With the widespread use of antibiotics, drug-resistant bacterial infections have become a significant threat to human health. Finding new antibacterial strategies that can effectively control drug-resistant bacterial infections has become an urgent task. Unlike small molecule drugs that target bacterial proteins, antisense oligonucleotide (ASO) can target genes related to bacterial resistance, pathogenesis, growth, reproduction and biofilm formation. By regulating the expression of these genes, ASO can inhibit or kill bacteria, providing a novel approach for the development of antibacterial drugs. To overcome the challenge of delivering antisense oligonucleotide into bacterial cells, various drug delivery systems have been applied in this field, including cell-penetrating peptides, lipid nanoparticles and inorganic nanoparticles, which have injected new momentum into the development of antisense oligonucleotide in the antibacterial realm. This review summarizes the current development of small nucleic acid drugs, the antibacterial mechanisms, targets, sequences and delivery vectors of antisense oligonucleotide, providing a reference for the research and development of antisense oligonucleotide in the treatment of bacterial infections.

OBJECTIVE: To explore the molecular mechanism of Shenmai Injection (SMI) against doxorubicin (DOX) induced cardiomyocyte apoptosis. METHODS: A total of 40 specific pathogen-free (SPF) male Sprague Dawley (SD) male rats were divided into 5 groups based on the random number table, including the control group, the model group, miR-30a agomir group, SMI low-dose (SMI-L) group, and SMI high-dose (SMI-H) group, with 8 rats in each group. Except for the control group, the rats were injected weekly with DOX (2 mg/kg) in the tail vein for 4 weeks to induce myocardial injury, and were given different regimens of continuous intervention for 2 weeks. Cardiac function was detected by echocardiography and myocardial pathological changes were observed by Van Gieson (VG) staining. Myocardial injury serum markers, including creatine kinase (CK), lactate dehydrogenase (LDH), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), soluble ST2 (sST2), and growth differentiation factor-15 (GDF-15) were detected by enzyme linked immunosorbent assay (ELISA). Cardiomyocyte apoptosis was observed by terminal deoxynucleotidyl transferase-mediated biotinylated dUTP triphosphate nick end labeling (TUNEL) and transmission electron microscopy, and the expressions of target proteins and mRNA were detected by Western blot and quantitative real time polymerase chain reaction (qRT-RCR), respectively. RESULTS: The treatment with different doses of SMI reduced rat heart mass index and left ventricular mass index (P<0.05), significantly improved the left ventricular ejection fraction (P<0.05), decreased the levels of serum CK, LDH, cTnT, and NT-proBNP (P<0.05 or P<0.01), reduced the levels of serum sST2 and GDF-15 (P<0.05 or P<0.01), decreased the collagen volume fraction, reduced the expressions of rat myocardial type I and type III collagen (P<0.05 or P<0.01), and effectively alleviated myocardial fibrosis. And the study found that SMI promoted the expression levels of miR-30a and Bcl-2 in myocardium, and down-regulated the expression of Bax, which inhibited the activation of Caspase-3 and Caspase-9 (P<0.05 or P<0.01), and improved myocardial cell apoptosis. CONCLUSIONS SMI can alleviate myocardial injury and apoptosis caused by DOX, and its mechanism possibly by promoting the targeted expression of myocardial Bcl-2 protein through miR-30a.
Animals ; Myocytes, Cardiac/metabolism* ; Apoptosis/drug effects* ; MicroRNAs/genetics* ; Rats, Sprague-Dawley ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Doxorubicin/pharmacology* ; Proto-Oncogene Proteins c-bcl-2/genetics* ; Drug Combinations ; Injections ; Rats

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy.

Objective To compare regression models for age estimation constructed based on the Pulp Dentinal Index(PDI)of the first permanent molars and explore a more accurate and applicable novel method.Methods A total of 900 Cone Beam Computed Tomography(CBCT)image datasets from adult Han Chinese individuals(455 males and 445 females)residing in Sichuan province,China,were collected from the Affiliated Hospital of North Sichuan Medical College.The PDI of the first permanent molars were measured using Mimics software.Regression analysis was performed with age as the dependent variable and PDI as the independent variable to establish and validate the optimal mathematical model for age estimation.Results Strong correlations were observed between the PDI of all four first permanent molars and age,with the correlation being stronger for maxillary teeth compared to mandibular teeth,and the highest correlation found in the left maxillary first molar among females(r=0.881).Significant differences in PDI were identified between maxillary and mandibular positions as well as between genders(P＜0.05),but not between left and right positions(P＞0.05).Among the 11 mathematical models constructed,the cubic regression model outperformed others,with the left maxillary first molar model demonstrating the best performance(Age=73.93-70.79x-68.75x2+94.33x3),yielding a mean absolute error(MAE)of 4.88 years.Conclusion Among the 11 regression models constructed in this study based on CBCT-measured PDI values of the first permanent molars,the cubic regression model exhibited the highest accuracy,with an MAE of 4.88 years.

OBJECTIVE: To retrospectively analyze the characteristics and influencing factors of COVID-19 infection in patients with multiple myeloma (MM) who underwent autologous hematopoietic stem cell transplantation (AHSCT). METHODS: The clinical data of MM patients who underwent AHSCT in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 26, 2021 to December 26, 2022 were collected. The onset of COVID-19 infection, corresponding symptoms and laboratory tests were followed up in outpatient or by the means of telephone contact and online questionnaires. Related analysis was then performed. RESULTS: This study included 96 patients, and 72 cases among them were infected with COVID-19 while 24 cases were uninfected. Logistic regression analysis showed that vaccination did not significantly reduce the risk of COVID-19 infection, but patients who received two doses of the vaccine had a lower risk of developing moderate and severe disease than those who did not receive or received one dose (OR =0.06, P =0.029). Patients who received daratumumab before had a higher risk of COVID-19 infection (OR =5.78, P =0.039), while those with a history of immunomodulatory drugs (IMiDs) had the opposite effect (OR =0.31, P =0.028). The use of both drugs did not affect the severity of COVID-19 infection. CONCLUSION For MM patients undergoing AHSCT as first-line chemotherapy, COVID-19 vaccination does not significantly reduce the infection rate, but it plays a role in preventing moderate and severe cases. The application of antineoplastic drugs with different mechanisms has a certain impact on the susceptibility to the COVID-19, which should be considered comprehensively when creating treatment plans.
Humans ; Multiple Myeloma/complications* ; COVID-19/epidemiology* ; Hematopoietic Stem Cell Transplantation ; Transplantation, Autologous ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Male ; Female ; Middle Aged ; SARS-CoV-2 ; Adult ; Antibodies, Monoclonal

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

To investigate the role of the DPP4-nestin axis in liver fibrosis induced by alveolar cyst infection,a murine model was established using C57BL/6 mice via hepatic portal vein injection.Liver histopathological changes were assessed using HE staining,while immunohistochemistry and immunofluorescence were employed to evaluate the expression levels of nestin and DPP4 in infected mouse livers.In vitro,J S1 cell line was stimulated with recombinant DPP4 protein to es-tablish a cellular model,and qPCR,Western blot,and shRNA lentivirus interference techniques were utilized to examine the involvement of the DPP4-nestin axis in hepatic stellate cell activation.The findings demonstrated that compared to the Sham group,liver tissue structure disruption and collagen deposition were evident along with significantly increased expressions of nestin and DPP4(P＜0.050 0),which colocalized with nesin and α-SMA.Furthermore,stimulation with recombi-nant DPP4 protein significantly enhanced JS1 cell activation(P＜0.050 0)as well as upregulated nestin expression(P＜0.050 0)when compared to control group cells.Notably,shRNA lentivirus-mediated inhibition of nestin expression effectively suppressed the activating effects exerted by re-combinant DPP4 protein on JS1 cells(P＜0.050 0).Collectively,these results highlight the crucial regulatory role played by the DPP4-nestin axis in hepatic stellate cell activation triggered by alveo-lar infection;thus,targeting this axis may represent a novel therapeutic strategy for treating alveo-lar infection-induced liver fibrosis.

Central nervous system(CNS)degenerative disorders refer to a spectrum of pathological alterations triggered by struc-tural damage to cerebral neural tissues,clinically manifested as diverse neurological dysfunction syndromes,including multiple sclerosis(MS),neurodegenerative diseases(NDs),and ische-mic stroke.The hallmark pathological features of these disorders involve irreversible neuronal damage and decompensation of functional neural networks,ultimately leading to progressive neurological deficits.Notably,with the accelerating global popu-lation aging,the incidence of these diseases has surged signifi-cantly.According to WHO statistics,they now rank among the top three global causes of disability and mortality.Current re-search has confirmed that the pathogenesis of CNS degenerative disorders exhibits high heterogeneity,encompassing multifaceted pathophysiological processes such as genetic predisposition,oxi-dative stress,protein misfolding,and metabolic dysregulation.This intricate pathogenic network not only complicates clinical differential diagnosis but also poses substantial challenges to the development of precision therapeutic strategies.Importantly,re-cent studies have revealed that mitochondrial homeostasis disrup-tion-induced inflammatory cascades(termed mitochondrial in-flammation)play a pivotal regulatory role in neurodegenerative progression.Key molecular mechanisms include impaired mito-phagy,aberrant mitochondrial DNA(mtDNA)release and NL-RP3 inflammasome activation.This review systematically deci-phers the molecular regulatory network of mitochondrial inflam-mation,with a focus on its biological effects in critical pathologi-cal events such as blood-brain barrier disruption,microglial hy-peractivation and neuronal apoptosis.The overarching aim is to provide a theoretical foundation for developing innovative thera-peutic strategies targeting mitochondrial homeostasis restoration.

Background and Aims:Single-incision laparoscopic cholecystectomy(LC)has become increasingly popular due to its minimal invasiveness and cosmetic advantages,but challenges remain in biliary identification and limited operative space.Indocyanine green(ICG)fluorescence navigation enables real-time visualization of the biliary tract and may enhance surgical safety and efficiency.This study aimed to evaluate the clinical application value of ICG fluorescence navigation in single-incision LC.Methods:A retrospective analysis was conducted on 59 patients with benign gallbladder diseases who underwent elective single-incision LC at Yixing Hospital affiliated to Jiangsu University from January 2023 to December 2024.Patients were divided into a fluorescence group(n=27)and a white-light group(n=32)according to whether ICG fluorescence navigation was applied.The two groups were compared in terms of Calot's triangle dissection time,operative time,intraoperative blood loss,surgeon satisfaction,hospital stay,and postoperative complications.Results:No significant differences were observed in baseline clinical characteristics between the two groups(all P＞0.05).In the fluorescence group,the cystic duct,common hepatic duct,and common bile duct were all successfully visualized.Compared with the white-light group,the fluorescence group had significantly shorter Calot's triangle dissection time[(25.56±3.49)min vs.(38.81±5.59)min],shorter operative time[(44.67±3.06)min vs.(61.31±4.96)min],and less intraoperative blood loss[(13.44±1.70)mL vs.(14.50±2.11)mL](all P＜0.05),with significantly higher surgeon satisfaction(P＜0.05).No intraoperative bile duct injury,conversion to three-port surgery,or postoperative complications occurred in either group.Conclusion:ICG fluorescence navigation can significantly improve biliary identification efficiency in single-incision LC,shorten operative time,reduce blood loss,and enhance surgeon satisfaction,demonstrating promising clinical application prospects.

Objective:To prepare decellularized extracellular matrix (dECM)-gelatin methacryloyl (GelMA) composite hydrogels and to study their effects on hepatocyte proliferation.Methods:Hepatic dECM was prepared by elution, and GelMA hydrogel and 10%, 30% and 50% dECM-GelMA composite hydrogels were prepared by pepsin solubilization. The morphology of normal liver and dECM liver was observed by eyes and scanning electron microscopy using hematoxylin-eosin, Sirius red and periodate-Schiff staining, respectively. The internal structure of the dECM-GelMA composite hydrogels was observed by scanning electron microscopy, and the pore diameter was measured. Liver HL-7702 cells were co-cultured with GelMA hydrogel and 10%, 30% and 50% dECM-GelMA composite hydrogels, and the cell proliferation viability was determined by cell counting kit-8. The expression of proliferating cell nuclear antigen (PCNA), Wnt family protein 5a (Wnt5a), β-catenin, extracellular-regulated protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2) were detected by Western blotting. Comparisons were made using independent sample t-test or one-factor analysis of variance. Results:After decellularization, the hepatocyte morphology showed rounded depressions, and the extracellular matrix structure was intact. The GelMA hydrogel and 10%, 30% and 50% dECM-GelMA composite hydrogels showed inernally porous structures. The pore diameter increased from (3.06±1.35) μm in the GelMA hydrogel to (16.01±4.02) μm in the 50% dECM-GelMA composite hydrogel. On the 3rd, 5th and 7th day, the relative cell proliferation was higher in the 50% dECM-GelMA composite hydrogel group than that in the GelMA hydrogel group (1.89±0.04 vs 1.53±0.01, 9.36±0.04 vs 3.89±0.09, 7.15±0.27 vs 4.89±0.15, all P<0.05). The relative expression levels of PCNA, Wnt5a, β-catenin, and p-ERK1/2/ERK1/2 proteins in the 50% dECM-GelMA composite hydrogel group were higher than those in the GelMA hydrogel group (2.14±0.04 vs 1.00±0.03, 2.36±0.09 vs 1.00±0.08, 1.45±0.03 vs 1.00±0.04, 1.43±0.04 vs 1.00±0.01, all P<0.05). Conclusions:A dECM-GelMA composite hydrogel can be prepared, which may promote hepatocyte proliferation by upregulating the phosphorylation of ERK1/2 and activating Wnt/β-catenin signaling pathway.