Colon cancer inhibitory properties of Caulerpa lentillifera polysaccharide and its molecular mechanisms based on three-dimensional cell culture model.

Caulerpa lentillifera is rich in polysaccharides, and its polysaccharides show a significant effect in different biological activities including anti-cancer activity. As an edible algae-derived polysaccharide, exploring the role of colon cancer can better develop the application from a dietary therapy perspective. However, more in-depth studies of C. lentillifera polysaccharide on anti-colon cancer activity and mechanism are needed. In this study, we found that Caulerpa lentillifera polysaccharides (CLP) showed potential anti-colon cancer effect on human colon cancer cell HT29 in monolayer (IC50 = 1.954 mg/mL) and spheroid (IC50 = 0.402 mg/mL). Transcriptomics and metabolomics analyses revealed that CLP had an inhibitory effect on HT29 3D spheroid cells by activating aminoacyl-tRNA biosynthesis as well as arginine and proline metabolism pathways. Furthermore, the anti-colon cancer effects of CLP were confirmed through other human colon cancer cell HCT116 and LoVo in monolayer cells (IC50 = 1.890 mg/mL and 1.437 mg/mL, respectively) and 3D spheroid cells (IC50 = 0.344 mg/mL and 0.975 mg/mL, respectively), and three patient-derived organoids with IC50 values of 6.333-8.780 mg/mL. This study provided basic data for the potential application of CLP in adjuvant therapeutic food for colon cancer on multiple levels, while further investigation of detailed mechanism in vivo was still required.

Butylparaben induced zebrafish (Danio rerio) kidney injury by down-regulating the PI3K-AKT pathway.

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 µM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.

Transarterial chemoembolization with molecular targeted therapies plus camrelizumab for recurrent hepatocellular carcinoma.

BACKGROUND: The safety and efficacy of transarterial chemoembolization plus molecular targeted therapy (MTT) combined with immune checkpoint inhibitors (ICIs) in primary liver cancer have been demonstrated. However, the evidence for TACE plus MTT combined with ICIs in the treatment of recurrent hepatocellular carcinoma (RHCC) is limited. Given the excellent performance of this combination regimen in primary liver cancer, it is necessary to evaluate the efficacy of TACE plus MTT combined with ICIs in RHCC. METHODS: A total of 88 patients with RHCC treated with TACE plus MTT combined with camrelizumab (TACE-TC group, n = 46) or TACE plus MTT (TACE-T group, n = 42) were retrospectively collected and analyzed. In this study, we evaluated the effectiveness and safety of combination therapy for patients with RHCC by analyzing tumor response, progression-free survival (PFS), overall survival (OS), laboratory biochemical indices, and adverse events (AEs). RESULTS: TACE-TC was superior to TACE-T in PFS (14.0 vs. 8.9 months, p = 0.034) and OS (31.1 vs. 20.2 months, p = 0.009). Moreover, TACE-TC achieved more preferable benefits with respect to disease control rate (89.1% vs. 71.4%, p = 0.036) and objective response rate (47.8% vs. 26.2%, p = 0.036) compared with TACE-T in patients with RHCC. Compared with the TACE-T group, the AFP level in the TACE-TC group decreased more significantly after 3 months of treatment. Multivariate analysis showed that treatment option was a significant predictor of OS and PFS, while the portal vein tumor thrombus and interval of recurrence from initial treatment were another prognostic factor of PFS. There was no significant difference between the TACE-TC and TACE-T groups for Grade 3-4 adverse events. CONCLUSIONS: A combination therapy of TACE, MTT, and camrelizumab significantly improved tumor response and prolonged survival duration, showing a better survival prognosis for RHCC patients.

Betaine supplementation alleviates corticosterone-induced hepatic cholesterol accumulation through epigenetic modulation of HMGCR and CYP7A1 genes in laying hens.

Excessive corticosterone (CORT) exposure could cause hepatic cholesterol accumulation in chickens and maternal betaine supplementation could decrease hepatic cholesterol deposition through epigenetic modifications in offspring chickens. Nevertheless, it remains uncertain whether providing betaine to laying hens could protect CORT-induced hepatic cholesterol accumulation via epigenetic mechanisms. This study aimed to examine the effects of dietary betaine on plasma and hepatic cholesterol contents, expression of cholesterol metabolic genes, as well as DNA methylation on their promoters in the liver of laying hens exposed to CORT. A total of 72 laying hens at 130 d of age were randomly divided into 3 groups: control (CON), CORT, and CORT+betaine (CORT+BET) groups. The experiment lasted for 35 d. Chickens in CON and CORT groups were fed a basal diet, whereas the CORT+BET group chickens were fed the basal diet supplemented with 0.1% betaine for 35 d. On d 28 of the experiment, chickens in CORT and CORT+BET groups received daily subcutaneous injections of CORT (4.0 mg/kg body weight), whereas the CON group chickens were injected with an equal volume of solvent for 7 d. The results showed that CORT administration led to a significant increase (P < 0.05) in the contents of cholesterol in plasma and liver, associated with activation (P < 0.05) of sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), lecithin-cholesterol acyltransferase (LCAT) and low-density lipoprotein receptor (LDLR) genes expression, and inhibition of cholesterol-7-alpha hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) genes expression in the liver compared to the CON. In contrast, CORT-induced up-regulation of HMGCR mRNA and protein abundances and downregulation of CYP7A1 mRNA and protein abundances were completely normalized (P < 0.05) by betaine supplementation. Besides, CORT injection led to significant hypomethylation (P < 0.05) on HMGCR promoter and hypermethylation (P < 0.05) on CYP7A1 promoter. Moreover, dietary betaine rescued (P < 0.05) CORT-induced changes in methylation status of HMGCR and CYP7A1 genes promoters. These results indicate that dietary betaine addition protects laying hens from CORT-induced hepatic cholesterol accumulation via epigenetic modulation of HMGCR and CYP7A1 genes.

Clinical application of vancomycin TDM in ventilated patients with gastrointestinal cancer: a propensity-matched analysis.

BACKGROUND: Therapeutic drug monitoring (TDM) of vancomycin is widely recommended for clinical treatment. Due to the complexity of 24-h area under the curve (AUC) guided vancomycin monitoring in clinical practice, the vancomycin trough level remains the most common and practical method. The purpose of this study was designed to investigate the differences in the safety and efficacies of vancomycin TDM based on the two different monitoring methods, and further explore the clinical application of trough-guided vancomycin monitoring in patients with gastrointestinal cancer requiring mechanical ventilation. METHODS: We included a total of 78 gastrointestinal cancer patients who required mechanical ventilation due to various diseases. All patients included in this study were aged 18 years or older and were treated with intravenous vancomycin therapy for more than 2 days due to documented or suspected Gram-positive bacterial infections, and have at least one available vancomycin plasma concentration. First, we compared the safety and efficacies of vancomycin TDM based on different monitoring methods as trough-guided monitoring or AUC-guided monitoring. Then, based on whether the initial vancomycin concentration achieving the target trough concentration (less than 48 h), patients were divided into early and delayed groups, and the clinical factors were compared between them. The primary endpoints include the incidence of new-onset acute kidney injury (AKI) or renal replacement therapy (RRT), clinical success rate and 28-day all-cause mortality. Finally, the overall relationship between trough concentration and potential covariates is screened by univariate and multivariate analysis to explore potential information covariates. RESULTS: The research revealed that patients with gastrointestinal cancer exhibited significantly lower initial vancomycin trough concentrations (median [interquartile range (IQR)]: 6.90[5.28-11.20] mg/L). And there were no statistically significant differences in the safety and efficacies of vancomycin TDM based on the two different monitoring methods for the primary endpoint. Moreover, base on trough-guided vancomycin monitoring, the early group demonstrated a notably shorter duration of mechanical ventilation compared with the delayed group (χ2 = 4.532; p < 0.05; Fig. 2E). Propensity score weighting further confirmed that the duration of mechanical ventilation (χ2 = 6.607; p < 0.05; Fig. 2F) and duration of vasoactive agent (χ2 = 6.106; p < 0.05; Fig. 2D) were significantly shorter in the early group compared with delayed group. Multivariate regression analysis revealed that Cystatin C (Cys-C) was the most important variable for vancomycin target trough achievement (odds ratio, 5.274; 95% CI, 1.780 to 15.627; p = 0.003). CONCLUSIONS: Trough-guided vancomycin monitoring is a simple and effective marker of TDM for ventilated patients with gastrointestinal cancer. Timely achievement of target trough concentrations for vancomycin can improve partial clinical outcomes in Gram-positive bacterial infections. Cys-C level is a potentially valuable parameter for predicting the vancomycin concentration.

Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis enhances antigen cross-presentation and antitumor efficacy through ROS production.

Introduction: Lactococcus lactis (L.L) is safe and can be used as vehicle. In this study, the immunoregulatory effect of L.L on dendritic cell (DC) activation and mechanism were investigated. The immune responses and antigen cross-presentation mechanism of DC-based vaccine prepared with OVA recombinant L.L were explored. Methods: Confocal microscopy and flow cytometry were used to analyze the mechanism of L.L promoting DC maturation, phagosome membrane rupture and antigen presentation. The antitumor effect of DC vaccine prepared with L.L-OVA was assessed in the B16-OVA tumor mouse model. Results: L.L significantly promoted DC maturation, which was partially dependent on TLR2 and downstream MAPK and NF-κB signaling pathways. L.L was internalized into DCs by endocytosis and did not co-localized with lysosome. OVA recombinant L.L enhanced antigen cross-presentation of DCs through the phagosome-to-cytosol pathway in a reactive oxygen species (ROS)- and proteasome-dependent manner. In mouse experiments, L.L increased the migration of DCs to draining lymph node and DC vaccine prepared with OVA recombinant L.L induced strong antigen-specific Th1 and cytotoxic T lymphocyte responses, which significantly inhibited B16-OVA tumor growth. Conclusion: This study demonstrated that recombinant L.L as an antigen delivery system prepared DC vaccine can enhance the antigen cross-presentation and antitumor efficacy.

Synergistic Anti-Tumor Effect of Toosendanin and Paclitaxel on Triple-Negative Breast Cancer via Regulating ADORA2A-EMT Related Signaling.

Triple negative breast cancer (TNBC) is an aggressive cancer with very poor prognosis. Combination therapy has proven to be a promising strategy for enhancing TNBC treatment efficacy. Toosendanin (TSN), a plant-derived triterpenoid, has shown pleiotropic effects against a variety of tumors. Herein, it is evaluated whether TSN can enhance the efficacy of paclitaxel (PTX), a common chemotherapeutic agent, against TNBC. It is found that TSN and PTX synergistically suppress the proliferation of TNBC cell lines such as MDA-MB-231 and BT-549, and the combined treatment also inhibits the colony formation and induces cell apoptosis. Furthermore, this combination shows more marked migratory inhibition when compared to PTX alone. Mechanistic study shows that the ADORA2A pathway in TNBC is down-regulated by the combination treatment via mediating epithelial-to-mesenchymal transition (EMT) process. In addition, the combined treatment of TSN and PTX significantly attenuates the tumor growth when compared to PTX monotherapy in a mouse model bearing 4T1 tumor. The results suggest that combination of TSN and PTX is superior to PTX alone, suggesting that it may be a promising alternative adjuvant chemotherapy strategy for patients with TNBC, especially those with metastatic TNBC.

Body composition predicts prognosis of hepatocellular carcinoma patients undergoing immune checkpoint inhibitors.

PURPOSE: Immune checkpoint inhibitors (ICIs) with anti-PD-1/PD-L1 antibody are promising treatments for hepatocellular carcinoma (HCC), but lack reliable biomarkers of response. In the present study, we aimed to investigate the correlation between pre-treatment body composition measures (muscle, adipose, etc.) and the prognosis of patients with HCC treated with ICIs. METHODS: We measured the total area of all skeletal muscles, total adipose tissue area, subcutaneous adipose tissue area, and visceral adipose tissue area at the level of the third lumbar vertebra using quantitative CT. Then, we calculated the skeletal muscle index, visceral adipose tissue index, subcutaneous adipose tissue index (SATI), and total adipose tissue index. The Cox regression model was used to determine the independent factors of the patient prognosis and construct a nomogram to predict survival. The consistency index (C-index) and calibration curve were used to determine the predictive accuracy and discrimination ability of the nomogram. RESULTS: Multivariate analysis revealed that the SATI (high- vs. low SATI; HR 0.251; 95% CI 0.109-0.577; P = 0.001), sarcopenia (sarcopenia vs. no sarcopenia; HR 2.171; 95% CI 1.100-4.284; P = 0.026), and portal vein tumor thrombus (PVTT) (PVTT vs. No PVTT; HR 2.429; 95% CI 1. 197-4. 929; P = 0.014) were indicated as independent prognostic factors for OS in multivariate analysis. Multivariate analysis indicated that Child-Pugh class (HR 0.477, 95% CI 0.257-0.885, P = 0.019) and sarcopenia (HR 2.376, 95% CI 1.335-4.230, P = 0.003) were independent prognostic factors of PFS. We established a nomogram using SATI, SA, and PVTT to predict the 12-month and 18-month survival probability of HCC patients treated with ICIs. The C-index of the nomogram was 0.754 (95% CI 0.686-0.823), and the calibration curve confirmed that the predicted results were in good agreement with the actual observations. CONCLUSION: Subcutaneous adipose and sarcopenia are significant prognostic factors of patients with HCC receiving ICIs. A nomogram based on body composition parameters and clinical factors could well predict survival in HCC patients treated with ICIs.

Hypouricemic effect of gallic acid, a bioactive compound from Sonneratia apetala leaves and branches, on hyperuricemic mice.

As a tropical medicinal plant, Sonneratia apetala is mainly distributed in the southeast coastal areas of China. Recently, the hypouricemic effect of Sonneratia apetala leaves and branches (SAL) has been reported, but the active compound and its mechanism are unclear. Thus, this study aims to explore the effective fraction of SAL and the mechanism of its active compound on uric acid formation and excretion. SAL was extracted with ethyl acetate and concentrated to obtain solvent-free extracts (SAL-EA). The remains fraction (SAL-E) and the supernatant fraction (SAL-S) of SAL resulting from water extraction and alcohol precipitation were collected and dried. The effects of different fractions were explored on hyperuricemic mice. SAL-S showed excellent activities in decreasing the levels of uric acid (UA), blood urea nitrogen (BUN), and creatinine (CRE) in serum and in attenuating kidney damage. Then, the active compound gallic acid (GA) identified by HPLC was assayed for its mechanism of regulating uric acid metabolism in hyperuricemic mice. The hypouricemic effect of GA was probably associated with the downregulation of URAT1 and GLUT9, upregulation of ABCG2 and decreased activities of adenosine deaminase (ADA) and xanthine oxidase (XOD). Moreover, GA suppressed the level of MDA, IL-6, IL-1ß, TNF-α, TGF-ß1, COX-2 and cystatin-C (Cys-C), and enhanced the activities of SOD, GSH-Px, CAT, and Na+-K+-ATPase (NKA) in the kidneys. These results indicated that GA protects against hyperuricemia-induced kidney injury via suppressing oxidative stress and inflammation as well as decreasing the serum levels of UA by regulating urate transporters.

Jian-Ti-Kang-Yi decoction alleviates poly(I:C)-induced pneumonia by inhibiting inflammatory response, reducing oxidative stress, and modulating host metabolism.

Jian-Ti-Kang-Yi decoction (JTKY) is widely used in the treatment of COVID-19. However, the protective mechanisms of JTKY against pneumonia remain unknown. In this study, polyinosinic-polycytidylic acid (poly(I:C)), a mimic of viral dsRNA, was used to induce pneumonia in mice; the therapeutic effects of JTKY on poly(I:C)-induced pneumonia model mice were evaluated. In addition, the anti-inflammatory and anti-oxidative potentials of JTKY were also investigated. Lastly, the metabolic regulatory effects of JTKY in poly(I:C)-induced pneumonia model mice were studied using untargeted metabolomics. Our results showed that JTKY treatment decreased the wet-to-dry ratio in the lung tissue, total protein concentration, and total cell count of the bronchoalveolar lavage fluid (BALF). Hematoxylin and Eosin (HE) and Masson staining indicated that the JTKY treatment alleviated the pathological changes and decreased the fibrotic contents in the lungs. JTKY treatment also decreased the expression of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α)] and increased the levels of immunomodulatory cytokines (IL-4 and IL-10) in the BALF and serum. Flow cytometry analysis showed that the JTKY treatment lowered the ratio of CD86+/CD206+ macrophages in the BALF, decreased inducible nitric oxide synthase (iNOS) level, and increased arginase 1 (Arg-1) level in lung. JTKY also lowered CD11b+Ly6G+ neutrophils in BALF and decreased myeloperoxidase (MPO) activity in lung. Moreover, it also elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and decreased methane dicarboxylic aldehyde (MDA) level in lung. Untargeted metabolomic analysis showed that the JTKY treatment could affect 19 metabolites in lung, such as L-adrenaline, L-asparagine, ornithine, and alpha-ketoglutaric acid. These metabolites are associated with the synthesis and degradation of ketone bodies, butanoate, alanine, aspartate, and glutamate metabolism, and tricarboxylic acid (TCA) cycle processes. In conclusion, our study demonstrated that treatment with JTKY ameliorated poly(I:C)-induced pneumonia. The mechanism of action of JTKY may be associated with the inhibition of the inflammatory response, the reduction of oxidative stress, and the regulation of the synthesis and degradation of ketone bodies, TCA cycle, and metabolism of alanine, aspartate, glutamate, and butanoate processes in lung.

Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization.

BACKGROUND: N6-methyladenosine (m6A) has been identified to regulate the tumorigenesis and development of various tumors, including non-small cell lung cancer (NSCLC). Isoliquiritigenin (ISL), derived from the Chinese herb licorice, shows a significant anti-tumor activity on multiple human cancers. However, the role of ISL on NSCLC through m6A is still unclear. PURPOSE: Here, we investigated the anti-tumor effect of ISL on NSCLC, and explored whether ISL affected the NSCLC phenotype by modulating its m6A modification. METHODS: Cell proliferation, migration and invasion assays were performed to evaluate the inhibitory effects of ISL on NSCLC cells. M6A enrichment was determined by m6A quantitative analysis. The mechanism regarding IGF2BP3 was explored using RIP-PCR, MeRIP-qPCR and RNA decay analysis. RESULTS: ISL significantly repressed the proliferation, migration and invasion of NSCLC cells in vitro. In addition, m6A reader IGF2BP3 expression significantly increased in NSCLC tissues compared to adjacent tissues, and was positively correlated with NSCLC patients' poor survival. Mechanistically, ISL reduced m6A modification and down-regulated IGF2BP3 expression in NSCLC. Furthermore, IGF2BP3 enhanced the mRNA stability of twist family bHLH transcription factor 1 (TWIST1) in m6A-dependent manner. Moreover, ISL treatment combined with TWSIT1 knockdown effectively reversed IGF2BP3 overexpression-induced NSCLC cells' proliferation, migration and invasion. CONCLUSION: Our findings uncover that ISL might function as an anticarcinogen through targeting IGF2BP3/m6A/TWIST1 axis for NSCLC.

Incidence rates and predictors of stomal-related complications: a 1-year prospective study.

BACKGROUND: Stomal-related complications (SRCs) increase the health care burden and impair quality of life. PURPOSE: To determine the incidence rates and predictors of stomal and peristomal complications (SCs and PCs, respectively). METHODS: This was a prospective cohort study. In total, 215 patients who had undergone ostomy were enrolled and followed-up at 3, 30, 90, 180, and 360 days after surgery. During the follow-up period, SRCs were assessed by 1 colorectal surgeon and 2 wound, ostomy, and continence nurses. The SRCs were classified into SCs and PCs. RESULTS: SRCs were observed in 105 patients (48.8%). The 105 patients had 145 SRCs (66 [45.5%] SCs and 79 [54.5%] PCs). A logistic regression analysis revealed that emergency surgery (odds ratio [OR]: 2.78; P = .041), laparoscopic surgery (OR: 2.91; P = .023), and inappropriate stomal location (OR: 19.23; P < .001) were significant predictors of SCs. Inappropriate stomal location also was significantly associated with PCs (OR: 7.70; P < .001). The cumulative incidence rate of SRCs was 73% in patients who underwent stomal surgery and were followed for 360 days. CONCLUSIONS: Stomas created through emergency or laparoscopic surgery and those created at inappropriate sites were associated with a higher risk of SCs. Inappropriate stomal site was found to be a significant predictor for SCs and PCs.

DNA-free CRISPR-Cas9 gene editing of wild tetraploid tomato Solanum peruvianum using protoplast regeneration.

Wild tomatoes (Solanum peruvianum) are important genomic resources for tomato research and breeding. Development of a foreign DNA-free clustered regularly interspaced short palindromic repeat (CRISPR)-Cas delivery system has potential to mitigate public concern about genetically modified organisms. Here, we established a DNA-free CRISPR-Cas9 genome editing system based on an optimized protoplast regeneration protocol of S. peruvianum, an important resource for tomato introgression breeding. We generated mutants for genes involved in small interfering RNAs biogenesis, RNA-DEPENDENT RNA POLYMERASE 6 (SpRDR6), and SUPPRESSOR OF GENE SILENCING 3 (SpSGS3); pathogen-related peptide precursors, PATHOGENESIS-RELATED PROTEIN-1 (SpPR-1) and PROSYSTEMIN (SpProSys); and fungal resistance (MILDEW RESISTANT LOCUS O, SpMlo1) using diploid or tetraploid protoplasts derived from in vitro-grown shoots. The ploidy level of these regenerants was not affected by PEG-Ca2+-mediated transfection, CRISPR reagents, or the target genes. By karyotyping and whole genome sequencing analysis, we confirmed that CRISPR-Cas9 editing did not introduce chromosomal changes or unintended genome editing sites. All mutated genes in both diploid and tetraploid regenerants were heritable in the next generation. spsgs3 null T0 regenerants and sprdr6 null T1 progeny had wiry, sterile phenotypes in both diploid and tetraploid lines. The sterility of the spsgs3 null mutant was partially rescued, and fruits were obtained by grafting to wild-type (WT) stock and pollination with WT pollen. The resulting seeds contained the mutated alleles. Tomato yellow leaf curl virus proliferated at higher levels in spsgs3 and sprdr6 mutants than in the WT. Therefore, this protoplast regeneration technique should greatly facilitate tomato polyploidization and enable the use of CRISPR-Cas for S. peruvianum domestication and tomato breeding.

Aggregation-Enhanced Sonodynamic Activity of Phthalocyanine-Artesunate Conjugates.

The clinical prospect of sonodynamic therapy (SDT) has not been fully realized due to the scarcity of efficient sonosensitizers. Herein, we designed phthalocyanine-artesunate conjugates (e.g. ZnPcT4 A), which could generate up to ca. 10-fold more reactive oxygen species (ROS) than the known sonosensitizer protoporphyrin IX. Meanwhile, an interesting and significant finding of aggregation-enhanced sonodynamic activity (AESA) was observed for the first time. ZnPcT4 A showed about 60-fold higher sonodynamic ROS generation in the aggregated form than in the disaggregated form in aqueous solutions. That could be attributed to the boosted ultrasonic cavitation of nanostructures. The level of the AESA effect depended on the aggregation ability of sonosensitizer molecules and the particle size of their aggregates. Moreover, biological studies demonstrated that ZnPcT4 A had high anticancer activities and biosafety. This study thus opens up a new avenue the development of efficient organic sonosensitizers.

Sonneratia apetala seed oil attenuates potassium oxonate/hypoxanthine-induced hyperuricemia and renal injury in mice.

Sonneratia apetala seeds are considered as prospective nutraceuticals with a high content of unsaturated fatty acids (UFAs) which are mainly distributed in the oil. It is well-known that UFAs could exhibit urate-lowering potency and protect against renal injury, indicating that S. apetala seed oil (SSO) may possess hypouricemic and nephroprotective effects. Consequently, the present work attempted to probe into the effects and mechanisms of SSO on potassium oxonate/hypoxanthine-induced hyperuricemia and associated renal injury. The results indicated that SSO treatment prominently inhibited the increase of serum uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) levels and hepatic xanthine oxidase (XOD) activity in hyperuricemia mice. Kidney indexes and histopathological lesions were also remarkably ameliorated. Additionally, SSO treatment improved the renal anti-oxidant status in hyperuricemia mice by significantly reversing the increase in ROS and MDA levels as well as the decline in SOD, CAT and GSH-Px activities. SSO dramatically downregulated the expression and secretion of pro-inflammatory factors involving MCP-1, IL-1ß, IL-6, IL-18 and TNF-α elicited by hyperuricemia. Furthermore, after SSO treatment, increased protein expressions of GLUT9, URAT1 and OAT1 in the hyperuricemia mice were obviously reversed. SSO treatment enormously restored Nrf2 activation and subsequent translation of related anti-oxidative enzymes in the kidneys. TXNIP/NLRP3 inflammasome activation was also obviously suppressed by SSO. In conclusion, SSO exerted favorable hypouricemic effects owing to its dual functions of downregulating the XOD activity and modulating the expressions of renal urate transport-associated proteins, and it also could alleviate hyperuricemia-induced renal injury by restoring the Keap1-Nrf2 pathway and blocking the TXNIP/NLRP3 inflammasome activation.

The Extract of Sonneratia apetala Leaves and Branches Ameliorates Hyperuricemia in Mice by Regulating Renal Uric Acid Transporters and Suppressing the Activation of the JAK/STAT Signaling Pathway.

Sonneratia apetala Buch-Ham., an exotic mangrove species with antidiabetic, antibacterial, and antioxidant capacities, mainly distributes in the southeast coastal areas in China. The present work investigated the protective effects of Sonneratia apetala leaves and branches extraction (SAL) on hyperuricemia (HUA) in mice. Potassium oxonate (PO) and hypoxanthine (HX) were used to establish the HUA model by challenge for consecutive 7 days. Results revealed that SAL inhibited the increases in kidney weight and index compared to the vehicle group. Meanwhile, SAL significantly decreased the levels of uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) in serum. Additionally, SAL inhibited the activity of xanthine oxidase (XOD) in the liver. SAL ameliorated PO- and HX-induced histopathological changes. Moreover, it regulated oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content. Also, SAL inhibited the increases in renal levels of interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1ß (IL-1ß), tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), and transforming growth factor-ß (TGF-ß). SAL remarkably reduced suppressor of cytokine signaling 3 (SOCS3), Janus kinase 2 (JAK2), and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) expression. In addition, SAL inhibited the activation of nuclear factor kappa-B (NF-κB) in the kidney. Furthermore, SAL protected against HUA by regulating renal UA transporters of organic anion transporter (OAT1), urate reabsorption transporter 1 (URAT1), and glucose transporter 9 (GLUT9). These findings suggested that SAL ameliorated HUA by inhibiting the production of uric acid and enhancing renal urate excretion, which are related to oxidative stress and inflammation, and the possible molecular mechanisms include its ability to inhibit the JAK/STAT signaling pathway. Thus, SAL might be developed into a promising agent for HUA treatments.

CRISPR/Cas12a-mediated liposome-amplified strategy for the photoelectrochemical detection of nucleic acid.

This study reports a photoelectrochemical biosensor for dopamine-loaded liposome-encoded magnetic beads cleaved by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas 12a system for the quantification of human papilloma virus (HPV)-related DNA using neodymium-doped BiOBr nanosheets (Nd-BiOBr) as a photoactive matrix. Magnetic beads and dopamine-loaded liposomes are covalently attached to the both ends of ssDNA to construct dumbbell-shaped dopamine-loaded liposome-encoded magnetic bead (DLL-MB) probes. When the guide RNA binds to the target HPV-16, the ssDNA will be cleaved by Cas12a, thereby degrading the double dumbbell probes. After magnetic separation, the dissolved DLLs are treated with Triton X-100 to release the dopamine (as an electron donor), which was then detected by an amplified photocurrent using the Nd-BiOBr-based photoelectrode.

Application of an indocyanine green-mediated fluorescence imaging navigation system in detecting mice tumors.

BACKGROUND: Surgical operation plays an important role in the treatment of cancer. The success of the operation lies in the complete removal of the primary and disseminated tumor tissue while preserving the normal tissue. The development of optical molecular image navigation technology has provided a new option for intraoperative tumor visualization. In this study, a fluorescence imaging navigation system was used to detect the diameter of mice tumors and provide experimental evidence for the further development of digital diagnosis and treatment equipment. METHODS: The minimum detection concentration in vitro of the fluorescence imaging navigation system for indocyanine green (ICG) was first detected, then 120 female Institute of Cancer Research (ICR) mice and 120 female BALB/c nude mice were randomly divided into three groups by weight, high-dose (H, 4 mg/kg), middle-dose (M, 2 mg/kg), and low-dose (L, 1 mg/kg) groups of ICG solution. After inoculating solid tumors, high, medium, and low doses of ICG were injected via the tail vein, and the tumor diameter was measured by a fluorescence imaging navigation system and vernier caliper within 24 hours of injection. RESULTS: The minimum detectable diameter of the system could reach 0.2 mm compared with the vernier caliper, and the actual measurement error was within 0.2 mm. CONCLUSIONS: A fluorescence imaging navigation system has high accuracy and sensitivity in the application of tumor detection, which may assist the clinical diagnosis and treatment of tumors.

Bidentatide, a Novel Plant Peptide Derived from Achyranthes bidentata Blume: Isolation, Characterization, and Neuroprotection through Inhibition of NR2B-Containing NMDA Receptors.

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.