PURPOSE: To investigate the regulatory role of nerve injury-induced protein 1 (NINJ1) in the anti-inflammatory function of human umbilical cord mesenchymal stem cells (hUC-MSCs) co-stimulated by interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). METHODS: hUC-MSCs were expanded in vitro using standard protocols, with stem cell characteristics confirmed by flow cytometry and multilineage differentiation assays. The immunomodulatory properties and cellular activity of cytokine-co-pretreated hUC-MSCs were systematically evaluated via quantitative reverse transcription RT-qPCR, lymphocyte proliferation suppression assays, and Cell Counting Kit-8 viability tests. Transcriptome sequencing, Western blotting and small interfering RNA interference were integrated to analyze the regulatory mechanisms of NINJ1 expression. Functional roles of NINJ1 in pretreated hUC-MSCs were elucidated through gene silencing combined with lactate dehydrogenase release assays, Annexin V/Propidium Iodide apoptosis analysis, macrophage co-culture models, and cytokine Enzyme-Linked Immunosorbent Assay. Therapeutic efficacy was validated in a cecal ligation and puncture-induced septic mouse model: 80 mice were randomly allocated into 4 experimental groups (n=20/group): sham group (laparotomy without cecal ligation); phosphate-buffered saline-treated group (cecal ligation and puncture (CLP) + 0.1 mL phosphate-buffered saline); hUC-MSCs (small interfering RNA (siRNA)-interferon-gamma and tumor necrosis factor-alpha co-stimulation (IT))-treated group (CLP + hUC-MSCs transfected with scrambled siRNA); and hUC-MSCs (siNINJ1-IT)-treated group (CLP + hUC-MSCs with NINJ1-targeting siRNA). RESULTS: hUC-MSCs demonstrated compliance with International Society for Cellular Therapy criteria, confirming their stem cell identity. IFN-γ/TNF-α co-pretreatment enhanced the immunosuppressive capacity of hUC-MSCs, accompanied by the reduction of cellular viability, while concurrently upregulating pro-inflammatory cytokines such as interleukin-6 and interleukin-1β. This co-stimulation significantly elevated NINJ1 expression in hUC-MSCs, whereas genetic silencing of NINJ1 effectively suppressed pro-inflammatory cytokine production and attenuated damage-associated molecular patterns release through inhibition of programmed plasma membrane rupture. Furthermore, the NINJ1 interference potentiated the ability of cytokine-pretreated hUC-MSCs to suppress LPS-induced pro-inflammatory responses in RAW264.7 macrophages. In cecal ligation and puncture-induced sepsis model, NINJ1-silenced hUC-MSCs exhibited enhanced therapeutic efficacy, manifested by reduced systemic inflammation and multi-organ damage. CONCLUSION Our findings shed new light on the immunomodulatory functions of cytokine-primed MSCs, offering groundbreaking insights for developing MSC-based therapies against inflammatory diseases via interfering the expression of NINJ1.
Mesenchymal Stem Cells/drug effects* ; Animals ; Interferon-gamma/pharmacology* ; Tumor Necrosis Factor-alpha/pharmacology* ; Humans ; Mice ; Umbilical Cord/cytology* ; Cells, Cultured ; Apoptosis ; Male

Objective:To investigate the preventive and therapeutic effects of compound wild chrysanthemum eye pad on blue light-induced alteration of meibomian gland function in mice and its mechanism.Methods:Sixty-four 15-week-old male C57BL/6J mice were divided into two groups of 32 mice each according to random numbers for the prevention test and the treatment test.The respective 32 mice in the prevention and treatment experiments were randomly divided into normal group, blue light group, solvent group and eye pad group according to random numbers, with eight mice in each group, respectively.In the prevention experiments, mice in each group were exposed to blue light at a wavelength of 460 nm and a light intensity of 2 000 lx for 6 hours per day for 15 consecutive days to establish a mouse model of meibomian gland function changes except for the normal group.The solvent group and the eye pad group were treated with the corresponding eye pad before and after the blue light exposure for 25 minutes daily for the 15 consecutive days.The blue light group was treated with blue light exposure only for 15 days, and the mice were photographed at the edge of the meibomian gland on day 15 to observe the function of the meibomian gland except for the normal group.In the treatment test, all groups of mice except the normal group were induced the altered function of the mouse meibomian gland by the above method.The solvent and eye pad groups were treated with corresponding eye pads for 25 minutes in the morning and afternoon of each day for 15 consecutive days after blue light exposure.The blue light group was kept in a standard environment for 15 days and the changes in meibomian gland function of mice were detected by meibomian gland photographs on day 15.Photography of the eyelid margin in vitro, oil red O staining, and hematoxylin-eosin staining were performed to observe the histologic changes in the meibomian glands of mice after the preventive and experimental treatment.The relative expression of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) mRNA in mouse meibomian gland tissues was detected by real-time fluorescence quantitative PCR.The expression of nuclear factor-κB (NF-κB) and phosphorylation of NF-κB (p-NF-κB) proteins in mice meibomian gland tissues was detected by Western blot to assess the degree of amelioration of blue light-induced inflammation in mouse meibomian glands by the compound wild chrysanthemum eye pad.This study was conducted in accordance with the Statement of the Association for Research in Vision and Ophthalmology on the Use of Animals in Ophthalmology and Vision Research, and was approved by the Animal Ethics Committee of Xiamen University (No.XMULAC20220258). Results:Compared with the normal group, a gradually increased number of blocked meibomian gland openings, and a gradually decreased remaining area of lower meibomian gland, were observed in the mice after 15 days of blue light group, and all the differences were statistically different (all at P<0.05). In the prevention test, the number of obstructed opening in the eye pad group was 1.833±0.753, which was significantly less than 3.667±1.033 in the solvent group ( P<0.05). The relative remaining area of the lower lid meibomian gland in the eye pad group was 0.718±0.091, which was significantly greater than 0.624±0.130 in the solvent group ( P<0.05). Hematoxylin-eosin staining showed inflammatory cell infiltration in mouse meibomian gland in the blue light and solvent groups.There was no inflammatory cell infiltration in eye pad group, and the morphology of the acini was similar to that of the normal group.Oil red O staining showed that there was no significant lipid deposition in the groups.The relative expressions of IL-1β, IL-6, TNF-α, and IFN-γ mRNA were significantly lower, and the relative expressions of NF-κB and p-NF-κB proteins were significantly lower in the eye pad group than in the solvent group, showing statistically significant differences (all at P<0.05). In the treatment test, the number of obstructed openings in the eye pad group and solvent group was 4.333±1.211 and 4.833±1.722, respectively, and the relative remaining area of the lower meibomian gland was 0.572±0.151 and 0.588±0.154, respectively, showing no statistically significant differences (both at P>0.05). Hematoxylin-eosin staining showed inflammatory cell infiltration in mouse meibomian glands in the blue light and solvent groups, with a similar morphology of acini as in the normal group.There was no inflammatory cell infiltration in eye pad group.Oil red O staining showed that there was no significant lipid deposition in the groups.The relative expressions of IL-1β, IL-6, and IFN-γ mRNA were significantly lower and the relative expressions of NF-κB and p-NF-κB proteins were significantly lower in the eye pad group than in the solvent group (all at P<0.05). Conclusions:Compound wild chrysanthemum eye pad may have preventive and therapeutic effects on blue light-induced changes in meibomian gland function by reducing the inflammatory response of meibomian gland tissue through the inhibition of the NF-κB signaling pathway.

Purpose: The prevalence of psychological distress is frequently observed among old adults with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, current researches are insufficient to clarify the correlation among these relevant factors. This study examined the effects of symptom burden, psychological resilience, coping styles, and social support on psychological distress. Methods: Two hundred fifty five elderly patients with AECOPD were conveniently selected in Taian, Shandong Province. The General Information Questionnaire, Distress Thermometer, The Revised Memorial Symptom Assessment Scale, Connor-Davidson Resilience Scale, Simplified Coping Style Questionnaire, Perceived Social Support Scale were used to investigate. The relationship among factors was estimated by using a structural equation model. Results: Psychological distress score of elderly patients with AECOPD was (5.25 ± 1.01); coping styles, psychological resilience, symptom burden, and social support directly affected psychological distress (thedirect effects were À.93, .17, .17, and À.09); coping styles had the largest total effect on psychological distress (the total effect was À.93); psychological resilience indirectly affected psychological distress through coping styles (the indirect effect was À.74); symptom burden indirectly affected psychologicaldistress through psychological resilience (the indirect effect was .25); social support indirectly affected psychological distress through symptom burden, psychological resilience, and coping styles (the indirecteffect was À.80). Conclusion The psychological distress of elderly patients with AECOPD is at a moderate level; coping styles, psychological resilience, and social support have positive effects on alleviating the psychological distress of elderly patients with AECOPD; symptom burden is negatively correlated with psychological distress.Healthcare professionals should pay more attention to elderly patients with AECOPD who are particularly prone to experience higher levels of psychological distress, especially in the presence of low coping style, limited psychological resilience, inadequate levels of social support, and high symptom burden.

Objective To analyze adverse drug event(ADE)signals associated with exenatide based on data from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS),and to provide insights for rational medication use in clinical settings.Methods ADE reports of exenatide as the primary suspected drug were obtained by collecting the data of FAERS database from the first quarter 2014 to the second quarter 2024.ADE signals were analyzed by joint reporting odds ratio(ROR)method,proportional reporting odds ratio(PRR)method,Bayesian confidence interval progressive neural network(BCPNN)method and multi-item gamma Poisson shrinker(MGPS)method.Results After data cleaning,118 745 reports of exenatide-related ADEs were collected.These ADEs spanned 14 system-organ classes and involved 185 preferred terms.Commonly reported ADEs included reactions at the injection site,hypoglycemia,reduced appetite,and cholelithiasis.Severe ADEs were primarily cases of acute pancreatitis,in consistent with the drug's labeling.Moreover,the instructions did not record ADE signals of pancreatic cancer,thyroiditis,and reduced frustration tolerance.Conclusion Prescription of the exenatide should be vigilant about the signals not listed on the product labeling,such as pancreatic cancer,thyroid cancer,and decreased frustration tolerance,to improve the safety of medication use in patients.

Objective To mine adverse drug event(ADE)signals of pioglitazone,and to provide references for the safe clinical use of the medication.Methods The reporting odds ratio(ROR)method and the Bayesian confidence propagation neural network(BCPNN)method were utilized to analyze pioglitazone ADE reports from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,spanning from the first quarter of 2013 to the second quarter of 2024.Results After data cleaning,a total of 16 904 pioglitazone ADE reports were retrieved.The ADE reports primarily involved individuals over the age of 45,with a male predominance,and were mainly reported from the United States.After screening,180 ADE signals were identified,affecting 27 system-organ classes(SOC).Out of these,34 ADE signals were classified as medium to high risk,with 9 ADE signals not mentioned in the product labeling,including ureteral cancer,urethral cancer,gallbladder tumors,malignant tumors of the renal pelvis,pericardial tamponade,left ventricular dysfunction,pulmonary edema,cystitis,and somniloquy.Conclusion In addition to closely monitoring weight gain,systemic edema,and heart failure,clinical attention should be given to left ventricular dysfunction,pulmonary edema,cystitis,and pericardial tamponade ADEs that are not mentioned in the instructions,to ensure the safety of pioglitazone use in clinical practice.

Objective To investigate post-marketing adverse drug event(ADE)signals associated with lixisenatide,and to provide guidance for safe clinical use.Methods The ADE reporting data of lixisenatide ADE were mined and the signals were detected from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database from the first quarter 2013 to the second quarter 2024 using the reporting odds ratio(ROR)method and Bayesian confidence propagation neural network(BCPNN)method.Results After data cleaning,a total of 5 162 ADE reports with lixisenatide as the primary suspected drug were collected.The 85 ADE signals identified by the two statistical analysis methods,affected 14 system-organ classes(SOC).They were primarily concentrated in injuries,poisonings,and procedural complications(25.88％),various examinations(14.12％),systemic diseases and reactions at administration sites(14.12％),gastrointestinal diseases(9.41％),and various neurological diseases(5.88％).There were 28 ADE signals such as pancreatitis,visual impairment,and color blindness,that were not included in the drug instructions.Conclusion In addition to monitoring for common ADE associated with GLP-1 receptor agonists such as hypoglycemia,gastrointestinal,and neurological effects,clinicians should also be vigilant for underlying ADE like pancreatic-related diseases,eye toxicity reaction when using lixisenatide to ensure safe and rational medication use.

bjective To mine signals of post-marketing adverse drug events(ADEs)associated with dapagliflozin,and to provide insights for safe medication in clinical settings.Methods Data on ADEs related to dapagliflozin from U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)were collected from the first quarter of 2013 to the third quarter of 2024.The analyses involved data mining and signal monitoring using disproportionality analysis techniques including the reporting odds ratio(ROR)method,Medicines and Healthcare Products Regulatory Agency(MHRA)method,Bayesian confidence propagation neural network(BCPNN)method,and multi-item gamma Poisson shrinker(MGPS)method.Results After data cleaning,a total of 55 832 qualified dapagliflozin case reports were obtained,involving 25 090 patients,with a slightly higher percentage of males(44.99％)than females(41.18％).The predominant age group was 45 to 64 years(20.78％).A total of 379 ADE signals were detected across 22 system-organ classes(SOC).The ADEs of dapagliflozin were mainly concentrated in the SOC such as infections and infestations,general disorders and administration sites conditions,and metabolism and nutrition disorders,aligning with information provided in the drug instructions.Additionally,the ADE signals were not documented in drug inserts such as scrotal gangrene,periperineal cellulitis,scrotal abscess,hyperglycemia,ketonuria,and pancreatitis.Conclusion When clinically using dapagliflozin,it is essential to conduct a thorough medication assessment.In addition to closely monitoring diabetes ketoacidosis,fungal infection,and acute renal injury.The latent ADEs that are not mentioned in the instructions to should be noticed ensure safe medication.

Objective To mine the real-world risk signals associated with saxagliptin-related adverse drug event(ADE),and to provide insights for evidence-based use of the drug in clinical practice.Methods Data on ADE related to saxagliptin from U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)were collected from the first quarter of 2013 to the third quarter of 2024,and analyzed using the reporting odds ratio(ROR)and Bayesian confidence propagation neural network(BCPNN)techniques.Results After data cleaning,the study analyzed 2 036 qualified case reports from patients who were using saxagliptin,uncovering 4 497 adverse events and identifying 131 adverse event signals across 19 system-organ classes(SOCs),including cardiac organ system diseases(20.61％),various types of investigations(10.69％),and gastrointestinal tract diseases(13.74％).Among them,heart failure,pancreatitis,pancreatic cancer,and hypoglycaemic coma were high-intensity signals.Conclusion In clinical practice,the indications for saxagliptin should be strictly managed.It is advisable to avoid using saxagliptin as monotherapy in patients with a history of heart failure or in patients at elevated risk for arteriosclerotic cardiovascular disease.Continuous monitoring of essential organ functions,especially cardiac and pancreatic,is essential throughout the course of treatment to ensure the safety of the medication.

Objective To analyze adverse drug event(ADE)signals associated with exenatide based on data from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS),and to provide insights for rational medication use in clinical settings.Methods ADE reports of exenatide as the primary suspected drug were obtained by collecting the data of FAERS database from the first quarter 2014 to the second quarter 2024.ADE signals were analyzed by joint reporting odds ratio(ROR)method,proportional reporting odds ratio(PRR)method,Bayesian confidence interval progressive neural network(BCPNN)method and multi-item gamma Poisson shrinker(MGPS)method.Results After data cleaning,118 745 reports of exenatide-related ADEs were collected.These ADEs spanned 14 system-organ classes and involved 185 preferred terms.Commonly reported ADEs included reactions at the injection site,hypoglycemia,reduced appetite,and cholelithiasis.Severe ADEs were primarily cases of acute pancreatitis,in consistent with the drug's labeling.Moreover,the instructions did not record ADE signals of pancreatic cancer,thyroiditis,and reduced frustration tolerance.Conclusion Prescription of the exenatide should be vigilant about the signals not listed on the product labeling,such as pancreatic cancer,thyroid cancer,and decreased frustration tolerance,to improve the safety of medication use in patients.

Objective To mine adverse drug event(ADE)signals of pioglitazone,and to provide references for the safe clinical use of the medication.Methods The reporting odds ratio(ROR)method and the Bayesian confidence propagation neural network(BCPNN)method were utilized to analyze pioglitazone ADE reports from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,spanning from the first quarter of 2013 to the second quarter of 2024.Results After data cleaning,a total of 16 904 pioglitazone ADE reports were retrieved.The ADE reports primarily involved individuals over the age of 45,with a male predominance,and were mainly reported from the United States.After screening,180 ADE signals were identified,affecting 27 system-organ classes(SOC).Out of these,34 ADE signals were classified as medium to high risk,with 9 ADE signals not mentioned in the product labeling,including ureteral cancer,urethral cancer,gallbladder tumors,malignant tumors of the renal pelvis,pericardial tamponade,left ventricular dysfunction,pulmonary edema,cystitis,and somniloquy.Conclusion In addition to closely monitoring weight gain,systemic edema,and heart failure,clinical attention should be given to left ventricular dysfunction,pulmonary edema,cystitis,and pericardial tamponade ADEs that are not mentioned in the instructions,to ensure the safety of pioglitazone use in clinical practice.