Periodontitis is a chronic inflammatory disease triggered by periodontal pathogens and mediated by immune responses. Traditionally, gingival fibroblasts (GFs) were considered to be primarily responsible for maintaining periodontal matrix homeostasis. However, recent studies reveal that GFs play a significant immunoregulatory role in periodontitis. Through signaling pathways, such as the Toll-like receptor 4 (TLR4) pathway, GFs recognize virulence factors from pathogens, such as Porphyromonas gingivalis, and secrete various inflammatory mediators, thus driving extracellular matrix degradation and osteoclast differentiation. Simultaneously, GFs modulate immune cells, including neutrophils and macrophages, amplifying inflammatory responses and fostering a chronic inflammatory microenvironment. Risk factors, such as hyperglycemia and smoking, exacerbate GFs dysfunction via oxidative stress-mediated activation of the nuclear factor kappa B (NF-κB) pathway and other mechanisms, while inflammation and cellular senescence form a vicious cycle. Senescent GFs further aggravate alveolar bone destruction by activating the mechanistic target of the rapamycin (mTOR) pathway. Therapeutic strategies targeting GFs, such as suppressing NF-κB signaling or modulating mTOR-mediated senescence, may disrupt the link between inflammation and tissue destruction, showing promising therapeutic potential. Future studies should employ advanced technologies such as spatial multi-omics and single-cell proteomics to elucidate the spatial distribution, functional interactomes, and heterogeneity of GFs subsets, in order to deepen our understanding of their roles in periodontitis progression. This review summarizes the multifaceted mechanisms of GFs in periodontitis and explores potential therapeutic strategies targeting GFs, offering novel insights for periodontitis prevention and treatment.

Introduction: Cafeteria environments within universities have a significant influence over sustainable and healthy dietary behaviours. Hence, this study aimed to understand the nutritional landscape of food options in university cafeterias and to identify the factors contributing to unhealthy food options from the perspective of food service vendors. Methods: Using a mixed-methods approach, 122 food options from all 12 residential campus cafeterias in Universiti Malaya (UM) were collected between October and December 2024. All food options were grouped into (i) bread, (ii) meat dishes, (iii) drinks, (iv) Western dishes, and (v) rice- or noodle-based fried food group; they were further analysed for calories, fat, saturated fat, dietary fibre, and salt using the Malaysian Food Composition Database (MyFCD) and the Singapore Food Composition Database (SFCD). Nutrient classification (high vs. low) was based on the criteria outlined in the Labelling Guidelines 2023. Additionally, food service vendors were interviewed to explore operational challenges, with data collection ceasing upon reaching thematic saturation. The interviews were then transcribed and analysed using thematic analysis. Results: Quantitative findings showed that there were 36 bread-based meals, 16 meat-based dishes, 18 beverages, 30 Westernstyle meals, and 22 rice- or noodle-based fried foods. The study also revealed an over-reliance on high-calorie, high-fat, and low-fibre foods, with limited availability of sustainable and nutritious options. Qualitative findings highlighted the influence of affordability, vendor practices, and student preferences on campus food choices. Conclusion: The study underscored the need for internal policy intervention, improved vendor education and sustainability practices, and increased accessibility to healthier meals on campus.

INTRODUCTION: Preterm birth (PTB) remains a leading cause of perinatal morbidity and mortality worldwide. Understanding Singapore's PTB trends and associated risk factors can inform effective strategies for screening and intervention. This study analyses PTB trends in Singapore from 2017 to 2023, identifies risk factors in this multi-ethnic population and evaluates a predictive model for PTB. METHOD: A retrospective analysis of all PTBs between 22+0 and 36+6 weeks of gestation, from 1 January 2017 to 31 December 2023, was performed by extracting maternal and neonatal data from electronic medical records. These PTBs were taken from the registry of births for Singapore and SingHealth cluster data. Cochran- Armitage trend test and multinomial logistic regression were used. An extreme gradient boosting (XGBoost) model was developed to test and predict the risk of PTB. RESULTS: The PTB rate in Singapore did not show a significant change. However, there was modest downward trend in the SingHealth population from 11.3% to 10.2%, mainly in late spontaneous PTBs (sPTBs). sPTBs accounted for ∼60% of PTBs. Risk factors for very/extreme sPTB included Chinese ethnicity, age ≥35 years, body mass index (BMI) ≥23 kg/m², being unmarried, primiparity, twin pregnancy and maternal blood group AB. The XGBoost model achieved an area under the receiver operating characteristic curve of 0.75, indicating moderate ability to predict PTB. CONCLUSION The overall PTB rate in Singapore has not improved. This study underscores the importance of local factors, particularly advanced maternal age, BMI, primiparity, unmarried, Chinese ethnicity and maternal blood group AB influencing PTB risk. Artificial intelligence methods show promise in improving PTB risk stratification, ultimately supporting personalised care and intervention.
Humans ; Singapore/epidemiology* ; Retrospective Studies ; Female ; Risk Factors ; Premature Birth/ethnology* ; Pregnancy ; Adult ; Infant, Newborn ; Asian People/statistics & numerical data* ; Gestational Age ; Body Mass Index ; Maternal Age ; Logistic Models ; Ethnicity

BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

Ulcerative colitis(UC) is a recurrent, chronic, nonspecific inflammatory bowel disease. The longer the course of the disease, the higher the risk of cancerization. In recent years, the incidence and mortality rates of colon cancer in China have been increasing year by year, seriously threatening the life and health of patients. Therefore, studying the mechanism of "inflammation cancer transformation" in UC and conducting early intervention is crucial. The "Kenang" theory is an important component of traditional Chinese medicine(TCM) theory of phlegm and blood stasis. It is based on the coexistence of phlegm and blood stasis in the body and deeply explores the pathogenic syndromes and characteristics of phlegm and blood stasis. Kenang is a pathological product formed when long-term Qi stagnation leads to the internal formation of phlegm and blood stasis, which is hidden deep within the body. It is characterized by being hidden, progressive, and difficult to treat. The etiology and pathogenesis of "inflammation cancer transformation" in UC are consistent with the connotation of the "Kenang" theory. The internal condition for the development of UC "inflammation cancer transformation" is the deficiency of healthy Qi, with Qi stagnation being the key pathological mechanism. Phlegm and blood stasis are the main pathogenic factors. Phlegm and blood stasis accumulate in the body over time and can produce cancer toxins. Due to the depletion of healthy Qi and a weakened constitution, the body is unable to limit the proliferation and invasion of cancer toxins, eventually leading to cancer transformation in UC. In clinical treatment, the focus should be on removing phlegm and blood stasis, with syndrome differentiation and treatment based on three basic principles: supporting healthy Qi to strengthen the body's foundation, resolving phlegm and blood stasis to break up the Kenang, and regulating Qi and blood to smooth the flow of energy and resolve stagnation. This approach helps to dismantle the Kenang, delay, block, or even reverse the cancerization process of UC, reduce the risk of "inflammation cancer transformation", improve the patient's quality of life, and provide new perspectives and strategies for early intervention in the development of colon cancer.
Humans ; Colitis, Ulcerative/immunology* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Cell Transformation, Neoplastic

Emodin is a hydroxyanthraquinone compound that is widely distributed and has multiple pharmacological activities, including anti-diarrheal, anti-inflammatory, and liver-protective effects. Research indicates that emodin may be one of the main components responsible for inducing hepatotoxicity. However, studies on the mechanisms of liver injury are relatively limited, particularly those related to bile acids(BAs) metabolism. This study aims to systematically investigate the effects of different dosages of emodin on BAs metabolism, providing a basis for the safe clinical use of traditional Chinese medicine(TCM)containing emodin. First, this study evaluated the safety of repeated administration of different dosages of emodin over a 5-week period, with a particular focus on its impact on the liver. Next, the composition and content of BAs in serum and liver were analyzed. Subsequently, qRT-PCR was used to detect the mRNA expression of nuclear receptors and transporters related to BAs metabolism. The results showed that 1 g·kg~(-1) emodin induced hepatic damage, with bile duct hyperplasia as the primary pathological manifestation. It significantly increased the levels of various BAs in the serum and primary BAs(including taurine-conjugated and free BAs) in the liver. Additionally, it downregulated the mRNA expression of farnesoid X receptor(FXR), retinoid X receptor(RXR), and sodium taurocholate cotransporting polypeptide(NTCP), and upregulated the mRNA expression of cholesterol 7α-hydroxylase(CYP7A1) in the liver. Although 0.01 g·kg~(-1) and 0.03 g·kg~(-1) emodin did not induce obvious liver injury, they significantly increased the level of taurine-conjugated BAs in the liver, suggesting a potential interference with BAs homeostasis. In conclusion, 1 g·kg~(-1) emodin may promote the production of primary BAs in the liver by affecting the FXR-RXR-CYP7A1 pathway, inhibit NTCP expression, and reduce BA reabsorption in the liver, resulting in BA accumulation in the peripheral blood. This disruption of BA homeostasis leads to liver injury. Even doses of emodin close to the clinical dose can also have a certain effect on the homeostasis of BAs. Therefore, when using traditional Chinese medicine or formulas containing emodin in clinical practice, it is necessary to regularly monitor liver function indicators and closely monitor the risk of drug-induced liver injury.
Emodin/administration & dosage* ; Bile Acids and Salts/metabolism* ; Animals ; Male ; Liver/injuries* ; Chemical and Drug Induced Liver Injury/genetics* ; Drugs, Chinese Herbal/adverse effects* ; Humans ; Rats, Sprague-Dawley ; Mice ; Rats

In this study, lipopolysaccharide(LPS), ovalbumin(OVA), and compound 48/80(C48/80) were administered to establish non-infectious pneumonia models under simulated clinical conditions, and the correlation between their pathological characteristics and traditional Chinese medicine(TCM) syndromes was compared, providing the basis for the selection of appropriate animal models for TCM efficacy evaluation. An acute pneumonia model was established by nasal instillation of LPS combined with intraperitoneal injection for intensive stimulation. Three doses of OVA mixed with aluminum hydroxide adjuvant were injected intraperitoneally on days one, three, and five and OVA was administered via endotracheal drip for excitation on days 14-18 to establish an OVA-induced allergic pneumonia model. A single intravenous injection of three doses of C48/80 was adopted to establish a C48/80-induced pneumonia model. By detecting the changes in peripheral blood leukocyte classification, lung tissue and plasma cytokines, immunoglobulins(Ig), histamine levels, and arachidonic acid metabolites, the multi-dimensional analysis was carried out based on pathological evaluation. The results showed that the three models could cause pulmonary edema, increased wet weight in the lung, and obvious exudative inflammation in lung tissue pathology, especially for LPS. A number of pyrogenic cytokines, inclading interleukin(IL)-6, interferon(IFN)-γ, IL-1β, and IL-4 were significantly elevated in the LPS pneumonia model. Significantly increased levels of prostacyclin analogs such as prostaglandin E2(PGE2) and PGD2, which cause increased vascular permeability, and neutrophils in peripheral blood were significantly elevated. The model could partly reflect the clinical characteristics of phlegm heat accumulating in the lung or dampness toxin obstructing the lung. The OVA model showed that the sensitization mediators IgE and leukotriene E4(LTE4) were increased, and the anti-inflammatory prostacyclin 6-keto-PGF2α was decreased. Immune cells(lymphocytes and monocytes) were decreased, and inflammatory cells(neutrophils and basophils) were increased, reflecting the characteristics of "deficiency", "phlegm", or "dampness". Lymphocytes, monocytes, and basophils were significantly increased in the C48/80 model. The phenotype of the model was that the content of histamine, a large number of prostacyclins(6-keto-PGE1, PGF2α, 15-keto-PGF2α, 6-keto-PGF1α, 13,14-D-15-keto-PGE2, PGD2, PGE2, and PGH2), LTE4, and 5-hydroxyeicosatetraenoic acid(5S-HETE) was significantly increased, and these indicators were associated with vascular expansion and increased vascular permeability. The pyrogenic inflammatory cytokines were not increased. The C48/80 model reflected the characteristics of cold and damp accumulation. In the study, three non-infectious pneumonia models were constructed. The LPS model exhibited neutrophil infiltration and elevated inflammatory factors, which was suitable for the efficacy study of TCM for clearing heat, detoxifying, removing dampness, and eliminating phlegm. The OVA model, which took allergic inflammation as an index, was suitable for the efficacy study of Yiqi Gubiao formulas. The C48/80 model exhibited increased vasoactive substances(histamine, PGs, and LTE4), which was suitable for the efficacy study and evaluation of TCM for warming the lung, dispersing cold, drying dampness, and resolving phlegm. The study provides a theoretical basis for model selection for the efficacy evaluation of TCM in the treatment of pneumonia.
Animals ; Disease Models, Animal ; Mice ; Pneumonia/genetics* ; Medicine, Chinese Traditional ; Male ; Humans ; Cytokines/immunology* ; Female ; Lipopolysaccharides/adverse effects* ; Lung/drug effects* ; Drugs, Chinese Herbal ; Ovalbumin ; Mice, Inbred BALB C

OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

Objective:This article aims to investigate the effect of optimized prehospital emergency intervention com-bined with green channel on prehospital delay and prognosis of patients with acute cor pulmonale(ACP).Methods:This randomized controlled study enrolled 116 ACP patients admitted in Hai'an People's Hospital between January 2021 and January 2023.They were divided into control group(n=58,routine emergency nursing procedure)and in-tervention group(n=58,optimized prehospital emergency intervention combined with green channel program).After 1-month intervention,therapeutic effect,emergency indicators,cardiopulmonary function,quality of life and incidence of complications were compared between two groups.Results:After 1-month,total effective rate of intervention group was significantly higher than that of control group(84.48％vs.62.07％,P=0.006).Com-pared with patients in control group,those in intervention group had significant lower emergency stay time[(19.80±1.90)min vs.(27.92±1.62)min],triage assessment time[(2.01±0.18)min vs.(2.99±0.17)min]and transport time[(33.69±1.90)min vs.(35.91±1.74)min],and significant higher left ventricular ejection frac-tion(LVEF)[(59.85±1.36)％vs.(46.97±1.79)％],forced expiratory volume in one second(FEV1)[(3.66±0.17)L vs.(3.00±0.17)L],scores of nursing quality and each domain of Quality of Life Instruments for Chro-nic Diseases-Chronic Pulmonary Heart Disease(QLICD-CPHD)(P＜0.001 all).Incidence of complications in intervention group was significantly lower than that of control group(5.17％vs.17.24％,P=0.039).Conclusion:Optimized prehospital emergency intervention combined with green channel has significant clinical effect on ACP patients.It could reduce emergency,triage and transport time,improve nursing quality and quality of life,enhance cardiopulmonary function,and reduce the incidence of complications.