An integrated machine learning model enhances delayed graft function prediction in pediatric renal transplantation from deceased donors.

BACKGROUND: Kidney transplantation is the optimal renal replacement therapy for children with end-stage renal disease; however, delayed graft function (DGF), a common post-operative complication, may negatively impact the long-term outcomes of both the graft and the pediatric recipient. However, there is limited research on DGF in pediatric kidney transplant recipients. This study aims to develop a predictive model for the risk of DGF occurrence after pediatric kidney transplantation by integrating donor and recipient characteristics and utilizing machine learning algorithms, ultimately providing guidance for clinical decision-making. METHODS: This single-center retrospective cohort study includes all recipients under 18 years of age who underwent single-donor kidney transplantation at our hospital between 2016 and 2023, along with their corresponding donors. Demographic, clinical, and laboratory examination data were collected from both donors and recipients. Univariate logistic regression models and differential analysis were employed to identify features associated with DGF. Subsequently, a risk score for predicting DGF occurrence (DGF-RS) was constructed based on machine learning combinations. Model performance was evaluated using the receiver operating characteristic curves, decision curve analysis (DCA), and other methods. RESULTS: The study included a total of 140 pediatric kidney transplant recipients, among whom 37 (26.4%) developed DGF. Univariate analysis revealed that high-density lipoprotein cholesterol (HDLC), donor after circulatory death (DCD), warm ischemia time (WIT), cold ischemia time (CIT), gender match, and donor creatinine were significantly associated with DGF (P < 0.05). Based on these six features, the random forest model (mtry = 5, 75%p) exhibited the best predictive performance among 97 machine learning models, with the area under the curve values reaching 0.983, 1, and 0.905 for the entire cohort, training set, and validation set, respectively. This model significantly outperformed single indicators. The DCA curve confirmed the clinical utility of this model. CONCLUSIONS: In this study, we developed a machine learning-based predictive model for DGF following pediatric kidney transplantation, termed DGF-RS, which integrates both donor and recipient characteristics. The model demonstrated excellent predictive accuracy and provides essential guidance for clinical decision-making. These findings contribute to our understanding of the pathogenesis of DGF.

Correlations among parameters of pentacam, iTrace, and LOCS III in assessing lens opacity.

OBJECTIVES: To investigate the diagnostic value of iTrace visual function analyzer, Pentacam 3D anterior segment analysis system and Lens Opacities Classification System III (LOCS III) in assessing lens opacity in patients with age-related cataract (ARC). METHODS: A total of 129 patients with ARC admitted to Anonymized from May 2019 to April 2021 were selected as the research objects. The degree of lens opacity was evaluated by LOCS III classification, iTrace and anterior segment analysis. RESULTS: The Pentacam nucleus staging (PNS) grade was strongly correlated with nuclear color (NC) (r = 0.537, p < 0.05) and moderately correlated with nuclear opalescence (NO) (r = 0.473, p < 0.05). The integrated density (IntDen) in 3-mm nuclear region was strongly correlated with NC (r = 0.548, p < 0.05) and NO (r = 0.539, p < 0.05). The dysfunctional lens index (DLI) in 3-mm area was negatively correlated with NC (r=-0.252, p < 0.05), NO (r=-0.239, p < 0.05) and posterior subcapsular cataract (r=-0.271, p < 0.05). PNS was weakly negatively correlated with the DLI in 3-mm area (r=-0.219, p < 0.05), and IntDen in 3-mm core area was weakly negatively correlated with the DLI in 3-mm area (r=-0.291, p < 0.05). CONCLUSION: A combination of iTrace, anterior segment analysis and LOCS III may be beneficial in objectively assessing the opacity of different regions of the lens.

[Maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation in relation to offspring ventricular septal defects]. / 母亲MTRåŸºå› å¤šæ€æ€§åŠå ¶ä¸Žå›´å­•æœŸå¶é ¸è¡¥å çš„äº¤äº’ä½œç”¨ä¸Žå­ä»£å®¤é—´éš”ç¼ºæŸçš„å ³è”ç ”ç©¶.

OBJECTIVES: To investigate how maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation are associated with the incidence of ventricular septal defects (VSD) in offspring. METHODS: A case-control study was conducted, recruiting 426 mothers of infants with VSD under one year old and 740 mothers of age-matched healthy infants. A questionnaire survey collected data on maternal exposures, and blood samples were analyzed for genetic polymorphisms. Multivariable logistic regression analysis and inverse probability of treatment weighting were used to analyze the associations between genetic loci and VSD. Crossover analysis and logistic regression were utilized to examine the additive and multiplicative interactions between the loci and folic acid intake. RESULTS: The CT and TT genotypes of the maternal MTR gene at rs6668344 increased the susceptibility of offspring to VSD (P<0.05). The GC and CC genotypes at rs3768139, AG and GG at rs1050993, AT and TT at rs4659743, GG at rs3768142, and GT and TT at rs3820571 were associated with a decreased risk of VSD (P<0.05). The variations at rs6668344 demonstrated an antagonistic multiplicative interaction with folic acid supplementation in relation to VSD (P<0.05). CONCLUSIONS: Maternal MTR gene polymorphisms significantly correlate with the incidence of VSD in offspring. Mothers with variations at rs6668344 can decrease the susceptibility to VSD in their offspring by supplementing with folic acid during the periconceptional period, suggesting the importance of periconceptional folic acid supplementation in genetically at-risk populations to prevent VSD in offspring.

Expression, potential biological behaviour and clinical significance of MCM3 in pancreatic adenocarcinoma: a comprehensive study integrating high throughput sequencing, CRISPR screening and in-house immunohistochemistry.

BACKGROUND: Minichromosome maintenance complex component 3 (MCM3) plays a key role in various tumours. However, it remains largely unknown what the specific role and clinical significance of MCM3 in pancreatic adenocarcinoma (PAAD) are. MATERIALS AND METHODS: We integrated high-throughput data from PAAD worldwide to analyse the expression level of MCM3 mRNA. We used immunohistochemistry to analyse MCM3 protein expression levels in 145 cases in the PAAD group and 29 cases in the non-PAAD group. We also mainly analysed the necessity of MCM3 for PAAD growth based on CRISPR screen data. In addition, we used enrichment analysis and protein-protein interaction networks to explore the molecular mechanism of MCM3 in PAAD. We also analysed the correlation between MCM3 expression, components of the immune microenvironment in PAAD tissue and clinical prognosis. RESULTS: In PAAD, we observed for the first time that MCM3 was significantly highly expressed at both the mRNA (SMD = 0.67, 95% CI: 0.38 ∼ 0.96) and the protein level (p < 0.05). The mRNA (AUC = 0.78, 95% CI: 0.74 ∼ 0.81; sensitivity = 0.66, 95% CI: 0.55 ∼ 0.76; specificity = 0.76, 95% CI: 0.67 ∼ 0.84) and protein (AUC = 0.929) expression levels of MCM3 had a good ability to distinguish between PAAD and non-PAAD tissue. There was heterogeneity reflected by the differential expression of MCM3 protein in PAAD cells. MCM3 played an essential role in PAAD growth, through abnormal DNA replication, p53 signalling and cell cycle checkpoints. PAAD with high MCM3 expression was sensitive to c-75, brivanib, flavopiridol and VNLG/124 drugs, with stable molecular docking models. CONCLUSION: MCM3 is likely to be a critical element in promoting the initiation and growth of PAAD. Flavopiridol may exert its anti-PAAD effect through the interaction between MCM3, classic CDK1 targets in the cell cycle checkpoint and p53 pathway as well as related molecules in other pathways.

MCM3 could potentially play a crucial role in promoting the onset and growth of PAAD.There is heterogeneity reflected by the differential expression of MCM3 protein in PAAD cells.The interplay between MCM3, well-established CDK1 targets in the cell cycle checkpoint and p53 pathway, along with relevant molecules in other pathways, may mediate the anti-pancreatic adenocarcinoma (PAAD) effect of flavopiridol.

The mechanosensitive ion channel Piezo1 contributes to podocyte cytoskeleton remodeling and development of proteinuria in lupus nephritis.

Piezo1 functions as a special transducer of mechanostress into electrochemical signals and is implicated in the pathogenesis of various diseases across different disciplines. However, whether Piezo1 contributes to the pathogenesis of lupus nephritis (LN) remains elusive. To study this, we applied an agonist and antagonist of Piezo1 to treat lupus-prone MRL/lpr mice. Additionally, a podocyte-specific Piezo1 knockout mouse model was also generated to substantiate the role of Piezo1 in podocyte injury induced by pristane, a murine model of LN. A marked upregulation of Piezo1 was found in podocytes in both human and murine LN. The Piezo1 antagonist, GsMTx4, significantly alleviated glomerulonephritis and tubulointerstitial damage, improved kidney function, decreased proteinuria, and mitigated podocyte foot process effacement in MRL/lpr mice. Moreover, podocyte-specific Piezo1 deletion showed protective effects on the progression of proteinuria and podocyte foot process effacement in the murine LN model. Mechanistically, Piezo1 expression was upregulated by inflammatory cytokines (IL-6, TNF-α and IFN-γ), soluble urokinase Plasminogen Activator Receptor and its own activation. Activation of Piezo1 elicited calcium influx, which subsequently enhanced Rac1 activity and increased active paxillin, thereby promoting cytoskeleton remodeling and decreasing podocyte motility. Thus, our work demonstrated that Piezo1 contributed to podocyte injury and proteinuria progression in LN. Hence, targeted therapy aimed at decreasing or inhibiting Piezo1 could represent a novel strategy to treat LN.

Exploring anesthesiology nurse' presenteeism in China: cross-sectional study.

BACKGROUND: The department of anesthesiology is the main battlefield for the treatment of acute and critical patients, with high work risk and high work pressure. Due to the particularity of the working environment and nature of work, medical staff have become a group with a high incidence of occupational exhaustion and presenteeism. OBJECTIVE: To investigate the current status of presenteeism among anesthesiology nurses in China and to analyze the related influencing factors. METHODS: Three hundred twelve anesthesiology nurses in Sichuan Province were surveyed by means of general data questionnaire, presenteeism scale, work-family conflict scale, perceived social support scale, occupational commitment scale and stress resistance scale from September to November 2023 by convenience sampling method. RESULTS: The total score of presenteeism was (14.67 ± 3.92), the score of work-family conflict was (45.44 ± 15.90), the score of professional commitment was (87.28 ± 14.30), and the score of perceived social support was (66.04 ± 12.78). The evaluation score of stress resistance was (73.35 ± 11.54). The results of multivariate analysis showed that age, education, mode of employment, position, overtime hours per week, work-family conflict, perceived social support and stress resistance were the factors that affected the presenteeism of anesthesiology nurses, which could explain 44.1% of the total variation. The position ( ß = 0.296, P < 0.001), overtime hours per week (h) ( ß = 0.271, P < 0.001), perceived social support ( ß = -0.279, P < 0.001) turned out as the stronger predictors of presenteeism. CONCLUSION: The presenteeism of anesthesiology nurses is at a high level and needs to be further improved. Clinical nursing managers should pay attention to the physical and mental health and special needs of anesthesiology nurses. Interventions are made according to the main influencing factors, so as to reduce the incidence of presenteeism and improve the quality and safety of surgery.

Dysbiosis and interactions of the mycobiome and bacteriome in mucosal lesions of erosive and non-erosive oral lichen planus patients.

Background: Oral lichen planus (OLP) is a common oral mucosal disease, clinically categorized into erosive OLP (EOLP) and non-erosive OLP (NEOLP) based on symptoms, but its pathogenic mechanism remains unclear. This study aims to explore the relationship between OLP and the oral microbiome. Methods: We collected oral mucosal samples from 49 patients and 10 healthy individuals and conducted 16S rRNA and ITS gene sequencing to explore the oral fungal and bacterial communities. Results: We observed significantly lower α diversity of fungi in the EOLP group, with Candida being significantly enriched as the main dominant genus. In the NEOLP group, Aspergillaceae were significantly enriched. The EOLP group showed significant enrichment of Aggregatibacter and Lactobacillus, but the relative abundance of Streptococcus was notably lower than in the other two groups. In the NEOLP group, two species including Prevotella intermedia were significantly enriched. The microbial co-occurrence and co-exclusion networks display distinct characteristics across the three groups, with Lactobacillus assuming a significant bridging role in the ELOP group. Conclusions: Our study indicates that EOLP and NEOLP experience varying degrees of dysbiosis at both the fungal and bacterial levels. Therefore, the pathogenic mechanisms and interactive relationships of these microbiota associated with OLP merit further in-depth investigation.

The microbial community in the oral lesions of EOLP patients exhibits highly distinctive features, both in terms of bacteria and fungi.In NEOLP patients, the overall bacterial composition does not exhibit significant differences compared to the healthy population, but P. intermedia and Aspergillaceae are notably enriched.

Cryptosporidium spp. Infection and Genotype Identification in Pre-Weaned and Post-Weaned Calves in Yunnan Province, China.

BACKGROUND: Cryptosporidium is a globally distributed zoonotic protozoan parasite in humans and animals. Infection is widespread in dairy cattle, especially in calves, resulting in neonatal enteritis, production losses and high mortality. However, the occurrence of Cryptosporidium spp. in pre- and post-weaned calves in Yunnan Province remains unclear. METHODS: We collected 498 fecal samples from Holstein calves on 10 different farms in four regions of Yunnan Province. Nested PCR and DNA sequencing were used to determine the infection, species and genotypes of Cryptosporidium spp. in these animals. RESULTS: The overall occurrence of Cryptosporidium spp. in Holstein calves was 32.9% (164/498), and the prevalence in pre- and post-weaned calves was 33.5% (106/316) and 31.9% (58/182), respectively. Four Cryptosporidium species were identified in these animals, namely C. bovis (n = 119), C. parvum (n = 23), C. ryanae (n = 20) and C. andersoni (n = 2). Based on sequencing analysis of the 60 kDa glycoprotein gene of C. bovis, C. parvum and C. ryanae, six subtypes of C. bovis (XXVIe, XXVIb, XXVIf, XXVIa XXVIc and XXVId), two subtypes of C. parvum (IIdA19G1 and IIdA18G1) and four subtypes of C. ryanae (XXIf, XXId, XXIe and XXIg) were identified. CONCLUSIONS: These results provide essential information to understand the infection rate, species diversity and genetic structure of Cryptosporidium spp. populations in Holstein pre-weaned and post-weaned calves in Yunnan Province. Further, the presence of IIdA18G1 and IIdA19G1 in C. parvum implies significant animal and public health concerns, which requires greater attention and more preventive measures.

Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Cepharanthine triggers ferroptosis through inhibition of NRF2 for robust ER stress against lung cancer.

BACKGROUND: Severe endoplasmic reticulum (ER) stress elicits apoptosis to suppress lung cancer. Our previous research identified that Cepharanthine (CEP), a kind of phytomedicine, possessed powerful anti-cancer efficacy, for which the underlying mechanism was still uncovered. Herein, we investigated how CEP induced ER stress and worked against lung cancer. METHODS: The differential expression genes (DEGs) and enrichment were detected by RNA-sequence. The affinity of CEP and NRF2 was analyzed by cellular thermal shift assay (CETSA) and molecular docking. The function assay of lung cancer cells was measured by western blots, flow cytometry, immunofluorescence staining, and ferroptosis inhibitors. RESULTS: CEP treatment enriched DEGs in ferroptosis and ER stress. Further analysis demonstrated the target was NRF2. In vitro and in vivo experiments showed that CEP induced obvious ferroptosis, as characterized by the elevated iron ions, ROS, COX-2 expression, down-regulation of GPX4, and atrophic mitochondria. Moreover, enhanced Grp78, CHOP expression, ß-amyloid mass, and disappearing parallel stacked structures of ER were observed in CEP group, suggesting ER stress was aroused. CEP exhibited excellent anti-lung cancer efficacy, as evidenced by the increased apoptosis, reduced proliferation, diminished cell stemness, and prominent inhibition of tumor grafts in animal models. Furthermore, the addition of ferroptosis inhibitors weakened CEP-induced ER stress and apoptosis. CONCLUSION: In summary, our findings proved CEP drives ferroptosis through inhibition of NRF2 for induction of robust ER stress, thereby leading to apoptosis and attenuated stemness of lung cancer cells. The current work presents a novel mechanism for the anti-tumor efficacy of the natural compound CEP.

Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer.

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Potential profiling of self-management skills in older co-morbid patients.

BACKGROUND: Under the general trend of global aging, geriatric comorbidity is increasingly common, which may have some impact on the quality of life of the older people. Self-management can effectively improve patient compliance, subjective initiative, and improve patient quality of life. However, the present situation of self-management in different old people is different. Therefore, this study classifies older co-morbid patients through potential profiling analysis, understands the category characteristics of self-management level of older co-morbid patients, and discusses the influencing factors of self-management level of different categories of older co-morbid patients, which can provide reference for personalized intervention programs for different comorbidity characteristics of elderly people in the future.  METHOD: Through a cross-sectional study, 616 cases of older co-morbid patients in three districts of Zhengzhou City, Henan Province, were selected as survey subjects by using the whole cluster sampling method. The General Information Questionnaire, Chronic Disease Self-Management Scale, Health Literacy Scale, Electronic Health Literacy Scale, Collaborative Social Support Scale, and Health Empowerment Scale were used to conduct the survey. RESULTS: The result of LPA shows that the self-management characteristics of older co-morbid patients should be classified into 3 categories: good self-management (19.4%), medium self-management(27.9%), and low self-management (52.7%). The results of multivariate logistic regression analyses show that literacy, religiosity, health literacy, e-health literacy, appreciative social support, and health empowerment are influential factors for self-management among older co-morbid patients (p < 0.05). CONCLUSION: There is obvious heterogeneity in the self-management level of older co-morbid patients. It is recommended that healthcare professionals give targeted interventions for their weaknesses according to the self-management characteristics of different categories of patients in order to enhance the self-management level of this population and improve their quality of life.

Diagnostic value of galectin-3, fractalkine, IL-6, miR-21 and cardiac troponin I in human ischemic cardiomyopathy.

OBJECTIVE: The primary objective of this study was to assess the diagnostic potential of galectin-3 (Gal-3), fractalkine (FKN), interleukin (IL)-6, microRNA(miR)-21, and cardiac troponin I (cTnI) in patients with ischemic cardiomyopathy (ICM). METHOD: A total of 78 ICM patients (Case group) and 80 healthy volunteers (Control group) admitted to our hospital for treatment or physical examination from Aug. 2018 to Feb. 2020 were included in the current study. The serum concentration of Gal-3, FKN, IL-6, miR-21, and plasma expression of cTnI of both groups were determined. The severity of ICM was classified using New York Heart Association (NYHA) scale. RESULTS: When compared with the control group, the case group had a significantly high blood concentration of Gal-3, FKN, IL-6, miR-21, and cTnI (P < 0.001). NYHA class II patients had lower blood levels of Gal-3, FKN, IL-6, miR-21, and cTnI than that in patients of NYHA class III and IV without statistical significance (P > 0.05). However, statistical significance could be achieved when comparing the above-analyzed markers in patients classified between class III and IV. Correlation analysis also revealed that serum levels of Gal-3, FKN, IL-6, miR-21, and cTnI were positively correlated with NYHA classification (R = 0.564, 0.621, 0.792, 0.981, P < 0.05). CONCLUSION: Our study revealed that up-regulated serum Gal-3, FKN, IL-6, miR-21, and cTnI levels were closely related to the progression of ICM. This association implies that these biomarkers have diagnostic potential, offering a promising avenue for early detection and monitoring of ICM progression.

Er-Dong-Xiao-Ke decoction regulates lipid metabolism via PPARG-mediated UCP2/AMPK signaling to alleviate diabetic meibomian gland dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD. AIM OF THE STUDY: To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism. MATERIALS AND METHODS: After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting. RESULTS: EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport. CONCLUSION: EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Phenylsulfate-induced oxidative stress and mitochondrial dysfunction in podocytes are ameliorated by Astragaloside IV activation of the SIRT1/PGC1α /Nrf1 signaling pathway.

Astragaloside IV (AS-IV) exhibits diverse biological activities. Despite this, the detailed molecular mechanisms by which AS-IV ameliorates diabetic nephropathy (DN) and shields podocytes from oxidative stress (OS) and mitochondrial dysfunction remain poorly understood. In this study, we used biochemical assays, histopathological analysis, Doppler ultrasound, transmission electron microscopy，flow cytometry, fluorescence staining, and Western blotting and other methods. AS-IV was administered to db/db mice for in vivo experimentation. Our findings indicated that AS-IV treatment significantly reduced diabetes-associated markers, proteinuria, and kidney damage. It also diminished ROS levels in the kidney, enhanced the expression of endogenous antioxidant enzymes, and improved mitochondrial health. Phenyl sulfate (PS), a protein-bound uremic solute of enteric origin, has been closely linked with DN and represents a promising avenue for further research. In vitro, PS exposure induced OS and mitochondrial dysfunction in podocytes, increasing ROS levels while decreasing antioxidant enzyme activity (Catalase, Heme Oxygenase-1, Superoxide Dismutase, and Glutathione Peroxidase). ROS inhibitors (N-acetyl-L-cysteine, NAC) as the positive control group can significantly reduce the levels of ROS and restore antioxidant enzymes protein levels. Additionally, PS reduced markers associated with mitochondrial biosynthesis and function (SIRT1, PGC1α, Nrf1, and TFAM). These adverse effects were partially reversed by AS-IV treatment. However, co-treatment with AS-IV and the SIRT1 inhibitor EX527 failed to restore these indicators. Overall, our study demonstrates that AS-IV effectively attenuates DN and mitigates PS-induced OS and mitochondrial dysfunction in podocytes via the SIRT1/PGC1α/Nrf1 pathway.

Dihydroartemisinin-driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer.

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.

Dihydroartemisinin-driven selective anti-lung cancer proliferation by binding to EGFR and inhibition of NRAS signaling pathway-induced DNA damage.

Chemotherapeutic agents can inhibit the proliferation of malignant cells due to their cytotoxicity, which is limited by collateral damage. Dihydroartemisinin (DHA), has a selective anti-cancer effect, whose target and mechanism remain uncovered. The present work aims to examine the selective inhibitory effect of DHA as well as the mechanisms involved. The findings revealed that the Lewis cell line (LLC) and A549 cell line (A549) had an extremely rapid proliferation rate compared with the 16HBE cell line (16HBE). LLC and A549 showed an increased expression of NRAS compared with 16HBE. Interestingly, DHA was found to inhibit the proliferation and facilitate the apoptosis of LLC and A549 with significant anti-cancer efficacy and down-regulation of NRAS. Results from molecular docking and cellular thermal shift assay revealed that DHA could bind to epidermal growth factor receptor (EGFR) molecules, attenuating the EGF binding and thus driving the suppressive effect. LLC and A549 also exhibited obvious DNA damage in response to DHA. Further results demonstrated that over-expression of NRAS abated DHA-induced blockage of NRAS. Moreover, not only the DNA damage was impaired, but the proliferation of lung cancer cells was also revitalized while NRAS was over-expression. Taken together, DHA could induce selective anti-lung cancer efficacy through binding to EGFR and thereby abolishing the NRAS signaling pathway, thus leading to DNA damage, which provides a novel theoretical basis for phytomedicine molecular therapy of malignant tumors.

Statin-Associated Liver Dysfunction and Muscle Injury: epidemiology, Mechanisms, and Management Strategies.

Surveillance of drug safety is an important aspect in the routine medical care. Adverse events caused by real-world drug utilization has become one of the leading causes of death and an urgent issue in the field of toxicology. Cardiovascular disease is now the leading cause of fatal diseases in most countries, especially in the elderly population who often suffer from multiple diseases and need long-term multidrug therapy. Among which, statins have been widely used to lower bad cholesterol and regress coronary plaque mainly in patients with hyperlipidemia and atherosclerotic cardiovascular diseases (ASCVD). Although the real-world benefits of statins are significant, different degrees and types of adverse drug reactions (ADR) such as liver dysfunction and muscle injury, have a great impact on the original treatment regimens as well as the quality of life. This review describes the epidemiology, mechanisms, early identification and post-intervention of statin-associated liver dysfunction and muscle injury based on the updated clinical evidence. It provides systematic and comprehensive guidance and necessary supplement for the clinical safety of statin use in cardiovascular diseases.

HT-2 mycotoxin and selenium deficiency: Effects on Femur development and integrity in Young mice.

Kashin-Beck Disease (KBD), an osteoarticular disorder, is potentially influenced by several factors, among which selenium deficiency and HT-2 mycotoxin exposure are considered significant. However, the combined effect of these factors on femoral development remains unclear, Conducted over eight weeks on forty-eight male mice categorized into control, selenium-deficient, and HT-2 toxin-exposed groups, including dual-exposure sets, this study comprehensively monitored body weight, bone metabolism markers, and cellular health. Employing biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy (TEM), we unearthed a reduction in body weight due to HT-2 toxin alone, with selenium deficiency exacerbating these effects synergistically. Our results unveil that both factors independently affect bone metabolism, yet their confluence leads to a pronounced degradation of bone health parameters, including alterations in calcium, phosphorus, and vitamin D levels, alongside marked changes in osteoblast and osteoclast activity and bone cell structures. The notable damage to femoral cortical and trabecular architectures underscores the perilous interplay between dietary selenium absence and HT-2 toxin presence, necessitating a deeper understanding of their separate and joint effects on bone integrity. These discoveries underscore the imperative for a nuanced approach to toxicology research and public health policy, highlighting the pivotal influence of environmental and nutritional factors on skeletal well-being.

Ubiquitin-specific protease-7 promotes expression of airway mucin MUC5AC via the NF-κB signaling pathway.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.