Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Comprehensive analysis of T-cell regulatory factors and tumor immune microenvironment in stomach adenocarcinoma.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide and is associated with high morbidity and mortality rates. However, the specific biomarkers used to predict the postoperative prognosis of patients with gastric cancer remain unknown. Recent research has shown that the tumor microenvironment (TME) has an increasingly positive effect on anti-tumor activity. This study aims to build signatures to study the effect of certain genes on gastric cancer. METHODS: Expression profiles of 37 T cell-related genes and their TME characteristics were comprehensively analyzed. A risk signature was constructed and validated based on the screened T cell-related genes, and the roles of hub genes in GC were experimentally validated. RESULTS: A novel T cell-related gene signature was constructed based on CD5, ABCA8, SERPINE2, ESM1, SERPINA5, and NMU. The high-risk group indicated lower overall survival (OS), poorer immune efficacy, and higher drug resistance, with SERPINE2 promoting GC cell proliferation, according to experiments. SERPINE2 and CXCL12 were significantly correlated, indicating poor OS via the Youjiang cohort. CONCLUSIONS: This study identified T cell-related genes in patients with stomach adenocarcinoma (STAD) for prognosis estimation and proposed potential immunotherapeutic targets for STAD.

Epinephelus coioides NLRP3 inhibits SGIV infection by upregulating Capspase-1 activity.

NLRP3 has an important role in the immune response and viral infection as an essential inflammasome component. However, it is unclear whether the grouper immune system is regulated by NLRP3 inflammasome. In this study, we cloned the NLRP3 gene from Epinephelus coioides. Ec-NLRP3 encodes 893 amino acids and contains two major structural domains, the NACHT domain (69-234aa) and the LRR domain (477-893aa). Tissue distribution analysis showed that Ec-NLRP3 was expressed in all tissues tested, with the spleen exhibiting the highest expression. Additionally, after being infected with SGIV, the expression of the Ec-NLRP3 gene was significantly increased. The results of subcellular localization revealed that Ec-NLRP3 was distributed throughout GS cells. In addition, Ec-NLRP3 co-localized with Ec-ASC and was observed as a cytosolic speck. Ec-NLRP3 overexpression significantly inhibited SGIV infection, which was further inhibited by co-overexpression of Ec-NLRP3 and Ec-ASC. Further studies revealed that overexpression of Ec-NLRP3 significantly upregulated caspase-1 activity, and co-overexpression of Ec-NLRP3 and Ec-ASC further upregulated caspase-1 activity. In addition, inhibition of Caspase-1 activity with VX-765 significantly increased the infection of SGIV. Furthermore, the NLRP3 inflammasome activator Nigericin was able to inhibit the infection of SGIV significantly. The above findings suggest that Ec-NLRP3 inhibits SGIV infection by upregulating caspase-1 activity.

GWAS-based polygenic risk scoring for predicting cerebral artery dissection in the Chinese population.

OBJECTIVE: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital. METHODS: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD. RESULTS: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10- 8. Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%. CONCLUSIONS: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.

Donor engineering of a benzothiadiazole-based D-A-D-type molecular semiconductor for perovskite solar cells: a theoretical study.

Due to the easy formation of compact molecular packing arrangements and the favorable photophysical and electrochemical properties, donor-acceptor-donor (D-A-D)-type small molecule hole-transporting materials (HTMs) have been widely synthesized and researched to improve the efficiency and stability of perovskite solar cells (PSCs). The main approach in recent experiments has been to seek good acceptors, whereas the influence of the electron-donating units has been less reported. In this work, six new benzothiadiazole-based D-A-D-type HTMs are tailored by employing the ethyl-substituted phenoxazine (POZ), phenothiazine (PTZ) and carbazole (CZ) as the donors. To obtain an elementary understanding of new HTMs, the electronic, optical, hole-transporting and interfacial properties are simulated with quantum chemistry methods. The results indicate that all tailored HTMs exhibit suitable energy alignment compared with the band structures of the perovskite, and the continuous highest occupied molecular orbital (HOMO) levels will be helpful for interfacial energy regulation. In comparison with the YN1, the maximum absorption wavelengths of the newly designed HTMs are red-shifted due to the decreased excitation energies from the ground-state to the first singlet excited-state. Importantly, the hole mobilities of all designed HTMs are distinctly higher than the referenced YN1, which is contributed by the better planarity of the molecular skeleton and the easier orbital overlapping between adjacent molecules. The interfacial simulations manifest that the FAPbI3/SM37 system displays a more stable adsorption configuration and greater charge redistributions at the interface compared to YN1, which further promotes the separation of photogenerated electron-hole pairs. Moreover, larger Stokes shifts and better solubility are also acquired for the new HTMs. In summary, our calculations not only propose several potential highly efficient HTMs, but also provide useful insights at the atomic level for the experimental synthesis of new D-A-D-type HTMs.

Efficacy and safety of dabigatran and rivaroxaban in atrial fibrillation patients with impaired liver function: a multicenter retrospective cohort study.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients with impaired liver function (ILF) have not been sufficiently studied. The aim of this study was to evaluate the efficacy and safety of DOACs for stroke prevention in patients with AF and ILF. METHOD: This study was based on data from 15 centers in China, including 4,982 AF patients. The patients were divided into 2 subgroups based on their liver function status: patients with normal liver function (NLF)(n = 4213) and patients with ILF (n = 769). Logistic regression analysis was used to investigate the risk of total bleeding, major bleeding, thromboembolism, and all-cause deaths in AF patients with NLF and ILF after taking dabigatran or rivaroxaban, respectively. RESULTS: Among AF patients treated with dabigatran or rivaroxaban, patients with ILF were associated with significantly higher major bleeding, compared with NLF patients (aOR: 4.797; 95% CI: 2.224-10.256; P < 0.001). In patients with NLF, dabigatran (n = 2011) had considerably lower risk of total bleeding than rivaroxaban (n = 2202) (aOR: 1.23; 95% CI: 1.002-1.513; P = 0.049). In patients with ILF, dabigatran (n = 321) significantly favored lower risks of major bleeding compared with rivaroxaban(n = 448) (aOR: 5.484; 95% CI: 1.508-35.269; P = 0.026). CONCLUSION: After using dabigatran or rivaroxaban, patients with ILF had remarkably increased risk of major bleeding compared with patients with NLF. In AF patients with NLF, dabigatran had the distinct strength of significantly reduced risk of total bleeding compared with rivaroxaban. In patients with AF and ILF, dabigatran use was associated with lower risk for major bleeding compared with rivaroxaban.

Identification and prediction of frailty among community-dwelling older Japanese adults based on Bayesian network analysis: a cross-sectional and longitudinal study.

BACKGROUND: Frailty is a multifactorial syndrome; through this study, we aimed to investigate the physiological, psychological, and social factors associated with frailty and frailty worsening in community-dwelling older adults. METHODS: We conducted a cross-sectional and longitudinal study using data from the "Community Empowerment and Well-Being and Healthy Long-term Care: Evidence from a Cohort Study (CEC)," which focuses on community dwellers aged 65 and above in Japan. The sample of the cross-sectional study was drawn from a CEC study conducted in 2014 with a total of 673 participants. After excluding those who were frail during the baseline assessment (2014) and at the 3-year follow-up (2017), the study included 373 participants. Frailty assessment was extracted from the Kihon Checklist, while social relationships were assessed using the Social Interaction Index (ISI). Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO) regression and their predictive abilities were tested. Factors associated with frailty status and worsening were identified through the Maximum-min Hillclimb algorithm applied to Bayesian networks (BNs). RESULTS: At baseline, 14.1% (95 out of 673) participants were frail, and 24.1% (90 out of 373) participants experienced frailty worsening at the 3-years follow up. LASSO regression identified key variables for frailty. For frailty identification (cross-sectional), the LASSO model's AUC was 0.943 (95%CI 0.913-0.974), indicating good discrimination, with Hosmer-Lemeshow (H-L) test p = 0.395. For frailty worsening (longitudinal), the LASSO model's AUC was 0.722 (95%CI 0.656-0.788), indicating moderate discrimination, with H-L test p = 0.26. The BNs found that age, multimorbidity, function status, and social relationships were parent nodes directly related to frailty. It revealed an 85% probability of frailty in individuals aged 75 or older with physical dysfunction, polypharmacy, and low ISI scores; however, if their social relationships and polypharmacy status improve, the probability reduces to 50.0%. In the longitudinal-level frailty worsening model, a 75% probability of frailty worsening in individuals aged 75 or older with declined physical function and ISI scores was noted; however, if physical function and ISI improve, the probability decreases to 25.0%. CONCLUSION: Frailty and its progression are prevalent among community-dwelling older adults and are influenced by various factors, including age, physical function, and social relationships. BNs facilitate the identification of interrelationships among these variables, quantify the influence of key factors. However, further research is required to validate the proposed model.

Longitudinal assessment of the relationship between frailty and social relationships among Japanese older adults: a random intercept cross-lagged panel model.

OBJECTIVES: This study aimed to explore the bidirectional association between frailty and social relationships in older adults while distinguishing between interpersonal and intrapersonal effects. METHODS: A prospective cohort study of community-dwelling older adults was conducted in Japan in three waves spanning six years with follow-ups in every three years. Random intercept cross-lagged panel model was used to explore temporal associations between frailty and social relationships. RESULTS: Data for 520 participants (mean age 73.02 [SD 6.38] years, 56.7% women) were analyzed. Across individuals, frailty was associated with social relationships (ß = -0.514, p < 0.001). At the interpersonal level, frailty was cross-sectionally associated with social relationships separately at T1(ß = -0.389, p < 0.01), T2 (ß = -0.343, p < 0.001) and T3 (ß = -0.273, p < 0.05). Moreover, social relationships were associated with subsequent increases in symptoms of frailty in all measurement waves (ß = -0.332, p < 0.001; ß = -0.169, p < 0.01) and vice versa (ß = -0.149, p < 0.05; ß = -0.292, p < 0.001). CONCLUSIONS: The results suggest that frailty was associated with lower levels of social relationships. Frailty improvement programs can be combined with interventions to enhance social relationships, which will be beneficial in preventing frailty. The results emphasize the importance of combining clinical treatments of frailty with interventions to improve social relationships.

Functions and Clinical Significance of Myocardial Cell-Derived Immunoglobulins.

Immunoglobulins (Igs) have been widely accepted to be exclusively expressed by B cells. Nonetheless, this theory is challenged by mounting evidence which suggests that Igs can also be generated by non B cells (non B-Ig), including cardiomyocytes (CM). Non B-Ig exhibits unique physical and chemical characteristics, unique variable region sequences and functions, which diverge from those of B-Ig. For instance, non B-Ig demonstrates hydrophobicity, limited diversity in the variable region, and extracellular matrix protein activity. Likewise, cardiomyocytes can express different classes of Igs, including IgM, IgG, and free Igκ light chains (cardiomyocyte derived-Igs, CM-Igs). In particular, CM-Igs can be secreted into the extracellular space in various cardiovascular diseases, such as myocardial ischaemia and myocardial fibrosis where they might be involved in complement activation and direct damage to cardiomyocytes. Nevertheless, the precise pathological activity of CM-Igs remains unclear. Recently, Zhu et al. focused on studying the sequence characteristics and functions of CM-Igκ; they discovered that the CM-Igκ exhibits a unique VJ recombination pattern, high hydrophobicity, and is principally located on the intercalated discs and cross striations of the cardiomyocytes. Interestingly, loss of Igκ in cardiomyocytes results in structural disorders in intercalated discs and dysfunction in myocardial contraction and conduction. Mechanically, Igκ promotes the stabilisation of plectin, a cytoskeleton cross-linker protein that connects desmin to desomsome, to maintain the normal structure of the intercalated disc. This finding indicates that CM-Igκ plays an integral role in maintaining cytoskeleton structure. Consequently, it is imperative to reveal the physiological functions and mechanisms of pathological injury associated with CM-Igs.

Laparoscopic hepatectomy for hepatocellular carcinoma in patients with clinically significant portal hypertension: a systematic review and meta-analysis.

OBJECTIVE: To compare the effects of laparoscopic hepatectomy (LH) on the short-term and long-term outcomes in hepatocellular carcinoma (HCC) patients with and without clinically significant portal hypertension (CSPH). METHODS: A systematic literature search of the PubMed, EMBASE, and Cochrane databases was performed for articles published from inception to March 1, 2023. Meta-analysis of surgical and oncological outcomes was performed using a random effects model. Data were summarized as mean difference and risk ratio with 95% confidence intervals. RESULTS: Five cohort studies with a total of 310 HCC patients were included (CSPH 143; Non-CSPH 167). In terms of surgical outcomes, estimated blood loss and the length of hospital stay were significantly lower in the Non-CSPH group than in the CSPH group. There were no significant differences between the two groups regarding other surgical outcomes, including the operative time, ratio of conversion to open surgery, and overall complication rate. In addition, there were also no significant differences between the two groups regarding the oncological outcomes, such as 1-, 3-, and 5-year overall survival. CONCLUSIONS: HCC patients with and without CSPH who underwent LH had comparable surgical and oncological outcomes. LH is a safe and effective treatment for HCC patients with CSPH under the premise of rational screening of patients.

The toxic effects induced by benzethonium chloride on Daphnia carinata over two generations: Resistance and higher sublethal toxicity.

With the widespread utilization of the sanitizing product benzethonium chloride (BEC) throughout the coronavirus pandemic, concerns have emerged regarding its potential hazards. Nevertheless, the long-term and multigenerational toxic effects of BEC on aquatic organisms remains unexplored. This study investigates acute and chronic toxicity, oxidative stress, mitochondrial membrane potential, ATP concentrations, and gene expression using Daphnia carinata as the model organism. Meanwhile, hierarchical clustering analysis was utilized to investigate phenotypic effects among different treatment groups. The integrated biomarker response index version 2 (IBRv2) was employed to estimate the deviation in toxic effects over two generations. These results indicated that D. carinata in the second generation exhibited higher survival rate and lower levels of oxidative stress than the first generation. However, the higher sublethal effects were found in the second generation as follows, the weakened growth performance, mitochondrial membrane potential depolarization, reduced ATP concentrations, and down-regulated gene expression. The mitochondrial toxicity induced by BEC may account for the distinct toxic effects exhibited in two generations. The findings here can assist with the evaluation of potential risk for BEC on aquatic organisms, and provide new insight into the cross-generational toxicity mechanisms of pollutants in aquatic ecosystems.

Concentrations, Sources and Health Risk Assessment of Polycyclic Aromatic Hydrocarbons in Chinese Herbal Medicines.

The determination and evaluation of 16 polycyclic aromatic hydrocarbons (PAHs) in seven Chinese herbal medicines (CHMs) were conducted through a rapid and straightforward extraction and purification method, coupled with GC-MS. A sample-based solid-phase extraction (SPE) pretreatment technique, incorporating isotopic internal standards, was employed for detecting various medicinal parts of CHMs. The assay exhibited linearity within the range of 5 to 500 ng/mL, with linear coefficients (R2) for PAHs exceeding 0.999. The recoveries of spiked standards ranged from 63.37% to 133.12%, with relative standard deviations (RSDs) ranging from 0.75% to 14.54%. The total PAH content varied from 176.906 to 1414.087 µg/kg. Among the 16 PAHs, phenanthrene (Phe) was consistently detected at the highest levels (47.045-168.640 µg/kg). Characteristic ratio analysis indicated that oil, coal, and biomass combustion were the primary sources of PAHs in CHMs. The health risk associated with CHMs was assessed using the lifetime carcinogenic risk approach, revealing potential health risks from the consumption of honeysuckle, while the health risks of consuming Lycium chinense berries were deemed negligible. For the other five CHMs (glycyrrhizae, Coix lacryma, ginseng, lotus seed, seed of Sterculia lychnophora), the health risk from consumption fell within acceptable ranges. Furthermore, sensitivity analyses utilizing Monte Carlo exposure assessment methods identified PAH levels in CHMs as health risk sensitizers. It is crucial to recognize that the consumption of herbal medicines is not a continuous process but entails potential health risks. Hence, the monitoring and risk assessment of PAH residues in CHMs demand careful attention.

Dyadic effects of financial toxicity and social support on the fear of cancer recurrence in breast cancer patients and caregivers: an actor-partner interdependence mediation model.

PURPOSE: In this study, the actor-partner interdependence mediation model (APIMeM) was applied to breast cancer patients and their caregivers to assess the factors that affect the fear of cancer recurrence. In particular, the purpose of this study was to evaluate the mediating effect of social support on financial toxicity and the fear of cancer recurrence, providing an effective basis for developing plans to reduce the level of fear of cancer recurrence. METHODS: This study employed a cross-sectional design, and 405 dyads of breast cancer patients and their caregivers were enrolled. Financial toxicity, social support, and fear of cancer recurrence were assessed by computing comprehensive scores for financial toxicity based on patient-reported outcome measures, the Social Support Rating Scale, and the Fear of Cancer Recurrence Inventory Short Form, respectively. The data were analysed using SPSS 24.0 and AMOS 23.0. RESULTS: The results showed that the fear of cancer recurrence of breast cancer patients and their caregivers was significantly related to dyadic financial toxicity and social support. In addition, the financial toxicity of breast cancer patients and their caregivers had significant actor effects and partner effects on the fear of cancer recurrence through dyadic social support. CONCLUSIONS: The financial toxicity of breast cancer patients and their caregivers could produce actor and partner effects on the fear of cancer recurrence through the mediation of social support, which provided empirical support for improving reducing the level of fear of cancer recurrence among patients and caregivers at the dyadic level.

Hydrogenation of Furfural over Biomass-Based Electron-Deficient Co-NC Nanotube Catalyst.

The conversion of furfural to furfuryl alcohol is one of the most significant reactions from industrial-scale produced biomass platform molecules to value-added chemicals. In this work, biomass-based chitosan was used as both a carbon source and nitrogen source to synthesize nitrogen-doped carbon. With the addition of cobalt, the optimized 7.5Co-NC-900 catalyst had the largest surface area and the graphite nanotube structure with the least defects. It was employed for the hydrogenation of furfural to furfuryl alcohol and reached a nearly full conversion and an equivalent yield at 130 °C in 4 MPa initial H2. The structure-function relationship study indicated that the N could interact with the neighbor Co in this catalyst and formed an electron-deficient Co center which was in favor of the adsorption of furfural in the nanotube and had high catalytic activity. The interactions between Co and N stabilized the catalyst so that it could remain stable in five runs of catalytic reactions.

Proteome-wide identification and functional analysis of ubiquitinated proteins in Hepa1-6 cells by knockdown of E3 ubiquitin ligase SIAH1.

Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy that poses a serious threat to human life. The conventional therapies for HCC cannot substantially improve overall survival (OS), disease duration, and prognosis. Therefore, it is important to study the underlying mechanism of HCC and seek better methods for HCC prevention and treatment. Ubiquitination is a post-translational modification that modulates great cellular function by cooperating with E1, E2, and E3 ligases. Yet, the ubiquitination and lysine residues in HCC are still elusive. Seven in absentia homolog 1 (SIAH1), as an important E3 ubiquitin ligase, regulates ubiquitin-mediated proteolysis to function as a tumor suppressor in HCC. In the present study, we downregulated SIAH1 in the mouse HCC cell line Hepa1-6 and studied its function by using proteome-wide identification. Methods: SIAH1 was knocked down by SIAH1 short hairpin RNA (shRNA) in mouse HCC cell line Hepa1-6 cells, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was conducted to analyze the ubiquitinated proteins. Functional analysis was performed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment. Results: The systematic profiling showed a total of 550 differently expressed proteins (DEPs), including 263 upregulated DEPs and 287 downregulated DEPs. Considering the amino acid sequences around the modified lysine residues, seven proteins were identified as conserved ubiquitination motifs in the peptides. The ubiquitinated proteins were mainly distributed in the cytoplasm, nucleus, and plasma membrane. Functional analysis suggested that the ubiquitinated proteins were mostly enriched in the nucleus, cytoplasm, and extracellular space; in addition, the ubiquitinated proteins were mostly attributed to the protein binding, and disease. The ubiquitinated proteins modulate HCC by mapping lysine modification sites. Conclusions: The use of high-throughput characterization to identify novel and specific targets associated with SIAH1 is of great significance in terms of functional weight. The results obtained in this paper from the analysis of proteomic data provided novel insights into ubiquitination regulation in HCC, which pave the way for further research and mechanism discovery of HCC.

Revealing the Molecular Mechanism of Sageretia theezans in the Treatment of Hemorrhoids based on Network Pharmacology.

OBJECTIVE: Sageretia theezans is one of the classic medicines in ancient times, which is commonly used to treat scabies, lacquer sores, acute and chronic pharyngitis, Tonsillitis, Cholecystitis, secondary infection of hemorrhoids, and other symptoms. However, the potential molecular mechanism of Sageretia theezans is still unclear. In this study, we explored the active compounds of Sageretia theezans in the treatment of hemorrhoids (HD), predicted the potential targets of drugs, and verified their functions through network pharmacology and in vivo and in vitro experiments. METHODS: First, we identified the active compounds and key targets of Sageretia theezans in treating HD through network pharmacology. The key signaling pathways related to the role of Sageretia theezans were analyzed. HUVEC Human umbilical vein endothelial cells were used to study the function of Sageretia theezans and its target in vitro. In addition, we also used the SD rat hemorrhoid model to explore the efficacy of Sageretia theezans in HD in vivo. RESULT: A total of 159 drug targets were obtained from the TCMSP, ETCM, and PubChem databases. Constructing a drug component target network; differential analysis using sequencing data identified 1046 differentially expressed genes. Intersecting drug targets and differentially expressed genes obtained four intersection targets (GOT1, SLC25A10, SUCLG1, CLEC4E). Perform single gene GSEA functional enrichment analysis on intersection targets, select KEGG and GO of the top 10 for display, and merge the results. In order to investigate the interaction between intersecting genes and differentially expressed genes, we conducted a PPI protein interaction analysis on 1046 differentially expressed genes. Finally, a network of Chinese medicine active molecule intersection genes was proposed, and the genes and their corresponding active molecules (Successful acid, Taraxerone, Taraxerol) were Macromolecular docking, respectively. The results showed that these four genes could be successfully docked with the responsive active molecules and had high binding affinity. In vivo, the low-dose treatment group of Sageretia theezans, the medium-dose treatment group of Sageretia theezans, and the high-dose treatment group of Bromelia can inhibit the proliferation of HUVECs cells. In vitro, the middle dose of Sageretia theezans has the best therapeutic effect on hemorrhoids, and the treatment of Sageretia theezans on hemorrhoids is correlated with the expression of GOT1, SLC25A10, SUCLG1, and CLEC4E. CONCLUSION: To sum up, Sageretia theezans can alleviate the symptoms of hemorrhoids and is related to the expression of GOT1, SLC25A10, SUCLG1, and CLEC4E.

Oral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives.

Diabetes, characterized by hyperglycemia, is a major cause of death and disability worldwide. Peptides, such as insulin and glucagon-like peptide-1 (GLP-1) analogs, have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body. Compared to subcutaneous injection, oral administration of anti-diabetic peptides is a preferred approach. However, biological barriers significantly reduce the efficacy of oral peptide therapeutics. Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes. This review will highlight (1) the benefits of oral anti-diabetic peptide therapeutics; (2) the biological barriers for oral peptide delivery, including pH and enzyme degradation, intestinal mucosa barrier, and biodistribution barrier; (3) the delivery platforms to overcome these biological barriers. Additionally, the review will discuss the prospects in this field. The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

A transparent p-coumaric acid-grafted-chitosan coating with antimicrobial, antioxidant and antifogging properties for fruit packaging applications.

The study aimed to develop a novel, transparent and non-toxic coating with antimicrobial, antioxidant, and antifogging properties. The p-coumaric acid-grafted chitosan (CS-PCA) was synthesized via a carbodiimide coupling reaction and then characterized. The CS-PCA coatings were further prepared using the casting method. The CS-PCA coatings obtained exhibited excellent transparency, UV-light barrier ability, and antifogging properties, as confirmed by spectroscopy and antifogging tests. The CS-PCA coatings showed stronger antioxidant capacity and antimicrobial properties against Escherichia coli, Staphylococcus aureus and Botrytis cinerea compared to CS. The multifunctional coatings were further coated on the polyethylene cling film and their effectiveness was confirmed through a strawberry preservation test. The decay of the strawberries was reduced by CS-PCA coated film at room temperature.

Micro-and nano-plastics induce kidney damage and suppression of innate immune function in zebrafish (Danio rerio) larvae.

Aquatic environments serve as critical repositories for pollutants and have significantly accumulated micro- and nanoplastics (MNPs) due to the extensive production and application of plastic products. While the disease resistance and immunity of fish are closely linked to the condition of their aquatic habitats, the specific effects of nanoplastics (NPs) and microplastics (MPs) within these environments on fish immune functions are still not fully understood. The present study utilized zebrafish (Danio rerio) embryos and larvae as model organisms to examine the impacts of polystyrene NPs (100 nm) and MPs (5 µm) on fish immune responses. Our findings reveal that NPs and MPs tend to accumulate on the surfaces of embryos and within the intestines of larvae, triggering oxidative stress and significantly increasing susceptibility to Edwardsiella piscicida infection in zebrafish larvae. Transmission electron microscopy examined that both NPs and MPs inflicted damage to the kidney, an essential immune organ, with NPs predominantly inducing endoplasmic reticulum stress and MPs causing lipid accumulation. Transcriptomic analysis further demonstrated that both NPs and MPs significantly suppress the expression of key innate immune pathways, notably the C-type lectin receptor signaling pathway and the cytosolic DNA-sensing pathway. Within these pathways, the immune factor interleukin-1 beta (il1b) was consistently downregulated in both exposure groups. Furthermore, exposure to E. piscicida resulted in restricted upregulation of il1b mRNA and protein levels, likely contributing to diminished disease resistance in zebrafish larvae exposed to MNPs. Our findings suggest that NPs and MPs similarly impair the innate immune function of zebrafish larvae and weaken their disease resistance, highlighting the significant environmental threat posed by these pollutants.

Antioxidant interaction between α-tocopherol and γ-oryzanol in HepG2 cells.

Minor constituents exhibit certain antioxidant interactions in vitro, and the effects in different media are different. However, it is not clear whether there are antioxidant interactions in cells after digestion and absorption. We utilized the cellular antioxidant evaluation model in HepG2 cells to study the antioxidant interaction between α-tocopherol and γ-oryzanol, and the interaction mechanism of a binary mixture was also illustrated. A cellular antioxidant assay (CAA) model and a combined index (CI) method were firstly used to explore the antioxidant activity and interaction of the binary mixture in HepG2 cells. The CAA value was positively correlated with the single addition concentration, while the results displayed a biphasic tendency with increasing concentrations of the binary mixture. The combination of TO11 (1 µg mL-1 α-tocopherol and 10 µg mL-1 γ-oryzanol) showed the greatest antioxidant activity and synergistic effect, and the maximum CAA value reached up to 94.84 ± 4.2. Then the mechanism of the synergistic antioxidant effect of the binary mixture was explained from three aspects including cellular uptake, intracellular reactive oxygen species (ROS) level and endogenous enzyme activity. The results demonstrated that the antioxidant interaction of the binary mixture in cells was related to cellular uptake of minor constituents, and the combination of TO11 exerted a synergistic effect by scavenging ROS and up-regulating glutathione peroxidase (GSH-Px) activity, resulting in the strongest cellular antioxidant activity. This study throws light on the nature of antioxidant interaction between minor constituents, which may contribute to the development of related functional foods and rational dietary collocation.