DOX group and control group(all P＜0.05).There were significant differences in the above indexes between CAR-L group,CAR-H group and DOX group(all P＜0.05),and there were significant differences between CAR-L group and CAR-H group(all P＜0.05).The above indexes in Jagged1 group were significantly different from those in CAR-H group(all P＜0.05).Conclusion CAR can improve myocardial injury in DOX cardiotoxic rats,reduce oxidative stress,inflammatory reaction and pyroptosis,and its mechanism may be related to the inhibition of Notch/NF-κB pathway.

ObjectiveTo explore the possible mechanism of Chuanxiong （Rhizoma Chuanxiong） & Tianma （Rhizoma Gastrodiae） herbal pair in treating migraines based on AMP-activated protein kinase （AMPK）/transient receptor potential A1 channel （TRPA1） pathway. MethodsForty-eight healthy male SD rats were randomly divided into control group， model group， and Chuanxiong Tianma medication group， with 16 rats in each group. The control group and model group were given 10 ml/kg of normal saline by gavage， while the Chuanxiong Tianma medication group was given 0.675 g/kg of Chuanxiong Tianma herbal pair by gavage， once daily for 8 consecutive days in both groups. Migraime model was performed before the last administration， with subcutaneous injection of 10 ml/kg of normal saline in the control group， and subcutaneous injection of 10 ml/kg of nitroglycerin in the model group and Chuanxiong Tianma medication group. The Von Frey filament was used to measure the periorbital mechanical pain threshold of rats. The enzyme-linked immunosorbent assay （ELISA） was used to determine the levels of calcitonin gene-related peptide （CGRP） in rat serum and cerebrospinal fluid. The nitric oxide （NO） assay kit was used to determine the NO level in serum and cerebrospinal fluid. RT-PCR was usedto detect the mRNA expression levels of immediate-early genes in the trigeminal ganglion of rats （c-Fos）， CGRP， transient receptor potential V1 channel （TRPV1）， AMPK alpha subunit （PRKAA）， and TRPA1. Immunofluorescence was used to detect the number of c-Fos-positive cells in the trigeminal cervical complex （TCC） and the protein expression levels of phosphorylated AMPK （pAMPK） and TRPA1 in the trigeminal ganglion. ResultsCompared to those in the control group， the mechanical stimulation threshold and pAMPK protein expression in the model group decreased， while the levels of CGRP and NO in serum， c-Fos， CGRP， TRPV1 and TRPA1 mRNA levels in the trigeminal ganglion， TRPA1 protein expression， and the number of c-Fos-positive cells in the TCC significantly increased （P＜0.05）. Compared to those in the model group， the mechanical stimulation threshold and pAMPK protein expression in the Chuanxiong Tianma medication group significantly increased， while the levels of CGRP and NO in serum， c-Fos， CGRP， TRPV1 and TRPA1 mRNA levels in the trigeminal ganglion， TRPA1 protein expression， and the number of c-Fos-positive cells in the TCC significantly decreased （P＜0.05）. ConclusionChuanxiong Tianma herbal pair may improve migraine symptoms by regulating the AMPK/TRPA1 pathway in the trigeminal ganglion and increasing the mechanical pain threshold.

ObjectiveTemporal heterogeneity in lung cancer presents as fluctuations in the biological characteristics, genomic mutations, proliferation rates, and chemotherapeutic responses of tumor cells over time, posing a significant barrier to effective treatment. The complexity of this temporal variance, coupled with the spatial diversity of lung cancer, presents formidable challenges for research. This article will pave the way for new avenues in lung cancer research, aiding in a deeper understanding of the temporal heterogeneity of lung cancer, thereby enhancing the cure rate for lung cancer. MethodsRaman spectroscopy emerges as a powerful tool for real-time surveillance of biomolecular composition changes in lung cancer at the cellular scale, thus shedding light on the disease’s temporal heterogeneity. In our investigation, we harnessed Raman spectroscopic microscopy alongside multivariate statistical analysis to scrutinize the biomolecular alterations in human lung epithelial cells across various timeframes after benzo(a)pyrene exposure. ResultsOur findings indicated a temporal reduction in nucleic acids, lipids, proteins, and carotenoids, coinciding with a rise in glucose concentration. These patterns suggest that benzo(a)pyrene induces structural damage to the genetic material, accelerates lipid peroxidation, disrupts protein metabolism, curtails carotenoid production, and alters glucose metabolic pathways. Employing Raman spectroscopy enabled us to monitor the biomolecular dynamics within lung cancer cells in a real-time, non-invasive, and non-destructive manner, facilitating the elucidation of pivotal molecular features. ConclusionThis research enhances the comprehension of lung cancer progression and supports the development of personalized therapeutic approaches, which may improve the clinical outcomes for patients.

AIM To evaluate the quality of Beidougen Formula Granules.METHODS Fifteen batches of standard decoctions and three batches of formula granules were prepared,after which paste rate and contents,transfer rates of magnoflorine,daurisoline,dauricine were determined.HPLC specific chromatograms were established,and cluster analysis was adopted in chemical pattern recognition.RESULTS For three batches of formula granules,the paste rates were 15.1%-16.6%,the contents of magnoflorine,daurisoline,dauricine were 18.93-19.39,9.42-9.60,6.79-6.85 mg/g with the transfer rates of 34.42%-35.25%,43.81%-44.65%,27.27%-27.51%from decoction pieces to formula granules,respectively,and there were seven characteristic peaks in the specific chromatograms with the similarities of more than 0.95,which demonstrated good consistence with those of standard decoctions and accorded with related limit requirements.Fifteen batches of standard decoctions were clustered into two types,and the medicinal materials produced from Jilin,Hebei,Shangdong could be used for the preparation of formula granules.CONCLUSION This reasonable and reliable method can provide references for the quality control and clinical application of Beidougen Formula Granules.

Objective:To evaluate the 1-year postoperative efficacy and nutritional indicators of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) in obese patients.Methods:This retrospective observational study included patients with a body mass index (BMI) of ≥40.0 kg/m 2 regardless of other related metabolic diseases and patients with severe type 2 diabetes and a BMI between 27.5 and 40.0 kg/m 2. The clinical data of 66 obese patients who underwent SADI-S at the Bariatric and Metabolic Surgery Department of China-Japan Union Hospital of Jilin University from November 2018 to May 2022 were collected, including 53 cases of da Vinci robotic surgery and 13 cases of laparoscopic surgery. The patients comprised 38 men and 28 women with a median age of 35 (18–61) years and a mean preoperative BMI of 42.93 ± 6.82 kg/m 2. A total of 38 patients had type 2 diabetes, and 46 had hyperuricemia, 45 had hypertension, 35 had hyperlipidemia, 12 had hypercholesterolemia, and 12 had a high low-density lipoprotein (LDL) level. The main observation indicators were (1) intraoperative and postoperative conditions; (2) weight loss outcomes, including body weight, BMI, excess body weight loss (%EWL), and total body weight loss (%TWL) at 3, 6, and 12 months after surgery; (3) effects of treatment on metabolic disease; and (4) changes in nutrient indicators. Results:(1) Intraoperative and postoperative conditions: All patients successfully underwent SADI-S with neither conversion to laparotomy nor death. Four (6.1%) patients developed postoperative complications, and all of them recovered and were discharged after conservative or surgical treatment. (2) Weight loss outcomes: %EWL at 3, 6, and 12 months after surgery was 62.07 ± 26.56, 85.93 ± 27.92, and 106.65 ± 29.65, respectively, and %TWL was 22.67 ± 4.94, 32.10 ± 5.18, and 40.56 ± 7.89, respectively. Body weight and BMI 3 to 12 months after surgery were significantly lower than those before surgery (all P < 0.001). (3) Effect of treatment on metabolic disease: 3 to 12 months after surgery, fasting blood sugar, HbA1c, uric acid, systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, LDL, and other indicators were significantly lower than those before surgery (all P < 0.05). Twelve months after surgery, the remission rates of diabetes, hyperuricemia, hypertension, hypertriglyceridemia, hypercholesterolemia, and high LDL were 100% (38/38), 65.2% (30/46), 62.2% (28/45), 94.3% (33/35), 100% (12/12), and 100% (12/12), respectively. (4) Changes in nutrient indicators: Compared with the preoperative nutrient levels, the hemoglobin and hematocrit levels were lower at 3 to 12 months after surgery, the total protein level was lower at 6 to 12 months after surgery, the albumin level was lower at 6 months after surgery, and the ferritin level was lower at 3 months after surgery. The differences were statistically significant (all P < 0.05). The incidence of anemia was 6.1% (4/66), hypoalbuminemia was 4.5% (3/66), and ferritin deficiency was 4.5% (3/66), all of which were improved or normalized through conservative treatment. Twelve months after surgery, 30 (45.5%) patients had vitamin A deficiency, 17 (25.8%) had vitamin E deficiency, 11 (16.7%) had folic acid deficiency, 2 had potassium deficiency (3.0%), 3 (4.5%) had calcium deficiency, 2 (3.0%) had magnesium deficiency, 9 (13.6%) had iron deficiency, and 16 (24.2%) had zinc deficiency. However, no relevant clinical symptoms occurred. Conclusions:SADI-S has a very significant effect on weight loss and alleviation of metabolic diseases. Nutrient deficiencies after SADI-S mainly involve vitamin A, vitamin E, zinc, and folic acid. The long-term efficacy and safety of SADI-S still need further follow-up observation.

Objective:To evaluate the 1-year postoperative efficacy and nutritional indicators of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) in obese patients.Methods:This retrospective observational study included patients with a body mass index (BMI) of ≥40.0 kg/m 2 regardless of other related metabolic diseases and patients with severe type 2 diabetes and a BMI between 27.5 and 40.0 kg/m 2. The clinical data of 66 obese patients who underwent SADI-S at the Bariatric and Metabolic Surgery Department of China-Japan Union Hospital of Jilin University from November 2018 to May 2022 were collected, including 53 cases of da Vinci robotic surgery and 13 cases of laparoscopic surgery. The patients comprised 38 men and 28 women with a median age of 35 (18–61) years and a mean preoperative BMI of 42.93 ± 6.82 kg/m 2. A total of 38 patients had type 2 diabetes, and 46 had hyperuricemia, 45 had hypertension, 35 had hyperlipidemia, 12 had hypercholesterolemia, and 12 had a high low-density lipoprotein (LDL) level. The main observation indicators were (1) intraoperative and postoperative conditions; (2) weight loss outcomes, including body weight, BMI, excess body weight loss (%EWL), and total body weight loss (%TWL) at 3, 6, and 12 months after surgery; (3) effects of treatment on metabolic disease; and (4) changes in nutrient indicators. Results:(1) Intraoperative and postoperative conditions: All patients successfully underwent SADI-S with neither conversion to laparotomy nor death. Four (6.1%) patients developed postoperative complications, and all of them recovered and were discharged after conservative or surgical treatment. (2) Weight loss outcomes: %EWL at 3, 6, and 12 months after surgery was 62.07 ± 26.56, 85.93 ± 27.92, and 106.65 ± 29.65, respectively, and %TWL was 22.67 ± 4.94, 32.10 ± 5.18, and 40.56 ± 7.89, respectively. Body weight and BMI 3 to 12 months after surgery were significantly lower than those before surgery (all P < 0.001). (3) Effect of treatment on metabolic disease: 3 to 12 months after surgery, fasting blood sugar, HbA1c, uric acid, systolic blood pressure, diastolic blood pressure, triglycerides, total cholesterol, LDL, and other indicators were significantly lower than those before surgery (all P < 0.05). Twelve months after surgery, the remission rates of diabetes, hyperuricemia, hypertension, hypertriglyceridemia, hypercholesterolemia, and high LDL were 100% (38/38), 65.2% (30/46), 62.2% (28/45), 94.3% (33/35), 100% (12/12), and 100% (12/12), respectively. (4) Changes in nutrient indicators: Compared with the preoperative nutrient levels, the hemoglobin and hematocrit levels were lower at 3 to 12 months after surgery, the total protein level was lower at 6 to 12 months after surgery, the albumin level was lower at 6 months after surgery, and the ferritin level was lower at 3 months after surgery. The differences were statistically significant (all P < 0.05). The incidence of anemia was 6.1% (4/66), hypoalbuminemia was 4.5% (3/66), and ferritin deficiency was 4.5% (3/66), all of which were improved or normalized through conservative treatment. Twelve months after surgery, 30 (45.5%) patients had vitamin A deficiency, 17 (25.8%) had vitamin E deficiency, 11 (16.7%) had folic acid deficiency, 2 had potassium deficiency (3.0%), 3 (4.5%) had calcium deficiency, 2 (3.0%) had magnesium deficiency, 9 (13.6%) had iron deficiency, and 16 (24.2%) had zinc deficiency. However, no relevant clinical symptoms occurred. Conclusions:SADI-S has a very significant effect on weight loss and alleviation of metabolic diseases. Nutrient deficiencies after SADI-S mainly involve vitamin A, vitamin E, zinc, and folic acid. The long-term efficacy and safety of SADI-S still need further follow-up observation.

Objective To explore the postmortem diffusion rule of Aconitum alkaloids and their metabo-lites in poisoned rabbits,and to provide a reference for identifying the antemortem poisoning or post-mortem poisoning of Aconitum alkaloids.Methods Twenty-four rabbits were sacrificed by tracheal clamps.After 1 hour,the rabbits were administered with aconitine LD50 in decocting aconite root powder by intragastric administration.Then,they were placed supine and stored at 25℃.The biological samples from 3 randomly selected rabbits were collected including heart blood,peripheral blood,urine,heart,liver,spleen,lung and kidney tissues at 0 h,4 h,8 h,12 h,24 h,48 h,72 h and 96 h after intragastric administration,respectively.Aconitum alkaloids and their metabolites in the biological samples were ana-lyzed by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Results At 4 h after intragastric administration,Aconitum alkaloids and their metabolites could be detected in heart blood,peripheral blood and major organs,and the contents of them changed dynamically with the preservation time.The contents of Aconitum alkaloids and their metabolites were higher in the spleen,liver and lung,especially in the spleen which was closer to the stomach.The average mass fraction of benzoylmesaconine metabolized in rabbit spleen was the highest at 48 h after intragastric administration.In contrast,the contents of Aconitum alkaloids and their metabolites in kidney were all lower.Aconi-tum alkaloids and their metabolites were not detected in urine.Conclusion Aconitum alkaloids and their metabolites have postmortem diffusion in poisoned rabbits,diffusing from high-content organs(stomach)to other major organs and tissues as well as the heart blood.The main mechanism is the dispersion along the concentration gradient,while urine is not affected by postmortem diffusion,which can be used as the basis for the identification of antemortem and postmortem Aconitum alkaloids poisoning.

Purpose::Vibrio vulnificus ( V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. Methods::An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. Results::In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival ( p = 0.014), reduced the serum creatinine ( p = 0.002), urea nitrogen ( p = 0.030), aspartate aminotransferase ( p = 0.029), and alanine aminotransferase ( p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1β: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1β, IL-6, TNF-α in liver (IL-1β: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1β: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid ( p = 0.225), liver ( p = 0.186), or kidney ( p = 0.637). Conclusion::Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.