Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Involvement of transverse mesocolon is associated with development of colonic fistula in patients with acute necrotizing pancreatitis.

BACKGROUND: Involvement of transverse mesocolon (TM) during acute necrotizing pancreatitis(ANP) indicates that inflammation has spread from retroperitoneal space to peritoneum. Nevertheless, the impact of TM involvement, as confirmed by contrast-enhanced computed tomography (CECT), on local complications and clinical outcomes was poorly investigated. PURPOSE: This study aimed to explore the association between CECT-diagnosed TM involvement and the development of colonic fistula in a cohort of ANP patients. METHODS: This is a single-center, retrospective cohort study involving ANP patients admitted from January 2020 to December 2020. TM involvement was diagnosed by two experienced radiologists. The study subjects were enrolled consecutively and divided into two groups: TM involvement and non-TM involvement. The primary outcome was colonic fistula during the index admission. Clinical outcomes were compared between the two groups, and the association between the TM involvement and the development of colonic fistula was assessed using multivariable analysis to adjust for baseline unbalances. RESULTS: A total of 180 patients with ANP were enrolled, and 86 (47.8%) patients had TM involvement. The incidence of the colonic fistula is significantly higher in patients with TM involvement (16.3% vs. 5.3%;p = 0.017). Moreover, the length of hospital stay was 24(13,68) days in patients with TM involvement and 15(7,31) days in those not (p = 0.001). Analysis of multivariable logistic regression revealed that TM involvement is an independent risk factor for the development of colonic fistula (odds ratio: 10.253, 95% CI: 2.206-47.650, p = 0.003). CONCLUSION: TM involvement in ANP patients is associated with development of colonic fistula in ANP patients.

Bis-triazole-containing Compounds with Anticancer Potential: A Short Review.

The development of novel anticancer agents with high efficiency is of great importance due to the severe anticancer scenario of the currently used drugs. Dimerization is a useful method to develop new drug candidates with a broad biological spectrum, enhanced activity and potency to overcome drug resistance. A wide variety of bis-triazole-containing compounds have been developed with improved properties compared with their parent compounds. These derivatives could inhibit tumor proliferation, invasion and metastasis, revealing their potential as putative anticancer candidates. This review covers the recent advances of bis-triazole-containing compounds as anticancer candidates, and the structure-activity relationship are also discussed to set up the direction for the design and development of bis-triazole-containing compounds with higher efficiency.

Chalcone Derivatives and their Activities against Drug-resistant Cancers: An Overview.

Drug resistance, including multidrug resistance resulting from different defensive mechanisms in cancer cells, is the leading cause of the failure of the cancer therapy, posing an urgent need to develop more effective anticancer agents. Chalcones, widely distributed in nature, could act on diverse enzymes and receptors in cancer cells. Accordingly, chalcone derivatives possess potent activity against various cancers, including drug-resistant, even multidrug-resistant cancer. This review outlines the recent development of chalcone derivatives with potential activity against drug-resistant cancers covering articles published between 2010 and 2020 so as to facilitate further rational design of more effective candidates.

Nature-derived anticancer steroids outside cardica glycosides.

Steriods which are ubiquitous in natural resources are important components of cell membranes and involved in several physiological functions. Steriods not only exerted the anticancer activity through inhibition of various enzymes and receptors in cancer cells, inclusive of aromatase, sulfatase, 5α-reductase, hydroxysteroid dehydrogenase and CYP 17, but also exhibited potential activity against various cancer forms including multidrug-resistant cancer with low cytotoxicity, and high bioavailability. Accordingly, steroids are useful scaffolds for the discovery of novel anticancer agents. This review aims to outline the advances of nature-derived steroids outside cardica glycosides with anticancer potential, covering the articles published between Jan. 2015 and Aug. 2020.

Recent advances of podophyllotoxin/epipodophyllotoxin hybrids in anticancer activity, mode of action, and structure-activity relationship: An update (2010-2020).

Podophyllotoxins and epipodophyllotoxins, possess excellent activity against both drug-sensitive and drug-resistant even multidrug-resistant cancer cells via inhibition of tubulin polymerization. Several podophyllotoxin/epipodophyllotoxin derivatives such as etoposide and teniposide have already been applied for cancer therapy, revealing their potential as putative anticancer drugs. Hybridization of podophyllotoxin/epipodophyllotoxin moiety with other anticancer pharmacophores is a promising strategy to develop novel drug candidates so as to overcome drug resistance and improve the specificity, and numerous of podophyllotoxin/epipodophyllotoxin hybrids exhibit excellent in vitro antiproliferative and in vivo anticancer potency. This review emphasizes the recent development of podophyllotoxin/epipodophyllotoxin hybrids with potential application for cancer therapy covering articles published between 2010 and 2020. The mechanisms of action, the critical aspects of design as well as structure-activity relationships were also summarized.

Transplantation of human endometrial perivascular cells with elevated CYR61 expression induces angiogenesis and promotes repair of a full-thickness uterine injury in rat.

BACKGROUND: Disruptions of angiogenesis can have a significant effect on the healing of uterine scars. Human endometrial perivascular cells (CD146+PDGFRß+) function as stem cells in the endometrium. Cysteine-rich angiogenic inducer 61 (CYR61) plays an important role in vascular development. The purpose of this study was to observe the effects of the transplantation of human endometrial perivascular cells (En-PSCs) overexpressing CYR61 on structural and functional regeneration in rat models of partial full-thickness uterine excision. METHODS: We first sorted human En-PSCs from endometrial single-cell suspensions by flow cytometry. Human En-PSCs expressing low or high levels of CYR61 were then generated via transfection with a CYR61-specific small interfering ribonucleic acid (si-CYR61) construct or overexpression plasmid. To establish a rat model of uterine injury, a subset of uterine wall was then resected from each uterine horn in experimental animals. Female rats were randomly assigned to five groups, including a sham-operated group and four repair groups that received either PBS loaded on a collagen scaffold (collagen/PBS), En-PSCs loaded on a collagen scaffold (collagen/En-PSCs), En-PSCs with low CYR61 expression loaded on a collagen scaffold (collagen/si-CYR61 En-PSCs), and En-PSCs overexpressing CYR61 loaded on a collagen scaffold (collagen/ov-CYR61 En-PSCs). These indicated constructs were sutured in the injured uterine area to replace the excised segment. On days 30 and 90 after transplantation, a subset of rats in each group was sacrificed, and uterine tissue was recovered and serially sectioned. Hematoxylin and eosin staining and immunohistochemical staining were then performed. Finally, the remaining rats of each group were mated with fertile male rats on day 90 for a 2-week period. RESULTS: Sorted En-PSCs expressed all recognized markers of mesenchymal stem cells (MSCs), including CD10, CD13, CD44, CD73, CD90, and CD105, and exhibited differentiation potential toward adipocytes, osteoblasts, and neuron-like cells. Compared with En-PSCs and En-PSCs with low CYR61 expression, En-PSCs with elevated CYR61 expression enhanced angiogenesis by in vitro co-culture assays. At day 90 after transplantation, blood vessel density in the collagen/ov-CYR61 En-PSCs group (11.667 ± 1.287) was greater than that in the collagen/En-PSCs group (7.167 ± 0.672) (P < 0.05) and the collagen/si-CYR61 En-PSCs group (3.750 ± 0.906) (P < 0.0001). Pregnancy rates differed among groups, from 40% in the collagen/PBS group to 80% in the collagen/En-PSCs group, 12.5% in the collagen/si-CYR61 En-PSCs group, and 80% in the collagen/ov-CYR61 En-PSCs group. In addition, four embryos were evident in the injured uterine horns of the collagen/ov-CYR61 En-PSCs group, while no embryos were identified in the injured uterine horns of the collagen/PBS group. CONCLUSIONS: The results showed that CYR61 plays an important role in angiogenesis. Collagen/ov-CYR61 En-PSCs promoted endometrial and myometrial regeneration and induced neovascular regeneration in injured rat uteri. The pregnancy rate of rats treated with transplantation of collagen/En-PSCs or collagen/ov-CYR61 En-PSCs was improved. Moreover, the number of embryos implantation on the injured area in uterus was increased after transplantation of collagen/ov-CYR61 En-PSCs.

PITX2 enhances progression of lung adenocarcinoma by transcriptionally regulating WNT3A and activating Wnt/ß-catenin signaling pathway.

BACKGROUND: The homeodomain transcription factor, PITX2 is associated with tumorigenesis of multiple cancers. In this research, we aimed to study the expression, function and mechanism of PITX2 in lung adenocarcinoma (LUAD). METHODS: The TCGA dataset was used to analyze the expression and clinical significance of PITX2 in LUAD. The expression of PITX2 in tumor samples and LUAD cell lines was examined by quantitative real-time PCR (qRT-PCR) and western blotting. Small interfering RNAs (siRNAs) were constructed to knockdown PITX2 and to determine the physiological function of PITX2 in vitro. Xenograft model was used to confirm the role of PITX2 in vivo. RESULTS: PITX2 was overexpressed in LUAD and patients with high level of PITX2 had a worse overall survival and an advanced clinical stage. Knockdown of PITX2 inhibited cell proliferation, migration and invasion of LUAD cells. Further study revealed that the oncogenic role of PITX2 was dependent on activating Wnt/ß-catenin signaling pathway, especially by transcriptionally regulating the Wnt gene family member, WNT3A. Lastly, we identified miR-140-5p as a negative mediator of PITX2 by binding its 3'UTR and ectopic expression of miR-140-5p inhibited progression of LUAD cells via suppressing the expression of PITX2. CONCLUSIONS: Up-regulation of PITX2 acts as an oncogene in LUAD by activating Wnt/ß-catenin signaling pathway, suggesting that PITX2 may serve as a novel diagnostic and prognostic biomarker in LUAD.

Assessment of glioma response to radiotherapy using 3D pulsed-continuous arterial spin labeling and 3D segmented volume.

BACKGROUND: Gliomas are the most common primary brain tumors in adults, in some cases, radiotherapy may be the preferred treatment option especially for elderly people who cannot endure surgery. Therefore, it is necessary to evaluate the effects of radiotherapy on glioma. Arterial spin labeling (ASL) is an MR imaging technique that allows for a quantitative determination of cerebral blood flow (CBF) noninvasively. Tumor volume is still an important determinant for evaluating treatment response. The purpose of this study was to investigate the relationship between the tumor perfusion parameters and tumor volume and assess the effects of radiotherapy on glioma using pulsed-continuous arterial spin labeling (pcASL) technique. METHODS: 35 patients with gliomas, histologically classified as low-grade group (n=16) and high-grade group (n=19), treated with radiotherapy only or before using other therapies were included in this study. MR examinations, including T1 weighted image and pcASL, were performed before and 4, 8, 12, 16 weeks after radiotherapy. Regional CBF of normal tissue, mean tumor blood flow (TBFmean), maximum tumor blood flow (TBFmax), and tumor volume were evaluated at each time point. Both the percentage change in CBF (CBF ratio), TBFmean (TBFmean ratio), TBFmax (TBFmax ratio) and the percentage change in tumor volume (volume ratio) were calculated using values obtained before and after radiotherapy. The correlation between the volume ratio and CBF ratio, TBFmean ratio, TBFmax ratio was assessed using linear regression analysis and Pearson's correlation. RESULTS: The TBFmean and TBFmax of high-grade gliomas were significantly higher than that of low-grade group. In high-grade group, a strong correlation was demonstrated between the tumor volume and the TBFmax before radiotherapy (R2=0.35, rs=0.59, p<0.05). There was also a significant correlation between the TBFmax before radiotherapy and the tumor volume ratio before and 8 weeks after radiotherapy (R2=0.56, rs=-0.74, p<0.05). CONCLUSION: The TBFmax measured using pcASL could assess tumoral grade and also could become a potential tool for evaluating the therapeutic effects of radiation.

Esophagectomy combined with aortic segment replacement for esophageal cancer invading the aorta.

BACKGROUND: Surgical treatment for patients with esophageal carcinoma that invades the aorta locally (stage IIIc) remains a considerable challenge. This study aimed to introduce radical esophagectomy combined with off-pump descending aorta replacement in these patients and to assess the effects on both short-term and long-term outcomes. METHODS: The clinical data of 47 patients who had esophageal carcinoma invading the descending aorta and who underwent radical esophagectomy combined with off-pump aortic replacement between January 2001 and March 2012 in Jinling Hospital were retrospectively reviewed. The intraoperative, early postoperative, and follow-up results were analyzed. RESULTS: Overall, 80.9% and 19.1% of the patients had histopathologically confirmed aortic tunica adventitia invasion and media invasion, respectively. All patients received complete resection (R0) with an average intraoperative blood loss of 227.6±63.3 mL. The mean operative time and aortic cross-clamping time were 4.9±1.3 hours and 17.0±3.2 minutes, respectively. Complications were observed in 59.6% of patients, with no hospital mortality, and all patients resumed an oral diet 1 month after the procedure. The overall 1-, 3-, and 5-year survival rates were 80.9%, 44.7%, and 21.3%, respectively, with a median survival time of 33.6 months. CONCLUSIONS: In patients with esophageal carcinoma invading the aorta, it is feasible and safe to perform radical esophagectomy combined with off-pump descending aorta replacement to improve nutritional status and achieve satisfactory survival.