Pancreatic cancer is a kind of highly malignant tumor with a low survival rate and poor prognosis. The effectiveness of gemcitabine as a first-line chemotherapy drug is limited; however, it can activate dendritic cells and improve antigen presentation which increase the sensitivity of tumor cell to immunotherapy. Although immunotherapy has made some advancements in cancer treatment, the therapeutic benefit of programmed cell death receptor 1/programmed death receptor-ligand 1 (PD-1/PD-L1) blockade therapy remains relatively low. The chemokine C-X-C chemokine ligand 12 (CXCL12) contributes to an immunosuppressive tumor microenvironment by recruiting immunosuppressive cells. The receptor C-X-C motif chemokine receptor 4 (CXCR4), highly expressed in various tumors including pancreatic cancer, plays a crucial role in tumor development and progression. In this study, the anti-tumor immune response of human peripheral blood mononuclear cell (hPBMC) was enhanced using the combination of BsNb PX4 (anti-PD-L1&CXCR4 bispecific nanobody) and gemcitabine. In a co-culture system of gemcitabine-pretreated hPBMCs with tumor cells, the BsNb PX4 synergized gemcitabine to improve the cytotoxic activity of hPBMCs against tumor cells. Flow cytometry analysis confirmed increased ratio of CD8⁺ to CD4⁺ T cells in combination treatment. In NOD/SCID mice bearing pancreatic cancer, the combination treatment exhibited more infiltration of CD8⁺ T cells into tumor tissues, contributing to an effective anti-tumor response. This study presents potential new therapies for the treatment of pancreatic cancer. Ethical approval was obtained for collection of hPBMC samples from the Local Ethics Committee of Shanghai Jiao Tong University. All animal experiments were approved by the Animal Ethic Committee of Shanghai Jiao Tong University (authorizing number: A2024246).

This study aims to reveal the effect and mechanism of Gentianella turkestanorum total extract(GTI) in ameliorating non-alcoholic steatohepatitis(NASH). UPLC-Q-TOF-MS was employed to identify the chemical components in GTI. SwissTarget-Prediction, GeneCards, OMIM, and TTD were utilized to screen the targets of GTI components and NASH. The common targets shared by GTI components and NASH were filtered through the STRING database and Cytoscape 3.9.0 to identify core targets, followed by GO and KEGG enrichment analysis. AutoDock was used for molecular docking of key components with core targets. A mouse model of NASH was established with a methionine-choline-deficient high-fat diet. A 4-week drug intervention was conducted, during which mouse weight was monitored, and the liver-to-brain ratio was measured at the end. Hematoxylin-eosin staining, Sirius red staining, and oil red O staining were employed to observe the pathological changes in the liver tissue. The levels of various biomarkers, including aspartate aminotransferase(AST), alanine aminotransferase(ALT), hydroxyproline(HYP), total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione(GSH), in the serum and liver tissue were determined. RT-qPCR was conducted to measure the mRNA levels of interleukin 1β(IL-1β), interleukin 6(IL-6), tumor necrosis factor α(TNF-α), collagen type I α1 chain(COL1A1), and α-smooth muscle actin(α-SMA). Western blotting was conducted to determine the protein levels of IL-1β, IL-6, TNF-α, and potential drug targets identified through network pharmacology. UPLC-Q-TOF/MS identified 581 chemical components of GTI, and 534 targets of GTI and 1 157 targets of NASH were screened out. The topological analysis of the common targets shared by GTI and NASH identified core targets such as IL-1β, IL-6, protein kinase B(AKT), TNF, and peroxisome proliferator activated receptor gamma(PPARG). GO and KEGG analyses indicated that the ameliorating effect of GTI on NASH was related to inflammatory responses and the phosphoinositide 3-kinase(PI3K)/AKT pathway. The staining results demonstrated that GTI ameliorated hepatocyte vacuolation, swelling, ballooning, and lipid accumulation in NASH mice. Compared with the model group, high doses of GTI reduced the AST, ALT, HYP, TC, and TG levels(P<0.01) while increasing the HDL-C, SOD, and GSH levels(P<0.01). RT-qPCR results showed that GTI down-regulated the mRNA levels of IL-1β, IL-6, TNF-α, COL1A1, and α-SMA(P<0.01). Western blot results indicated that GTI down-regulated the protein levels of IL-1β, IL-6, TNF-α, phosphorylated PI3K(p-PI3K), phosphorylated AKT(p-AKT), phosphorylated inhibitor of nuclear factor kappa B alpha(p-IκBα), and nuclear factor kappa B(NF-κB)(P<0.01). In summary, GTI ameliorates inflammation, dyslipidemia, and oxidative stress associated with NASH by regulating the PI3K/AKT/NF-κB signaling pathway.
Animals ; Non-alcoholic Fatty Liver Disease/genetics* ; Mice ; Network Pharmacology ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Chromatography, High Pressure Liquid ; Liver/metabolism* ; Mice, Inbred C57BL ; Humans ; Mass Spectrometry ; Tumor Necrosis Factor-alpha/metabolism* ; Disease Models, Animal ; Molecular Docking Simulation

This study investigated the effects of total flavonoids of Dracocephalum moldavica(TFDM) on apoptosis in rat H9c2 cells induced by endoplasmic reticulum stress(ERS) established by oxygen-glucose deprivation and reoxygenation(OGD/R) injury and tunicamycin(TM), and explored the potential mechanisms. After successful modeling, the following groups were set in this experiment: control group, model(OGD/R or TM) group, and TFDM low-, medium-, and high-dose groups(12.5, 25, and 50 μg·mL~(-1)). The OGD/R injury model was constructed in vitro. Cell proliferation was assessed using the cell counting kit-8(CCK-8) method. The levels of lactate dehydrogenase(LDH) and creatine kinase MB isoenzyme(CKMB) in the cell supernatant were detected. Western blot was used to assess the expression of ERS-related proteins, including glucose regulatory protein 78(GRP78), C/EBP homologous protein(CHOP), activating transcription factor 6(ATF6), and apoptotic proteins B-cell lymphoma 2(Bcl-2) and Bcl-2-associated X protein(Bax). Apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) method. In the TM-induced ERS model, Western blot was used to measure the expression of ERS pathway-related proteins GRP78, CHOP, inositol-requiring enzyme 1(IRE1), X-box binding protein 1(XBP1), protein kinase RNA-like endoplasmic reticulum kinase(PERK), eukaryotic initiation factor 2α(eIF2α), ATF6, p-ATF6, and apoptotic proteins Bcl-2, Bax, cysteinyl aspartate specific proteinase-12(caspase-12), and cleaved caspase-12. Gene expression of GRP78, CHOP, PERK, and ATF6 was detected by real-time fluorescence quantitative PCR(RT-qPCR). Apoptosis was again detected using the TUNEL method. The results showed that in the OGD/R model, compared with the control group, the levels of LDH and CKMB in the cell supernatant were significantly increased in the OGD/R group. Compared with the OGD/R group, the levels of LDH and CKMB in the TFDM group were significantly reduced. Western blot results revealed that compared with the control group, the expression of ERS-related proteins and Bax in the OGD/R group was significantly increased, while the expression of Bcl-2 was significantly decreased. Compared with the OGD/R group, the expression of ERS-related proteins and Bax in the TFDM groups was significantly reduced, and the expression of Bcl-2 was significantly increased. TUNEL assay showed that apoptosis was significantly decreased after TFDM treatment. In the TM-induced ERS experiment, compared with the control group, the expression of ERS-related genes, ERS-related proteins, and apoptotic proteins in the TM group was significantly increased, while the expression of Bcl-2 was significantly decreased. Compared with the TM group, the expression of ERS-related genes, ERS-related proteins, and apoptotic proteins in the TFDM group was significantly reduced, and the expression of Bcl-2 was significantly increased. These results suggest that ERS exists in the OGD/R-injured H9c2 cell model, and TFDM can effectively inhibit ERS-induced apoptosis. The mechanism may be related to the downregulation of ERS pathway-related proteins and apoptotic proteins.
Animals ; Endoplasmic Reticulum Stress/drug effects* ; Apoptosis/drug effects* ; Rats ; Flavonoids/pharmacology* ; Glucose/metabolism* ; Cell Line ; Lamiaceae/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Oxygen/metabolism* ; Reperfusion Injury/physiopathology* ; Myocytes, Cardiac/cytology*

To investigate the mechanism of action of Syngnathus extract in treating knee osteoarthritis of rats, forty-eight male SD rats were randomly divided into the blank group, model group, positive drug group, as well as low-dose, medium-dose, and high-dose groups of Syngnathus extract. The rat model of knee osteoarthritis was constructed by intra-articular injection of sodium iodoacetate. After successful modeling, celecoxib(18 mg·kg~(-1)·d~(-1)) and Syngnathus extract(0.4, 0.8, and 1.6 g·kg~(-1)·d~(-1)) were given in different groups by gavage intervention for two weeks. Hematoxylin-eosin(HE) staining was used to observe the histopathological changes of cartilage in knee joints, and enzyme-linked immunosorbent assay(ELISA) was used to detect the expression level of inflammatory factors in serum. Real-time fluorescence quantitative PCR, Western blot, and immunohistochemistry were used to detect the levels of phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target protein of rapamycin(mTOR) pathway-related mRNA and protein expression. The results showed that, comparied with the blank group, the cartilage surface of the knee joints of rats in the model group was uneven, with disorganized levels and defective cartilage tissue. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) and the mRNA levels of PI3K, Akt, and mTOR in cartilage tissue, as well as the protein expression levels of phosphorylated PI3K(p-PI3K)/PI3K, phosphorylated Akt(p-Akt)/Akt, phosphorylated mTOR(p-mTOR)/mTOR, and P62 were significantly increased. Beclin1 protein expression was decreased. Comparied with the model group, the number of chondrocytes in the knee joint of rats in each group of Syngnathus extract increased, and the arrangement of chondrocytes was relatively neat. The cartilage layer was restored, and the serum levels of IL-1β, IL-6, and TNF-α, as well as the mRNA expression levels of PI3K, Akt, and mTOR in cartilage tissue were significantly reduced. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, p-mTOR/mTOR, and P62 were significantly reduced in the rats in the middle-dose and high-dose groups of Syngnathus extract, and the Beclin1 protein expression was significantly increased. The protein expression levels of p-PI3K/PI3K, p-Akt/Akt, and P62 in rats in the low-dose group of Syngnathus extract were significantly reduced. In summary, Syngnathus extract may be used to treat knee osteoarthritis by inhibiting the expression of PI3K/Akt/mTOR signaling pathway, so as to alleviate the inflammatory response in the organism, enhance the autophagy activity of chondrocytes, and reduce the apoptosis of chondrocytes.
Animals ; TOR Serine-Threonine Kinases/genetics* ; Male ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Rats ; Osteoarthritis, Knee/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Phosphatidylinositol 3-Kinases/genetics* ; Humans

This study predicts the potential mechanism of Hippocampus in the treatment of knee osteoarthritis(KOA) through network pharmacology, with preliminary verification using molecular docking and animal experiments. The database was used to screen the active chemical components of Hippocampus and the targets of KOA, and Gene Ontology(GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and molecular docking were performed on the relevant core targets to preliminarily explore the potential targets and mechanisms of Hippocampus in the treatment of KOA. A rat KOA model was constructed by intra-articular injection of sodium iodoacetate, and the rats were intervened with different doses of Hippocampus decoction and celecoxib. The expression of relevant targets was detected through hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), RT-qPCR, and Western blot to further validate the network pharmacology results. A total of 23 drug-like components of the Hippocampus were screened, and 128 common targets with KOA were identified, involving interleukin-17(IL-17) signaling pathway, transcription factor(FoxO) signaling pathway, tumor necrosis factor(TNF) signaling pathway. Molecular docking results showed that the screened core chemical components exhibited good affinity with key targets. HE staining demonstrated that Hippocampus improved the morphology of the cartilage layer. ELISA confirmed that Hippocampus significantly reduced the levels of IL-6 and TNF-α in the serum of KOA rats. Western blot and RT-qPCR analysis showed that Hippocampus significantly reduced the expression of IL-6, TNF-α, matrix metalloproteinase(MMP) 13, IL-17A, nuclear factor κB activator 1(ACT1), tumor necrosis factor receptor-associated factor 6(TRAF6) and nuclear factor κB(NF-κB) in cartilage tissue. The results suggest that Hippocampus can alleviate the degree of joint damage in the KOA rat model induced by sodium iodoacetate. The mechanism of action is related to the inhibition of the IL-17 signaling pathway, reduction of inflammation, and inhibition of extracellular matrix(ECM) degradation.
Animals ; Molecular Docking Simulation ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Network Pharmacology ; Male ; Osteoarthritis, Knee/metabolism* ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; Humans ; Interleukin-17/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Disease Models, Animal ; Hippocampus/chemistry*

Poor water solubility is the primary obstacle preventing the development of many pharmacologically active compounds into oral preparations. Self-nanoemulsifying drug delivery systems(SNEDDS) have become a widely used strategy to enhance the oral bioavailability of poorly soluble drugs by inducing a supersaturated state, thereby improving their apparent solubility and dissolution rate. However, the supersaturated solutions formed in SNEDDS are thermodynamically unstable systems with solubility levels exceeding the crystalline equilibrium solubility, making them prone to drug precipitation in the gastrointestinal tract and ultimately hindering drug absorption. Therefore, maintaining a stable supersaturated state is crucial for the effective delivery of poorly soluble drugs. Incorporating polymers as precipitation inhibitors(PPIs) into the formulation of supersaturated self-nanoemulsifying drug delivery systems(S-SNEDDS) can inhibit drug aggregation and crystallization, thus maintaining a stable supersaturated state. This has emerged as a novel preparation strategy and a key focus in SNEDDS research. This review explores the preparation design of SNEDDS and the technical challenges involved, with a particular focus on polymer-based S-SNEDDS for enhancing the solubility and oral bioavailability of poorly soluble drugs. It further elucidates the mechanisms by which polymers participate in transmembrane transport, summarizes the principles by which polymers sustain a supersaturated state, and discusses strategies for enhancing drug absorption. Altogether, this review provides a structured framework for the development of S-SNEDDS preparations with stable quality and reduced development risk, and offers a theoretical reference for the application of S-SNEDDS technology in improving the oral bioavailability of poorly soluble drugs.
Solubility ; Administration, Oral ; Polymers/chemistry* ; Drug Delivery Systems/methods* ; Humans ; Emulsions/chemistry* ; Biological Availability ; Animals ; Pharmaceutical Preparations/administration & dosage*

Fritillariae Cirrhosae Bulbus is the dried bulb of perennial herbaceous plants in the Fritillaria genus(Liliaceae family) and is a representative traditional Chinese medicinal material with distinctive regional characteristics. Clinically, it is widely used in the treatment of dry cough, bronchial asthma, and other respiratory diseases, possessing significant medicinal and economic value and being highly esteemed in TCM. Currently, Fritillariae Cirrhosae Bulbus primarily relies on wild harvesting. However, due to excessive collection, its wild resources have drastically declined, and all source species have been classified as category Ⅱ in the List of National Key Protected Wild Plants, exacerbating the supply-demand imbalance in the market. To mitigate this issue, large-scale cultivation through the domestication of wild Fritillariae Cirrhosae Bulbus has become an inevitable trend. However, its strict environmental requirements, low propagation efficiency, high seedling mortality, and immature cultivation techniques have severely hindered industrialization. This study investigates the domestication process of Fritillariae Cirrhosae Bulbus, focusing on seed propagation, seedling cultivation, and medicinal material production. It also reviews the species and distribution of wild resources, their endangered status, market supply-demand dynamics, and the historical and current development of domestication. The findings indicate that enhancing propagation efficiency, optimizing cultivation models, and distinguishing between seed propagation and medicinal material production are key measures to accelerate the industrialization of domesticated Fritillariae Cirrhosae Bulbus. This research aims to promote the industrialization of Fritillariae Cirrhosae Bulbus domestication and provide a reference model for the conservation and sustainable utilization of rare and endangered medicinal plant resources.
Fritillaria/chemistry* ; Endangered Species ; Plants, Medicinal/growth & development* ; Drugs, Chinese Herbal/economics* ; China

Incomplete debridement of chronic osteomyelitis is the main factor leading to recurrence. For the treatment of chronic osteomyelitis, the complete elimination of the source of infection is the key to preventing recurrence. This process includes not only the complete removal of infected lesions, dead bone, accreted scar tissue and granulation tissue, but also the elimination of dead space and improved local blood circulation. In these steps, debridement is a core procedure, and judging the scope of debridement is the premise of whether it could be completely debridement. This article systematically reviewed the application of different imaging techniques in evaluating the scope of chronic osteomyelitis infection, and discusses its future development trend. Although traditional plain X-ray film could preliminarily indicate osteomyelitis, it is difficult to determine the infection scope. CT scan has the function of accurate anatomic localization, which is important for preoperative assessment of the scope of bone infection, but the recognition of soft tissue information is limited. MRI, with its high sensitivity, clearly distinguishes between infected bone and soft tissue, which plays an important role in the evaluation of soft tissue infection, but may overestimate the extent of bone infection. Nuclide techniques such as 18F-FDG PET/CT and SPECT/CT show great potential for accurately assessing the extent of infection before surgery. In the future, by optimizing the combination of different imaging technologies, combining clinical symptoms, intraoperative conditions and pathological results, and developing an image analysis platform based on artificial intelligence, it will be able to more accurately assess the scope of infection, provide more effective and personalized treatment plans for patients with chronic osteomyelitis, enhance treatment effects, and significantly improve quality of life of patients.
Humans ; Osteomyelitis/diagnosis* ; Chronic Disease ; Magnetic Resonance Imaging ; Tomography, X-Ray Computed

OBJECTIVES: To study the differences in clinical characteristics of term and preterm neonates with necrotizing enterocolitis (NEC) undergoing surgical treatment. METHODS: A retrospective analysis was conducted on the clinical data of 142 NEC neonates who underwent surgery at the Children's Hospital of Chongqing Medical University from June 2017 to August 2023. The neonates were categorized into a preterm group (gestational age <37 weeks; 95 cases) and a term group (gestational age 37-42 weeks; 47 cases) to compare clinical characteristics. RESULTS: The preterm group had a higher postnatal age at both diagnosis and surgery compared to the term group (P<0.05). The preterm group also had a higher incidence of preoperative bloody stools, lower preoperative platelet counts, and higher rates of preoperative respiratory distress, apnea, reduced/absent bowel sounds, and mechanical ventilation compared to the term group (P<0.05). Postoperatively, the preterm group had higher rates of purulent meningitis, sepsis, and coagulation dysfunction, lower postoperative platelet counts, and lower intraoperative minimum body temperature than the term group (P<0.05). CONCLUSIONS There are significant differences in the clinical characteristics of preterm and term neonates with NEC undergoing surgery, suggesting the need for tailored perioperative management strategies based on these characteristics.
Humans ; Enterocolitis, Necrotizing/surgery* ; Infant, Newborn ; Retrospective Studies ; Male ; Female ; Infant, Premature ; Gestational Age

With the growing emphasis on maternal and child oral health, the significance of managing oral health across preconception, pregnancy, and infancy stages has become increasingly apparent. Oral health challenges extend beyond affecting maternal well-being, exerting profound influences on fetal and neonatal oral development as well as immune system maturation. This expert consensus paper, developed using a modified Delphi method, reviews current research and provides recommendations on maternal and child oral health management. It underscores the critical role of comprehensive oral assessments prior to conception, diligent oral health management throughout pregnancy, and meticulous oral hygiene practices during infancy. Effective strategies should be seamlessly integrated across the life course, encompassing preconception oral assessments, systematic dental care during pregnancy, and routine infant oral hygiene. Collaborative efforts among pediatric dentists, maternal and child health workers, and obstetricians are crucial to improving outcomes and fostering clinical research, contributing to evidence-based health management strategies.
Humans ; Pregnancy ; Female ; Infant ; Consensus ; Mouth Diseases/therapy* ; Pregnancy Complications/therapy* ; Oral Health ; Infant, Newborn ; Delphi Technique ; Oral Hygiene