Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

The incomplete degradation of tumour cells by macrophages (Mϕ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mϕ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mϕ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mϕ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mϕ phagosomes, causing Mϕ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mϕ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mϕ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mϕ to degrade tumour cells by suppressing NOX2.

The disorder of group 3 innate lymphoid cells(ILC3)subgroup,such as the predominance of NCR-ILC3 but the deple-tion of NCR+ILC3,is unfavorable to damaged intestinal barrier repair,which leads to the prolongations and obstinacy of ulcerative colitis(UC).Our previous studies had shown that luteolin promoted NCRILC3 differentitating into NCR+ILC3 to improving the de-pletion of NCR+ILC3 in UC mice,while the mechanism is unclear.This article aimed to explore the underlying mechanism of luteolin enhancing the proportion NCR+ILC3.UC mice model was established with 2％DSS and Notch signaling was blocked,then luteolin was used to intervene.The results showed that the effect of luteolin on ameliorating disease symptoms in UC mice,including inhibit-ing the weight loss,reducing the pathological damage of colon mucosa,etc.,was diminished with blocking Notch signaling pathway.In addition,luteolin increased the proportion of NCR+ILC3,NCR+MNK3 and IL-22+ILC3,decreased intestinal permeability,pro-moted mucin secretion,and promoted ZO-1 and Occludin expression,the above effect of luteolin was neutralized by Notch inhibitor LY-411575.Luteolin activated the abnormally blocked Notch signaling pathway in UC mice.And molecular docking predicted the af-finity of luteolin for RBPJ to be-7.5 kcal·mol-1 in mouse,respectively;the affinity of luteolin for Notchl and RBPJ was respectively scored to be-6.4 kcal·mol-1 and-7.7 kcal·mol-1 homo sapiens.These results proved that luteolin is positive for enhancing the propor-tion of NCR+ILC3 via Notch signaling,and it provides a basis for targeting NCR+ILC3 for restoring intestinal barrier function to alle-viating ulcerative colitis.

Diabetic nephropathy (DN) is a clinical syndrome characterized by persistent proteinuria and progressive decline in renal function, and is one of the microvascular complications of diabetes. With the in-depth understanding of the pathogenesis of DN, the role of intestinal flora imbalance in the disease has been found clinically. This suggests that restoring the host′s healthy gut flora may be a means of improving DN. In fact, recent studies have shown that many of the drugs currently used to treat DN affect gut microbiota composition. In this review, intestinal flora is regarded as one of the main factors affecting the development of DN, and DN therapy targeting intestinal flora is summarized to provide new ideas for the diagnosis and treatment of DN.

Inhibiting the death receptor 3(DR3)signaling pathway in group 3 innate lymphoid cells(ILC3s)pre-sents a promising approach for promoting mucosal repair in individuals with ulcerative colitis(UC).Paeoniflorin,a prominent component of Paeonia lactiflora Pall.,has demonstrated the ability to restore barrier function in UC mice,but the precise mechanism remains unclear.In this study,we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s.C57BL/6 mice were subjected to random allocation into 7 distinct groups,namely the control group,the 2％dextran sodium sulfate(DSS)group,the paeoniflorin groups(25,50,and 100 mg/kg),the anti-tumor necrosis factor-like ligand 1A(anti-TL1A)antibody group,and the IgG group.We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using Western blot and flow cytometry,respectively.Meanwhile,DR3-overexpressing MNK-3 cells and 2％ DSS-induced Rag1-/-mice were used for verification.The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier.Simultaneously,paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines(interleukin-17A,granulocyte-macrophage colony stimulating factor,and interleukin-22).Alternatively,paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage indepen-dently of the adaptive immune system.We additionally confirmed that paeoniflorin-conditioned me-dium(CM)restored the expression of tight junctions in Caco-2 cells via coculture.In conclusion,paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner,and its mechanism is associated with the inhibition of the DR3 signaling pathway.

OBJECTIVE: To quantitatively assess cardiac functions in patients with cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) using cardiac magnetic resonance-feature tracking (CMR-FT) technique and evaluate the prognostic value of CMR-FT in patients with CA. METHODS: We retrospectively collected the data from 31 CA patients with systemic amyloidosis confirmed by Congo red staining and serum immunohistochemistry after extracardiac tissue biopsy undergoing CMR at our hospital from March, 2013 to June, 2021.Thirty-one age and gender matched patients with asymmetric left ventricular wall hypertrophy and 31 healthy individuals without organic or functional heart disease served as the controls.Radial, circumferential and longitudinal strains and strain rates of the left ventricle at the global level and in each myocardial segment (basal, middle and apical) were obtained with CMR-FT technique and compared among the 3 groups.The predictive value of myocardial strains and strain rates for all-cause mortality in CA patients was analyzed using a stepwise COX regression model. RESULTS: The left ventricular volume, myocardial mass, ejection fraction and cardiac output differed significantly among the groups (P < 0.05).Except for apical longitudinal strain, the global and segmental strains were all significantly lower in CA group than in HCM group (P < 0.05).The global and segmental strains were all significantly lower in CA group than in the healthy individuals (P < 0.05).The basal strain rates in the 3 directions were significantly lower in CA group than in the healthy individuals (P < 0.05), but the difference in apical strain rates was not statistically significant between the two groups.Multivariate stepwise COX analysis showed that troponin T (HR=1.05, 95%CI: 1.01-1.10, P=0.017) and middle peak diastolic circumferential strain rate (HR=6.87, 95%CI: 1.52-31.06, P=0.012) were strong predictors of death in CA patients. CONCLUSION Strain and strain rate parameters derived from CMR-FT based on cine sequences are new noninvasive imaging markers for assessing cardiac impairment in CA and cardiac function changes in HCM, and provide independent predictive information for all-cause mortality in CA patients.
Humans ; Retrospective Studies ; Magnetic Resonance Imaging, Cine/methods* ; Cardiomyopathy, Hypertrophic/diagnostic imaging* ; Ventricular Function, Left ; Stroke Volume ; Amyloidosis/diagnostic imaging* ; Magnetic Resonance Spectroscopy ; Prognosis ; Predictive Value of Tests

Objective: To investigate the expression level of antisense transcript of pseudogene, general transcription factor Ⅱi psedugen23 (GTF2IP23), in breast cancer and its effect on the host gene general transcription factor Ⅱi (GTF2I). Methods: The expressions of GTF2IP23 and GTF2I were detected in 40 cases of invasive breast cancer tumors and their counterparts by using quantitative real-time polymerase chain reaction (qRT-PCR). The effects of GTF2IP23 on the expression of GTF2I gene and cell proliferation and migration were analyzed by overexpression of GTF2IP23 in breast cancer cells. Results: The expression of GTF2IP23 mRNA in breast cancer tissues was significantly higher than that in adjacent tissues (P<0.001), while the expression of GTF2I mRNA was significantly lower than that in adjacent tissues (P=0.007). The expression of GTF2IP23 was negatively correlated with GTF2I (r=-0.335, P=0.025). The expression of GTF2IP23 in breast cancer cells was significantly higher than in normal breast cells (P<0.01), while GTF2I expression in breast cancer cells was significantly lower than that in normal breast cells (P<0.01). Overexpression of GTF2IP23 in ZR-75-30 cells significantly reduced the expression of GTF2I (P=0.034) and enhanced cell proliferation (P=0.017) and migration (P=0.026) capacity. Conclusions GTF2IP23 is distinctly upregulated in breast cancer, it inhibits the expression of real gene GTF2I and promotes the proliferation of breast cancer cells.

Objective To investigate the expression level of antisense transcript of pseudogene, general transcription factor Ⅱi psedugen23 ( GTF2IP23), in breast cancer and its effect on the host gene general transcription factorⅡi (GTF2I).Methods The expressions of GTF2IP23 and GTF2I were detected in 40 cases of invasive breast cancer tumors and their counterparts by using quantitative real?time polymerase chain reaction (qRT?PCR).The effects of GTF2IP23 on the expression of GTF2I gene and cell proliferation and migration were analyzed by overexpression of GTF2IP23 in breast cancer cells. Results The expression of GTF2IP23 mRNA in breast cancer tissues was significantly higher than that in adjacent tissues ( P＜0.001), while the expression of GTF2I mRNA was significantly lower than that in adjacent tissues ( P＝0.007). The expression of GTF2IP23 was negatively correlated with GTF2I ( r＝－0.335, P＝0.025).The expression of GTF2IP23 in breast cancer cells was significantly higher than in normal breast cells ( P＜0.01), while GTF2I expression in breast cancer cells was significantly lower than that in normal breast cells (P＜0.01). Overexpression of GTF2IP23 in ZR?75?30 cells significantly reduced the expression of GTF2I (P＝0.034) and enhanced cell proliferation (P＝0.017) and migration (P＝0.026) capacity. Conclusions GTF2IP23 is distinctly upregulated in breast cancer, it inhibits the expression of real gene GTF2I and promotes the proliferation of breast cancer cells.

Objective To investigate the expression level of antisense transcript of pseudogene, general transcription factor Ⅱi psedugen23 ( GTF2IP23), in breast cancer and its effect on the host gene general transcription factorⅡi (GTF2I).Methods The expressions of GTF2IP23 and GTF2I were detected in 40 cases of invasive breast cancer tumors and their counterparts by using quantitative real?time polymerase chain reaction (qRT?PCR).The effects of GTF2IP23 on the expression of GTF2I gene and cell proliferation and migration were analyzed by overexpression of GTF2IP23 in breast cancer cells. Results The expression of GTF2IP23 mRNA in breast cancer tissues was significantly higher than that in adjacent tissues ( P＜0.001), while the expression of GTF2I mRNA was significantly lower than that in adjacent tissues ( P＝0.007). The expression of GTF2IP23 was negatively correlated with GTF2I ( r＝－0.335, P＝0.025).The expression of GTF2IP23 in breast cancer cells was significantly higher than in normal breast cells ( P＜0.01), while GTF2I expression in breast cancer cells was significantly lower than that in normal breast cells (P＜0.01). Overexpression of GTF2IP23 in ZR?75?30 cells significantly reduced the expression of GTF2I (P＝0.034) and enhanced cell proliferation (P＝0.017) and migration (P＝0.026) capacity. Conclusions GTF2IP23 is distinctly upregulated in breast cancer, it inhibits the expression of real gene GTF2I and promotes the proliferation of breast cancer cells.

Objective:Through detecting miRNA-26a,β-catenin,GSK-3β and α-SMA expressions in IgA nephropathy with varying degrees of renal interstitial fibrosis,the study was performed to explore the effect of miRNA-26a targeting GSK-3β on Wnt/β-catenin signal pathway simulated renal interstitial fibrosis.Methods:Incorporated 46 cases of IgA nephropathy patients were divided into three group based on the degree of renal interstitial fibrosis,namely,mild group,moderate group and severe group;7 cases of normal renal tissues away from the renal tumor tissues were selected as the control group.Expression levels of miRNA-26a in renal tissues of each group were detected based on RT-qPCR method,to analyze the correlation between miRNA-26a and renal fibrosis In patients with IgA nephropathy.Furthermore,mRNA and protein expression levels of β-catenin,GSK-3β and α-SMA in renal tissues were measured using RT-qPCR and immunohistochemistry,respectively,the comparison was then made in each group;subsequently,correlation analysis was further conducted to investigate the relationship of miRNA-26a with β-catenin,GSK-3β and α-SMA.Results:(1) Compared with the control group,miRNA-26a expression was down-regulated from renal biopsy of IgA nephropathy patients,the expression level of miRNA-26a was significantly decreased,showing statistical differences among groups (P＜0.05).(2) Compared with the control group,mRNA and protein expression levels of β-catenin,GSK-3β and α-SMA in renal tissues were all increased in IgA nephropathy patients,and the degree of expression increased gradually with the increase of the degree of renal interstitial lesion,differences were statistically significant among groups (P＜0.05).(3) Correlation analysis results indicated that there were negative correlation between miRNA-26a expression in renal tissues and the degree of renal interstitial fibrosis,differences were statistically significant among groups (r=-0.943,P ＜0.05),at the same time,expression intensities of GSK-3β,β-catenin and α-SMA in renal interstitium and renal tubules were positively correlated with the degree of renal interstitial fibrosis(r =0.917,P＜0.05;r =0.943,P＜0.05;r =0.926,P ＜0.05),meanwhile,positive correlation was also found regarding protein expression of GSK-3β and β-catenin in renal interstitium (r=0.834,P＜0.05).Conclusion:Collectively,miRNA-26a can be involved in Wnt/β-catenin signal pathway simulated renal interstitial fibrosis via the regulation of GSK-3β.