Indole-3-carbinol ameliorates ovarian damage in female old mice through Nrf2/HO-1 pathway activation.

Ovarian aging leads to infertility and birth defects. We aimed to clarify the role of Indole-3-carbinol (I3C) in resistance to oxidative stress, apoptosis, and fibrosis in ovarian aging. I3C was administered via intraperitoneal injection for 3 weeks in young or old mice. Immunohistochemistry; Masson, Sirius red, and TUNEL staining; follicle counting; estrous cycle analysis; and Western blotting were used for validating the protective effect of I3C against ovarian senescence. Human granulosa-like tumor cell line and primary granulosa cells were used for in vitro assay. The results indicated that I3C inhibited ovarian fibrosis and apoptosis while increasing the number of primordial follicles. Mechanistic studies have shown that I3C promoted the nuclear translocation of nuclear factor-erythroid 2-related factor (Nrf2) and upregulated the expression of heme oxygenase 1 (HO-1). Additionally, I3C increased cell viability and decreased lactate dehydrogenase, malondialdehyde, reactive oxygen species and JC-1 levels. Furthermore, the antioxidant effect of I3C was found to be dependent on the activation of Nrf2 and HO-1, as demonstrated by the disappearance of the effect upon inhibition of Nrf2 expression. In conclusion, I3C can alleviate the ovarian damage caused by aging and may be a protective agent to delay ovarian aging.

A new phenolic compound from Persicaria capitata.

Persicaria capitata was a frequently used Hmong medicinal flora in China. In this study, one new phenolic compound, capitaone A (1) together with 20 known ones, were isolated from the whole herb of P. capitata. Among them, 7 components (4, 9-11, 15-16, 20-21) were discovered from P. capitata for the first time. Their chemical structures were elucidated on the basis of extensive NMR and MS spectrum. Furthermore, three compounds (15, 20, 21) displayed remarkable cytotoxic activities against two human cancer cell lines (A549 and HepG2).

Genomic and transcriptomic studies on flavonoid biosynthesis in Lagerstroemia indica.

BACKGROUND: Lagerstroemia indica is a widely cultivated ornamental woody shrub/tree of the family Lythraceae that is used as a traditional medicinal plant in East Asia and Egypt. However, unlike other ornamental woody plants, its genome is not well-investigated, which hindered the discovery of the key genes that regulate important traits and the synthesis of bioactive compounds. RESULTS: In this study, the genomic sequences of L. indica were determined using several next-generation sequencing technologies. Altogether, 324.01 Mb sequences were assembled and 98.21% (318.21 Mb) of them were placed in 24 pseudo-chromosomes. The heterozygosity, repeated sequences, and GC residues occupied 1.65%, 29.17%, and 38.64% of the genome, respectively. In addition, 28,811 protein-coding gene models, 327 miRNAs, 552 tRNAs, 214 rRNAs, and 607 snRNAs were identified. The intra- and interspecies synteny and Ks analysis revealed that L. indica exhibits a hexaploidy. The co-expression profiles of the genes involved in the phenylpropanoid (PA) and flavonoid/anthocyanin (ABGs) pathways with the R2R3 MYB genes (137 members) showed that ten R2R3 MYB genes positively regulate flavonoid/anthocyanin biosynthesis. The colors of flowers with white, purple (PB), and deep purplish pink (DPB) petals were found to be determined by the levels of delphinidin-based (Dp) derivatives. However, the substrate specificities of LiDFR and LiOMT probably resulted in the different compositions of flavonoid/anthocyanin. In L. indica, two LiTTG1s (LiTTG1-1 and LiTTG1-2) were found to be the homologs of AtTTG1 (WD40). LiTTG1-1 was found to repress anthocyanin biosynthesis using the tobacco transient transfection assay. CONCLUSIONS: This study showed that the ancestor L. indica experienced genome triplication approximately 38.5 million years ago and that LiTTG1-1 represses anthocyanin biosynthesis. Furthermore, several genes such as LiDFR, LiOMTs, and R2R3 LiMYBs are related to anthocyanin biosynthesis. Further studies are required to clarify the mechanisms and alleles responsible for flower color development.

Clinicopathological Characteristics, Treatment and Prognosis in Duodenal Adenocarcinoma with Liver Metastasis: A SEER-Based Study.

Background and Objectives: Duodenal adenocarcinoma (DAC) is a rare tumor that is often accompanied by liver metastasis in advanced stages. The aim of this study was to evaluate the correlation between clinicopathological characteristics and survival in DAC patients with liver metastasis, and to explore appropriate treatment options. Methods: 482 DAC patients with liver metastasis were retrospectively identified from the Surveillance, Epidemiology and End Results (SEER) database (2011-2020). Univariate and multivariate Cox regression analyses were performed to explore the clinicopathological factors related to survival. The Kaplan-Meier method was used to identify the independent risk factors associated with survival. Results: The 1-year overall survival (OS) and cancer-specific survival (CSS) rates for the entire cohort were 25.4% and 28.3%, and the 5-year OS and CSS rates were 2.4% and 2.9% respectively. Univariable analysis and multivariate analysis identified chemotherapy and surgery as the independent risk factors for OS and CSS. Patients who underwent chemotherapy and surgery had better CSS and OS rates, whereas radiotherapy failed to improve outcomes. Conclusion: We identified several prognostic factors of DAC with liver metastasis. Chemotherapy and surgery can prolong the survival of DAC patients with liver metastasis, which lays the foundation for identifying the optimal treatment strategy.

Effectiveness of general anaesthesia with remimazolam tosilate on intraoperative haemodynamics and postoperative recovery: study protocol for a randomised, positive-controlled, pragmatic clinical trial (GARTH trial).

INTRODUCTION: It is encouraged to estimate the effectiveness of components within the enhanced recovery after surgery (ERAS) protocol through patient-reported outcomes, alongside doctor-reported outcomes and length of hospital stay. At present, studies on the contributions of optimal anaesthetic drugs within the ERAS protocol to patient-reported and doctor-reported outcomes are limited. Therefore, this study aims to pragmatically evaluate the effectiveness and safety of general anaesthesia (GA) with remimazolam tosilate within the ERAS protocol on intraoperative haemodynamics and postoperative recovery in adults undergoing elective surgeries, compared with propofol. METHODS AND ANALYSIS: This study is a single-centre, randomised, blinded, positive-controlled, pragmatic clinical trial. A total of 900 patients, aged ≥18 years old, scheduled for an elective surgical procedure under GA will be included. Patients will be randomised in a 1:1 ratio to the remimazolam group (the GA with remimazolam tosilate within the ERAS protocol group) or propofol group (the GA with propofol within the ERAS protocol group), stratified by general surgery, thoracic surgery and other surgeries (including urological surgery and otolaryngology surgery). The primary outcomes include the 24-hour postoperative quality of recovery-40 score and the rate of intraoperative hypotension. Secondary endpoints include the rate of sedative hypotension requiring treatment, the haemodynamic profiles, the 72-hour postoperative quality of recovery-40 score, the functional anaesthetic capability, adverse events and complications, quality of life within 3 months as well as economic health outcomes. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committee of Guangdong Provincial People's Hospital (KY-H-2022-005-03-08). Dissemination plans will be presented at scientific meetings and in scientific publications. TRIAL REGISTRATION NUMBER: ChiCTR2200062520.

Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury.

Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.

Crosstalk of cuproptosis-related prognostic signature and competing endogenous RNAs regulation in hepatocellular carcinoma.

BACKGROUND: Cuproptosis is a new type of programmed cell death involved in the regulation of neuroendocrine tumors, immune microenvironment, and substance metabolism. However, the role of cuproptosis-related genes (CRGs) in Hepatocellular carcinoma (HCC) remains unclear. METHOD: Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA (ceRNA) network. The correlation between CRGs and prognosis, immune infiltration, immune checkpoints, microsatellite instability (MSI) and tumor mutational burden (TMB) was analyzed by Kaplan-Meier curve, univariate Cox, multivariate regression, and Spearman's analysis in HCC patients. Besides, the qRT-PCR and immunohistochemistry assays were used to determine prognostic CRGs mRNA and protein expression in HCC. RESULTS: We established a novel 3-gene signature related to CRGs for evaluating the prognosis of HCC patients. HCC patients with high risk scores had a poor prognosis with an area under the curve of 0.737, 0.646, and 0.634 on 1-year, 3-year, and 5-year receiver operating characteristic curves. Significant correlation was observed between prognostic CRGs and immune infiltration, immune checkpoints, MSI and TMB. We also developed five ceRNA networks to regulate the occurrence and progression of HCC. CDKN2A, DLAT, and PDHA1 protein expression was up-regulated in HCC versus normal tissues. Besides, the mRNA expression levels of CDKN2A, DLAT, GLS, and PDHA1 were elevated in the HCC cell lines compared to the normal liver cell lines. CONCLUSIONS: This novel prognostic CRGs signature could be accurately predict the prognosis of patients with HCC. The ceRNA regulatory network might be potential prognostic biomarkers and therapeutic targets for HCC patients.

Tamoxifen induces ferroptosis in MCF-7 organoid.

BACKGROUND: Breast cancer is the most common female malignant tumor type globally. The occurrence and development of breast cancer involve ferroptosis, which is closely related to its treatment. The development of breast cancer organoids facilitates the analysis of breast cancer molecular background and tumor biological behavior, including clinical pathological characteristics, drug response, or drug resistance relationship, and promotes the advancement of precision treatment for breast cancer. The three-dimensional (3D) cell culture of breast cancer MCF-7 organoid is more similar to the in vivo environment and thus obtains more realistic results than 2D cell culture. Our study examined the new mechanism of tamoxifen in treating breast cancer through breast cancer MCF-7 organoids. METHODS: We used 3D cells to culture breast cancer MCF-7 organoid, as well as tamoxifen-treated MCF-7 and tamoxifen-resistant MCF-7 (MCF-7 TAMR) cells. We used transcriptome sequencing. We detected GPX4 and SLC7A11 protein levels using Western blotting and the content of ATP, glutathione, and ferrous ions using the Cell Counting Lite 3D Kit. We assessed cell viability using the Cell Counting Kit-8 (CCK-8) assay. RESULTS: Tamoxifen significantly inhibited the growth of MCF-7 organoids and significantly induced ferroptosis in MCF-7 organoids. The ferroptosis inhibitor reversed the significant tamoxifen-induced MCF-7 organoid inhibition activity. Moreover, the ferroptosis activator enhanced the tamoxifen-induced MCF-7 TAMR cell activity inhibition. CONCLUSION: Our study revealed that ferroptosis plays an important role in tamoxifen-induced MCF-7 organoid cell death and provides a new research idea for precise treatment of breast cancer through an organoid model.

Comprehensive pan-cancer investigation: unraveling the oncogenic, prognostic, and immunological significance of Abelson interactor family member 3 gene in human malignancies.

Background: Abelson interactor Family Member 3 (ABI3) encodes protein that not only suppresses the ectopic metastasis of tumor cells but also hinders their migration. Although ABI3 had been found to modulate the advancement of diverse neoplasms, there is no comprehensive pan-cancer analysis of its effects. Methods: The transcriptomics data of neoplasm and normal tissues were retrieved from the Genomic Data Commons (GDC) data portal, and UCSC XENA database. To gather protein information for ABI3, Human Protein Atlas (HPA) and GeneMANIA websites were utilized. Additionally, Tumor Immune Single-cell Hub (TISCH) database was consulted to determine the primary cell types expressing ABI3 in cancer microenvironments. Univariate Cox regression approach was leveraged to evaluate ABI3's prognostic role across cancers. The Cbioportal and Gene Set Cancer Analysis (GSCA) website were leveraged to scrutinize the genomic landscape information across cancers. TIMER2.0 was leveraged to probe the immune cell infiltrations associated with ABI3 across cancers. The associations of ABI3 with immune-related genes were analyzed through Spearman correlation method. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to search associated biological pathways. The CellMiner database and molecular docking were implemented to identify potential interactions between the ABI3 protein and specific anticarcinogen. Findings: ABI3 expression and its ability to predict prognosis varied distinct tumor, with particularly high expression observed in Tprolif cells and monocytes/macrophages. Copy number variation (CNV) and methylation negatively correlated with ABI3 expression in the majority of malignancies. Corresponding mutation survival analysis indicated that the mutation status of ABI3 was strongly connected to the prognosis of LGG patients. ABI3 expression was linked to immunotherapeutic biomarkers and response in cancers. ESTIMATE and immune infiltrations analyses presented ABI3 association with immunosuppression. ABI3 was significantly correlated with immunoregulators and immune-related pathways. Lastly, prospective ABI3-targeted drugs were filtered and docked to ABI3 protein. Interpretation: Our study reveals that ABI3 acts as a robust tumor biomarker. Its functions are vital that could inhibit ectopic metastasis of tumor cells and modulate cellular adhesion and migration. The discoveries presented here may have noteworthy consequences for the creation of fresh anticancer suppressors, especially those targeting BRCA.

Development and validation of a nomogram based on multiple preoperative immunoinflammatory indexes for survival prediction in patients with stage IA-IB endometrial cancer.

OBJECTIVES: To evaluate the preoperative systemic immune-inflammation index (SII), advanced lung cancer inflammation index (ALI), neutrophil to lymphocyte ratio (NLR), and prognostic nutritional index (PNI) capacity to predict the prognosis of stage IA-IB endometrial carcinoma (EC) patients after operation, and establish a nomogram model to guide clinical practice. METHODS: A total of 387 patients with EC (R0 resection, stage IA-IB) were assessed. Clinical information and the SII, NLR, ALI, and PNI values were obtained. The low and high ratio groups were separated using the receiver operating characteristic curve (ROC). Pearson's χ2-test or Fisher's exact test was used to determine their relationship with clinical variables. To determine the independent prognostic factors, Cox regression was utilized to do the univariate and multivariate survival analyses. The Kaplan-Meier method was used to draw the survival curve in our survival analysis. Depending upon the independent prognostic factors, the nomogram for Overall survival (OS) and Disease-free survival (DFS) nomogram was developed, and its discrimination ability was validated by the consistency index (C-index) and calibration curve. RESULTS: Cox regression analysis revealed that FIGO staging, Ki-67 expression level, PNI, and ALI are independent prognostic factors for both OS and DFS. Then a novel predictive nomogram was developed, and its C-index value for OS and DFS was 0.829 and 0.814, respectively. The calibration curves demonstrated consistency amid the predicted prognosis using the developed nomogram and the actual observed outcomes. CONCLUSIONS: The ALI and PNI could serve as readily available prognostic indicators for OS and DFS prediction in stage IA-IB EC patients. The nomogram developed owned superior power for OS and DFS prediction in stage IA-IB EC patients, and it would assist clinical oncologists in accurately predicting the individual's OS and DFS.

A Novel Peptide that Disrupts the Lck-IP3R Protein-Protein Interaction Induces Widespread Cell Death in Leukemia and Lymphoma.

There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP3R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP3R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca2+-dependent, cell killing of hematological cancer cells when the Lck-IP3R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP3R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP3R PPI has a wide range of pre-clinical activity in leukemia and lymphoma.

SALL1 promotes proliferation and metastasis and activates phosphorylation of p65 and JUN in colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC) is one of the most usual malignant tumors, and its incidence continues to rise. Our purpose was to explore the function and potential regulatory mechanisms of SALL1, a differentially methylated gene in CRC, in vivo and in vitro. METHODS: Firstly, methylation differential gene SALL1 in CRC was screened and validated. SALL1 overexpression plasmids or SALL1 siRNAs were transfected in HT-29 and SW480 cells. Moreover, 10 µM T-5224 was added in SALL1-overexpressed CRC cells. CCK-8, flow cytometry and transwell assays were utilized to assess cell proliferation, cycle, migration, and invasion, respectively. Then CRC organoids were cultured. Next, HT-29 and SW480 cells transfected with SALL1 overexpression lentivirus were analyzed by transcriptome sequencing. Finally, in vivo tumorigenesis was used to analyze the effect of SALL1 overexpression on subcutaneous tumorigenesis in nude mice. RESULTS: The methylation level of CpG island in SALL1 promoter was increased in CRC tissues and could distinguish tumor tissues. Overexpression of SALL1 accelerated proliferation, migration and invasion of HT-29 and SW480 cells, and silencing of SALL1 attenuated proliferation, migration and invasion of HT-29 and SW480 cells. Through analysis and validation, we found that overexpression of SALL1 also could upregulate p-p65 and p-JUN expressions. Besides, c-Fos/activator protein (AP)- 1 inhibitor (T-5224) could reverse the induction of CRC progression by SALL1 overexpression. In vivo, we also proved that overexpression of SALL1 significantly increased tumor volume, tumor weight, and p-JUN expression. CONCLUSIONS: SALL1 could promote the proliferation, migration, and invasion of CRC cells and activate phosphorylation of p65 and JUN.

Construction of a risk index system for the prediction of chronic post-surgical pain after video-assisted thoracic surgery for lung resection: A modified Delphi study.

In the present study, several research methods were adopted, including literature retrieval, theoretical analysis, and qualitative research, and then the draft of the prognostic factors for the chronic post-surgical pain (CPSP) index system after video-assisted thoracoscopic surgery (VATS) for lung resection was constructed. A Delphi survey was used for the study of 24 experts in the field of pain from three different grade-A tertiary hospitals in Guangzhou, China. In the two rounds of survey, the experts rated these indicators for the importance and feasibility of measurement (round 1, n = 21 participants; round 2, n = 20). Finally, we calculated Kendall's W index as a measure of consensus. A general consensus was reached on predicting CPSP after VATS, consisting of 10 first-level domains and 64 second-level indicators, involving biological, psychological and social perspectives. This study provides a comprehensive draft of risk factors developed and identified by experts to inform research-based evidence on chronic pain. Increased clinical awareness and a full understanding of how to screen and identify people with CPSP problems may lead to earlier recognition of chronic pain and greater facilitation of professional prevention.

Dissection of pyroptosis-related prognostic signature and CASP6-mediated regulation in pancreatic adenocarcinoma: new sights to clinical decision-making.

Recent studies have indicated that pyroptosis may participate in the regulation of tumorigenesis and immune microenvironment. However, the role of pyroptosis-related genes (PRGs) in pancreatic adenocarcinoma (PAAD) remains unclear. Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA network. The correlation between PRGs and prognosis, immune infiltration, immune checkpoints, and tumor mutational burden was analyzed by Kaplan-Meier curve, univariate Cox, multivariate regression, and Spearman's analysis in PAAD patients. The qRT-PCR, Western blotting, CCK-8, Wound healing, and Transwell assay were applied to examine the role of CASP6 in PANC-1 cell. Thirty-one PRGs were upregulated in PAAD. Functional enrichment analysis revealed that the PRGs were mainly involved in pyroptosis, NOD-like receptor signaling pathway, and response to bacteria. We established a novel 4-gene signature related to PRGs for evaluating the prognosis of PAAD patients. Patients with PAAD in the low-risk group had a better prognosis than those in the high-risk group. The nomogram suggested that the 1-, 3-, and 5-years survival probability exhibited robust predictive performance. Significant correlation was observed between prognostic PRGs and immune infiltration, immune checkpoints, and tumor mutational burden. We first identified the potential competing endogenous RNA regulatory axis in PAAD: lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8. Moreover, knockdown of CASP6 dramatically inhibited the proliferation, migration, and invasion ability of PANC-1 cell in vitro. In conclusion, CASP6 could be a potential biomarker, promoting the occurrence and progression in PAAD. The lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8 regulatory axis plays an vital role in regulating the anti-tumor immune responses for PAAD.

A novel type lavandulyl flavonoid from Sophora flavescens as potential anti-hepatic injury agent that inhibit TLR2/NF-κB signaling pathway.

ETHNOPHARMACOLOGY RELEVANCE: Sophora flavescens Aiton, was a crucial source of Traditional Chinese Medicine (TCM) that has benefited human health for hundreds of years. Alkaloids and flavonoids were the major bioactive constituents from S. flavescens, which had been widely used for liver disease treatment in China. However, the liver-protective components of flavonoids from S. flavescens and their mechanism of action were not clear. AIM OF THE STUDY: This work aimed to evaluate the in vitro hepatoprotective activities of 35 flavonoids from S. flavescens and screen active compounds. Furthermore, it was conducted to demonstrate the hepatoprotective effects of a new active compound (kurarinol A, 1) was isolated by authors and the ethyl acetate (EtOAc) extract form S. flavescens against carbon tetrachloride (CCl4)-induced hepatic injury in Kunming (KM) mice, meanwhile revealed the potential mechanism. MATERIALS AND METHODS: The 35 flavonoids from S. flavescens were co-incubated with HepG2 cells and treated with 0.35% CCl4 for 6 h cell viability was measured by (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. Then, in vivo animal experiments, the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the serum were analyzed, the degree of hepatic injury was examined using hematoxylin-eosin (H&E) staining, the mRNA expression of Superoxide Dismutase 2 (SOD2), Nuclear factor E2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), Interleukin 6 (IL-6), Tumor Necrosis Factor-α (TNF-α), interleukin-1ß (IL-1ß), and the protein levels of nuclear factor-kappa B p65/p-p65 (NF-κB p65/p-p65), toll-like receptor 2 (TLR2), IL-1ß and cyclooxygenase-2 (COX2) in hepatic tissues were detected. RESULTS: The lavandulyl flavonoid (kurarinol A, 1) and the EtOAc extract from S. flavescens showed protective effects on CCl4-injured HepG2 cells, increasing cell viability from 24.5% to 61.3% and 91.8%, respectively. What's more, we found that treatment with kurarinol A (1) and the EtOAc extract lead to a significant reduction in hepatotoxicity in response to acute CCl4 exposure. Compared with the model group, experimental results exhibited kurarinol A (10 mg/kg, i.p.) and the EtOAc extract (300 mg/kg, i.p.) could decrease the levels of AST, ALT, ALP and tissue damage. Further mechanistic investigations revealed that up-regulated the mRNA expression of SOD2, Nrf2, OH-1 and down-regulated the IL-1ß in liver tissues, respectively. Additionally, Western blot analyses elucidated that inhibition of IL-1ß, TLR2, COX-2, NF-κB (p65/p-p65) via TLR2/NF-κB signaling pathway by kurarinol A and the EtOAc extract contribute to its hepatoprotective activity. CONCLUSION: These findings demonstrated that the novel compound (kurarinol A, 1) possessed notable hepatoprotective activity against CCl4. It was confirmed that kurarinol A had a certain effect on mice with liver damage induced by CCl4, and its mechanism could be include inhibiting inflammation and reducing of oxidative stress reaction by regulating expression of related genes and proteins. Thus, kurarinol A could as a novel active agent that contributes to the hepatoprotective activity of S. flavescens for the treatment of live injury.

A novel peptide that disrupts the Lck-IP3R protein-protein interaction induces widespread cell death in leukemia and lymphoma.

There is increasing evidence that the T-cell protein, Lck, is involved in the pathogenesis of chronic lymphocytic leukemia (CLL) as well as other leukemias and lymphomas. We previously discovered that Lck binds to domain 5 of inositol 1,4,5-trisphosphate receptors (IP3R) to regulate Ca2+ homeostasis. Using bioinformatics, we targeted a region within domain 5 of IP3R-1 predicted to facilitate protein-protein interactions (PPIs). We generated a synthetic 21 amino acid peptide, KKRMDLVLELKNNASKLLLAI, which constitutes a domain 5 sub-domain (D5SD) of IP3R-1 that specifically binds Lck via its SH2 domain. With the addition of an HIV-TAT sequence to enable cell permeability of D5SD peptide, we observed wide-spread, Ca2+-dependent, cell killing of hematological cancer cells when the Lck-IP3R PPI was disrupted by TAT-D5SD. All cell lines and primary cells were sensitive to D5SD peptide, but malignant T-cells were less sensitive compared with B-cell or myeloid malignancies. Mining of RNA-seq data showed that LCK was expressed in primary diffuse large B-cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML). In fact, LCK shows a similar pattern of expression as many well-characterized AML oncogenes and is part of a protein interactome that includes FLT3-ITD, Notch-1, and Kit. Consistent with these findings, our data suggest that the Lck-IP3R PPI may protect malignant hematopoietic cells from death. Importantly, TAT-D5SD showed no cytotoxicity in three different non-hematopoietic cell lines; thus its ability to induce cell death appears specific to hematopoietic cells. Together, these data show that a peptide designed to disrupt the Lck-IP3R PPI has a wide range of pre-clinical activity in leukemia and lymphoma.

Natural borneol serves as an adjuvant agent to promote the cellular uptake of piperlongumine for improving its antiglioma efficacy.

Piperlongumine (PL) can selectively inhibit the proliferation of various cancer cells by increasing reactive oxygen species (ROS) level to cause a redox imbalance in cancer cells rather than in normal cells. However, the clinical application of PL is limited by its poor cellular uptake. Natural borneol (NB) is extracted from the fresh branches and leaves of Cinnamomum camphora (L.) Presl. with the purity of (+)-borneol no less than 96.0%. NB has been often used as an adjuvant agent to promote the cellular uptake of other drugs. This study aims to investigate the effect of NB on the cellular uptake of PL for improving its antiglioma efficacy and underlying mechanism. NB obviously promoted the cellular uptake of PL with a 1.3-fold increase in the maximum peak concentration and an earlier peak time of 30 min in C6 glioma cells. The cellular uptake of PL was enhanced by NB through down-regulating the expression levels of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). The combination of NB and PL significantly induced higher levels of ROS, which increased apoptosis and enhanced G2/M cycle arrest of C6 glioma cells, compared to PL alone administration. NB-enhanced antiglioma efficacy of PL without side effects was confirmed in tumor-bearing mice, which was attributed to the improved cellular uptake of PL. The distribution of PL in the tumor tissue of combined group increased 2.39 times than that of PL-treated group. We firstly report NB as an adjuvant agent to improve the antiglioma efficacy of PL in a ROS-dependent manner, which is due to the enhanced cellular uptake of PL by NB though down-regulating the expression levels of ABCB1 and ABCG2. This work provides a new strategy to promote the cellular uptake of PL with great potential for the treatment of glioma.

An imidazole-derived polarity sensitive probe for lipid droplet target and in vivo tumor imaging.

Accurate differentiation of tumor cells from normal cells is a fundamental and critical challenge for the early diagnosis of cancer. The intrinsic low-polarity and increased numbers of lipid droplets can be utilized as potential biomarkers for tumor cells. Therefore, we synthesized and screened the polar fluorescent probe (PI-CHO), which exhibiting notable fluorescence color change and spectral shift in solvents of different polarities. PI-CHO has a high sensitivity to polarity changes in the linear range of ET(30) = 37.4-63.1, with a fluorescence enhancement of more than 474-folds. Intracellular imaging experiments showed that PI-CHO has low cytotoxicity, excellent lipid droplet-targeted performance and discernibility between tumor and normal cells. Ex vivo imaging of the tumors and major organs demonstrated the great reliability and sensitive responsiveness of PI-CHO towards tumors. Moreover, the proposed probe was successfully applied to detect tumors in living mice, exhibiting the potential to become a powerful tool in early cancer diagnosis.

Comparison of outcomes between single- and multiple-perforator-based free perforator flaps: A systematic review and meta-analysis.

BACKGROUND: Perforator-based free perforator flaps have become an important tool for the reconstruction of tissue defects. The effect of the number of perforators on the outcomes of perforator flaps has been widely debated. This study aimed to compare the outcomes of single- and multiple-perforator-based free perforator flaps in free-flap reconstruction. METHODS: We searched PubMed, Web of Science, EMBASE, Chinese BioMedical Literature Database (CBM), Cochrane Library, and clinicaltrials.gov between January 2000 and June 2021 to identify studies that reported data on the outcomes of free perforator flaps. Two authors individually extracted data and performed quality assessment. Outcomes, including partial flap loss, total loss, fat necrosis, arterial insufficiency, venous insufficiency, hemorrhage and hematoma, wound dehiscence at recipient sites and donor site complications, were evaluated. RESULTS: Thirty-two studies with 2498 flaps were included in our analysis. No significant difference was found in the rates of partial loss and arterial insufficiency of flaps, hemorrhage and hematoma, wound dehiscence at recipient sites and donor site complications. However, the multiple-perforator group showed significantly lower rates of total loss (relative risk [RR] = 1.08, 95% confidence interval [CI]: 0.78-1.79, p = .754), fat necrosis (RR = 1.79, 95% [CI]: 1.36-2.36, p = .000) and venous insufficiency (RR = 1.72, 95% CI: 1.07-2.79, p = .026) than the single-perforator group. CONCLUSION: The rates of total loss, fat necrosis and venous insufficiency in the multiple-perforator group were lower than those in the single-perforator group. Hence, we recommend that multiple perforators be included in the free perforator flap when appropriate, to yield better clinical outcomes in reconstruction.