Predicting mechanism of immune response in microsatellite instability colorectal cancer.

Colorectal cancer (CRC), also known as colon cancer, is the third most common cancer and the fourth most cause of cancer-related death in the world. CRC can be classified into two major subtypes, including microsatellite instability (MSI) and microsatellite stability (MSS), which showed different characteristics in immunotherapy. Low sensitivity of diagnostic biomarkers and metastasis are still the principal cause of mortality, especially in MSI. Here, applying computational programs, we identified recurring expression programs based on single cell RNA sequencing (scRNA-Seq) data of CRC cell lines. Notably, three MSI specific recurring modules were identified by non-negative matrix factorization (NMF). High NMF score genes enriched in the function of metabolism and inflammatory response. Focusing on top specific active transcription factor (TF), RUNX3 (Runt-related transcription factor 3), our results suggest that T cell infiltration was increased in RUNX3 high MSI CRC samples. Unbiased Gene Set Enrichment Analysis (GSEA) showed that RUNX3 was strongly associated with immune and metastasis related functions, such as Interferon Gamma (IFN-γ) and EPITHELIAL MESENCHYMAL TRANSITION (EMT). In addition, RUNX3 shows specific highly activated at epigenetic level in MSI compared with other gastrointestinal carcinomas. Positive correlation between RUNX3 and most immune checkpoints further confirmed RUNX3 might have crucial roles in MSI cancer progression and immunotherapy. Taken together, these results indicate significant tumor heterogeneity of two CRC subtypes at single-cell level and epigenetic modification level. These results also linked transcriptional dysregulation with immune infiltration at single-cell level in MSI, which may advance the application of scRNA-Seq technology in immunotherapy and contribute to developing novel biomarkers of this malignancy.

LINC00858 facilitates formation of hepatic metastases from colorectal cancer via regulating the miR-132-3p/IGF2BP1 axis.

Hepatic metastasis is a major cause of colorectal cancer (CRC)-related deaths. Presently, the role of long non-coding RNAs (lncRNAs) in hepatic metastases from CRC is elusive. We dissected possible interplay between LINC00858/miR-132-3p/IGF2BP1 via bioinformatics approaches. Subsequently we analyzed mRNA expression of LINC00858, miR-132-3p and IGF2BP1 through qRT-PCR. Western blot was used to detect protein expression of IGF2BP1. RNA immunoprecipitation chip and dual-luciferase assay validated interaction between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Cell viability, invasion, and migration were examined via CCK-8, colony formation, transwell and wound healing assays. Effect of LINC00858 on CRC hepatic metastases was validated via in vivo assay. Upregulated LINC00858 and IGF2BP1, and downregulated miR-132-3p were predicted in tumor tissues of patients with hepatic metastases from CRC. There were targeting relationships between LINC00858 and miR-132-3p, as well as miR-132-3p and IGF2BP1. Besides, LINC00858 facilitated progression of CRC cells. Rescue assay suggested that silencing LINC00858 suppressed CRC cell progression, while further silencing miR-132-3p or overexpressing IGF2BP1 reversed such effects. LINC00858 could facilitate CRC tumor growth and hepatic metastases. LINC00858 induced CRC hepatic metastases via regulating miR-132-3p/ IGF2BP1, and this study may deliver a new diagnostic marker for the disease.

Oleanolic acid derivative alleviates cardiac fibrosis through inhibiting PTP1B activity and regulating AMPK/TGF-ß/Smads pathway.

Cardiac fibrosis (CF) in response to persistent exogenous stimuli or myocardial injury results in cardiovascular diseases (CVDs). Protein tyrosine phosphatase 1B (PTP1B) can promote collagen deposition through regulating AMPK/TGF-ß/Smads signaling pathway, and PTP1B knockout improves cardiac dysfunction against overload-induced heart failure. Oleanolic acid (OA) has been proven to be an inhibitor of PTP1B, and its anti-cardiac remodeling effects have been validated in different mouse models. To improve the bioactivity of OA and to clarify whether OA derivatives with stronger inhibition of PTP1B activity have greater prevention of cardiac remodeling than OA, four new OA derivatives were synthesized and among them, we found that compound B had better effects than OA in inhibiting cardiac fibrosis both in vivo in the isoproterenol (ISO)-induced mouse cardiac fibrosis and in vitro in the TGF-ß/ISO-induced 3T3 cells. Combining with the results of molecular docking, surface plasmon resonance and PTP1B activity assay, we reported that OA and compound B directly bound to PTP1B and inhibited its activity, and that compound B showed comparable binding capability but stronger inhibitory effect on PTP1B activity than OA. Moreover, compound B presented much greater effects on AMPK activation and TGF-ß/Smads inhibition than OA. Taken together, OA derivative compound B more significantly alleviated cardiac fibrosis than OA through much greater inhibition of PTP1B activity and thus much stronger regulation of AMPK/TGF-ß/Smads signaling pathway.

A Novel Esophagogastrostomy Technique for Laparoscopic Proximal Gastrectomy: Conical Remnant Gastroesophageal Side-overlap Fundoplication.

Background: There is currently no universally-accepted, ideal method of esophagogastric reconstruction to address reflux esophagitis and anastomotic complications of esophagogastrostomy after proximal gastrectomy. Case Report: In June 2022, two patients with Siewert type II carcinoma of esophagogastric junction underwent laparoscopic proximal gastrectomies, using a novel esophagogastrostomy technique of Conical remnant GastroEsophageal side-Overlap fundoplication (CGEO). On postoperative day 4, upper gastrointestinal fluoroscopy was performed, with patients in downward and left oblique positions, allowing gastrografin to accumulate within fundic reconstructions. No reflux into the esophagus was subsequently observed, and both patients were discharged (postoperative days 9 and 11). Six months after surgery, endoscopic view showed that the reconstructed cardia returned to its normal state, in the absence of any reflux symptoms. As of April 2023, we have operated on four patients using CGEO, and all of them recovered without obvious reflux symptoms. Conclusion: CGEO is a feasible and safe reconstructive esophagogastrostomy procedure following laparoscopic proximal gastrectomy for Siewert type II esophagogastric junction carcinoma.

Additive effect of the Streptomyces albus XJC2-1 and dimethomorph control pepper blight (Capsicum annuum L.).

BACKGROUND: Pepper blight, caused by Phytophthora capsici, is a destructive soilborne disease, which poses a serious threat to pepper, Capsicum annuum L., production. Chemical fungicides, which mainly are used to control pepper blight, have a negative effect on the environment, rendering biological control as a promising alternative to maintain the balance between ecology and pest management. The purpose of this study was to screen the biocontrol bacteria, reduce the dosage of fungicides and increase the stability of biocontrol bacteria, and to find the mixing ratio of biocontrol bacteria and fungicides giving the best control effect. RESULTS: We isolated actinomycetes strains from the soil surrounding the roots of healthy pepper plants amongst field-grown plants infected with P. capsici. Of these, Streptomyces albus XJC2-1 showed a strong inhibition effect on the growth of P. capsici, with an inhibition rate of ≤85%. XJC2-1 effectively inhibited the formation of sporangium and release of zoospores of P. capsici as well as directly destroyed its hyphae, to achieve the inhibitory effect. Transcriptomic profiling of pepper leaves, postirrigation of plants with the XJC2-1 fermentation broth, revealed upregulation of genes related to the photosynthesis pathway in pepper. Furthermore, XJC2-1 treatment improved the net photosynthetic rate and intercellular CO2 concentration, thereby improving the pepper plant's resistance to pathogens. The combination of XJC2-1 with the fungicide dimethomorph (8 µg mL-1 ) displayed strong synergism in inhibition of P. capsici infection, with a control efficiency as high as 75.16%, thus providing a basis for its application in the field. CONCLUSION: Our study demonstrated that S. albus XJC2-1 inhibited Phytophthora pathogens from infecting pepper plants and enhanced plant host resistance. The combination of XJC2-1 and dimethomorph displayed a more stable and stronger control effect on pepper blight, showing potential for the future application of XJC2-1 in the field of biological control. © 2023 Society of Chemical Industry.

Retraction: Icariin enhances intestinal barrier function by inhibiting NF-κB signaling pathways and modulating gut microbiota in a piglet model.

[This retracts the article DOI: 10.1039/C9RA07176H.].

The Treatment of Complementary and Alternative Medicine on Female Infertility Caused by Endometrial Factors.

Recently, with the development of the social economy, the incidence of infertility has increased year by year. With its complex etiology and diversified syndromes, infertility has become one of the most important diseases that plague the physical and mental health of women of childbearing age worldwide. Endometrial factors as an important part affecting female reproductive capacity, due to which induced repeated abortion and multiple uterine cavity operations occur, can destruct endometrium, failing to provide a normal implantation environment for zygote, thus resulting in infertility. Many patients failed to achieve expected results after receiving conventional treatments such as hormone therapy, assisted reproductive technology (ART), granulocyte colony-stimulating factor (G-CSF) therapy, and cell therapy, then turn to complementary and alternative medicine (CAM) therapies for help. Aiming at clarifying the effectiveness and mechanisms of CAM therapy in the treatment of infertility caused by endometrial factors, our paper systematically searched and studied present related literature on the PubMed, CNKI, and other databases, focusing on the aspects of clinical application and mechanism explorations and highlighting the therapeutic effects of Chinese herbal medicine (CHM), acupuncture, and moxibustion on such diseases. Moreover, this paper also introduces the CAM treatments of traditional Chinese medicine (TCM) retention enema, neuromuscular electrical stimulation (NMES), photobiomodulation therapy, dietary intervention, and other measures for infertility caused by endometrial factors, in order to provide a reference for subsequent basic research and clinical work.

Prognostic Factors in Stage IV Colorectal Cancer Patients With Resection of Liver and/or Pulmonary Metastases: A Population-Based Cohort Study.

Importance: Currently, surgical resection of distant metastatic lesions has become the preferred treatment for select colorectal cancer (CRC) patients with liver metastasis (LM) and/or pulmonary metastasis (PM). Metastasectomy is the most common curative method. However, evidence of the factors affecting the prognosis of CRC patients after resection of LM and/or PM is still insufficient. Objective: To explore the prognostic factors of CRC patients with LM and/or PM who have undergone resection of metastatic tumors and to provide reliable selection factors for surgical treatment in patients affected by LM and/or PM from CRC. Methods: The SEER database was used to identify eligible CRC LM and/or PM patients who underwent resection of the primary tumor and distant metastases from January 1, 2010, to December 31, 2018. The Kaplan-Meier method was used to calculate survival, and comparisons were performed using the log-rank test for univariate analysis. A Cox proportional hazards regression model was used to identify prognostic factors for the multivariate analysis. The outcomes included overall survival (OS) and cancer-specific survival (CSS). Results: A total of 3,003 eligible colorectal cancer patients with LM and/or PM were included in this study. The 3-year and 5-year OS rates were 53% and 33.6%, respectively, and the 3-year and 5-year CSS rates were 54.2% and 35.3%, respectively. In the adjusted multivariate analysis, age < 65 years (OS: p=0.002, CSS: p=0.002) was associated with better long-term outcomes, and primary tumors located on the left side of the colon (OS: p=0.004, CSS: p=0.006) or rectum (OS: p=0.004, CSS: p=0.006), T3 stage (OS: p<0.001, CSS: p<0.001), number of regional lymph nodes examined ≥ 12 (OS: p<0.001, CSS: p=0.001), and CRC LM (OS: p<0.001, CSS: p<0.001) were positive prognostic factors for survival after resection of metastatic tumors. Conclusion: Age < 65 years is associated with better long-term outcomes in colorectal cancer patients with LM and/or PM, analogously to the left sided primary tumor, T3 stage, number of regional lymph nodes examined ≥ 12 and liver metastases.

The Treatment with Complementary and Alternative Traditional Chinese Medicine for Menstrual Disorders with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a frequent gynecological female endocrinopathy, characterized by chronic anovulation, hyperandrogenism, and insulin resistance (IR). Menstrual disorders are one of the main clinical manifestations of PCOS. Other symptoms include hirsutism and/acne. At present, the treatment of PCOS with irregular menstruation is mainly based on oral contraceptives, but there are some side effects and adverse reactions. In recent years, more and more attention has been paid to the complementary and alternative medicine (CAM), which has been widely used in clinical practice. Modern Western medicine is called "conventional medicine" or "orthodox medicine," and the complementary and alternative medicine is called "unconventional medicine" or "unorthodox medicine." CAM includes traditional medicine and folk therapy around the world. Around 65-80% of world health management business is classified into traditional medicine by the World Health Organization, which is used as alternative medicine in Western countries. In our country, Chinese medicine, acupuncture, and other therapies are commonly used due to their significant efficacy and higher safety. Therefore, this review aims to summarize and evaluate the mechanisms and the effect of current complementary replacement therapy in the treatment of menstrual disorders caused by PCOS, so as to provide guidance for the following basic and clinical research.

Isobavachalcone inhibits acute myeloid leukemia: Potential role for ROS-dependent mitochondrial apoptosis and differentiation.

Isobavachalcone (IBC) has been shown to induce apoptosis and differentiation of acute myeloid leukemia (AML) cells. However, the underlying molecular mechanisms are not fully understood. Herein, IBC exhibited significant inhibition on the cell viability, proliferation, and the colony formation ability of AML cells. Moreover, IBC induced mitochondrial apoptosis evidenced by reduced mitochondrial membrane potential, increased Bax level, decreased Bcl-2, Bcl-xL, and Mcl-1 levels, elevated cytochrome c level in the cytosol and increased cleavage of caspase-9, caspase-3, and PARP. Furthermore, IBC obviously promoted the differentiation of AML cells, accompanied by the increase of the phosphorylation of MEK and ERK and the C/EBPα expression as well as the C/EBPß LAP/LIP isoform ratio, which was significantly reversed by U0126, a specific inhibitor of MEK. Notably, IBC enhanced the intracellular ROS level. More importantly, IBC-induced apoptosis and differentiation of HL-60 cells were significantly mitigated by NAC. In addition, IBC also exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Together, our study suggests that the ROS-medicated signaling pathway is highly involved in IBC-induced apoptosis and differentiation of AML cells.

Z-Ligustilide Selectively Targets AML by Restoring Nuclear Receptors Nur77 and NOR-1-mediated Apoptosis and Differentiation.

BACKGROUND: Acute myeloid leukemia (AML) is a devastating hematologic malignancy with a high mortality. The nuclear receptors Nur77 and NOR-1 are commonly downregulated in human AML blasts and have emerged as key therapeutic targets for AML. METHODS: This study aimed to identify Z-ligustilide (Z-LIG), the main phthalide of Rhizoma Chuanxiong, as a potential agent that can selectively target AML. The anti-AML activity of Z-LIG was evaluated in vitro and in vivo, and the effect and underlying mechanisms of Z-LIG on the restoration of Nur77 and NOR-1 was determined. Moreover, the role of Nur77 and NOR-1 in the regulation of Z-LIG-induced apoptosis and differentiation of AML cells was explored. RESULTS: Z-LIG preferentially inhibited the viability of human AML cells, as well as suppressed the proliferation and colony formation ability. Notably, a concentration-dependent dual effect of Z-LIG was observed in AML cells: inducing apoptosis at relatively high concentrations (25 µM to 100 µM) and promoting differentiation at relatively low concentrations (10 µM and 25 µM). Importantly, Z-LIG restored Nur77 and NOR-1 expression in AML cells by increasing Ace-H3 (lys9/14) enrichment in their promoters. Meanwhile, Z-LIG enhanced the recruitment of p300 and reduced the recruitment of HDAC1, HDAC4/5/7, and MTA1 in the Nur77 promoter and enhanced the recruitment of p-CREB and reduced HDAC1 and HDAC3 in the NOR-1 promoter. Furthermore, Z-LIG-induced apoptosis was shown to be correlated with the mitochondria localization of Nur77/NOR-1 and subsequent Bcl-2 conformational change, converting Bcl-2 from a cyto-protective phenotype into a cyto-destructive phenotype. Z-LIG-promoted differentiation was found to be related to Nur77/NOR-1-mediated myeloid differentiation-associated transcription factors Jun B, c-Jun, and C/EBPß. Finally, silencing of Nur77 and NOR-1 attenuated anti-AML activity of Z-LIG in NOD/SCID mice. CONCLUSIONS: Our study suggests that Z-LIG may serve as a novel bifunctional agent for AML by restoring Nur77/NOR-1-mediated apoptosis and differentiation.

Cantharidin Induces Apoptosis and Promotes Differentiation of AML Cells Through Nuclear Receptor Nur77-Mediated Signaling Pathway.

BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled proliferation and accumulation of myeloblasts in the bone marrow (BM), blood, and other organs. The nuclear receptors Nur77 is a common feature in leukemic blasts and has emerged as a key therapeutic target for AML. Cantharidin (CTD), a main medicinal component of Mylabris (blister beetle), exerts an anticancer effect in multiple types of cancer cells. PURPOSE: This study aims to characterize the anti-AML activity of CTD in vitro and in vivo and explore the potential role of Nur77 signaling pathway. STUDY DESIGN/METHODS: The inhibition of CTD on cell viability was performed in different AML cells, and then the inhibition of CTD on proliferation and colony formation was detected in HL-60 cells. Induction of apoptosis and promotion of differentiation by CTD were further determined. Then, the potential role of Nur77 signaling pathway was assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice. RESULTS: In our study, CTD exhibited potent inhibition on cell viability and colony formation ability of AML cells. Moreover, CTD significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. Meanwhile, CTD promoted the cleavage of caspases 8, 3 and PARP in HL-60 cells. Furthermore, CTD obviously suppressed the proliferation and induced the cell cycle arrest of HL-60 cells at G2/M phase. Meanwhile, CTD effectively promoted the differentiation of HL-60 cells. Notably, CTD transiently induced the expression of Nur77 protein. Interestingly, CTD promoted Nur77 translocation from the nucleus to the mitochondria and enhanced the interaction between Nur77 and Bcl-2, resulting in the exposure of the BH3 domain of Bcl-2, which is critical for the conversion of Bcl-2 from an antiapoptotic to a proapoptotic protein. Importantly, silencing of Nur77 attenuated CTD-induced apoptosis, reversed CTD-mediated cell cycle arrest and differentiation of HL-60 cells. Additionally, CTD also exhibited an antileukemic effect in NOD/SCID mice with the injection of HL-60 cells into the tail vein. CONCLUSIONS: Our studies suggest that Nur77-mediated signaling pathway may play a critical role in the induction of apoptosis and promotion of differentiation by CTD on AML cells.

Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study.

CONTEXT: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA). AIMS: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA. SETTINGS AND DESIGN: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013. MATERIALS AND METHODS: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group. STATISTICAL ANALYSIS USED: The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model. RESULTS: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival. CONCLUSIONS: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.

DT-13 induced apoptosis and promoted differentiation of acute myeloid leukemia cells by activating AMPK-KLF2 pathway.

Acute myeloid leukemia (AML) is a malignant disease originating from hematopoietic stem cells (HSC). Chemotherapy and/or HSC transplantation is unsatisfactory due to serious side effects, multidrug resistance, and high relapse rate. Thus, alternative strategies are urgently needed to develop more effective therapies. Liriope muscari baily saponins C (DT-13) is a novel compound isolated from Liriope muscari (Decne.) Baily, and exhibited a potent cytotoxicity against several solid tumors. However, the anti-AML activity of DT-13 and the potential mechanisms are still unknown. This study is the first to demonstrate that DT-13 had preferential cytotoxicity against AML cells, and remarkably inhibited proliferation and colony forming ability. Moreover, DT-13 induced the death receptor pathway-dependent apoptosis of HL-60 and Kasumi-1 cells by up-regulating Fas, FasL, DR5 and TRAIL as well as promoted the cleavage of caspase 8, caspase 3 and PARP. Meanwhile, DT-13 induced the differentiation with morphological change related to myeloid differentiation, elevated NBT and α-NAE positive cell rates, differentiation markers CD11b and CD14 as well as level of transcription factors C/EBPα and C/EBPß. RNA-sequencing analysis revealed that KLF2 may be one of the potential targets regulated by DT-13. Further studies indicated that KLF2 played a critical role in DT-13-induced apoptosis and differentiation. Moreover, activation of AMPK-FOXO was proved to be the upstream of KLF2 pathway that contributed to the induction of apoptosis and differentiation by DT-13. Additionally, restoration of KLF2 by DT-13 was highly correlated with the AMPK-related histone acetylation mechanisms. Finally, DT-13 exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Our study suggests that DT-13 may serve as a novel agent for AML by AMPL-KLF2-mediated apoptosis and differentiation.

Ethyl acetate extract of Caesalpinia sappan L. inhibited acute myeloid leukemia via ROS-mediated apoptosis and differentiation.

BACKGROUND: The dried heartwood of Caesalpinia sappan L. is traditionally prescribed in the formula of traditional Chinese medicine (TCM) for the treatment of acute myeloid leukemia (AML), while nothing is yet known of the active fractions and the underlying mechanisms. PURPOSE: This study aims to investigate the effect of the ethyl acetate extract of the dried heartwood of Caesalpinia sappan L. (C-A-E) on induction of apoptosis and promotion of differentiation in vitro and anti-AML activity in vivo. STUDY DESIGN/METHODS: The aqueous extract was sequentially separated with solvents of increasing polarity and the active fraction was determined through the inhibition potency. The inhibition of the active fraction on cell viability, proliferation and colony formation was performed in different AML cells. Induction of apoptosis and the promotion of differentiation were further determined. Then, the level of the reactive oxygen species (ROS) and its potential role were assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice. RESULTS: C-A-E exhibited the highest inhibition on the cell viability of HL-60 cells. Meanwhile, C-A-E significantly suppressed the proliferation and the colony formation ability of HL-60 and Kasumi-1 cells. Moreover, C-A-E significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. C-A-E also reduced the level of mitochondrial membrane potential, promoted the release of cytochrome C, decreased the Bcl-2/Bax ratio, and promoted the cleavage of caspase-9 and -3. In addition, Mdivi-1 (mitochondrial fission blocker) remarkably reduced the apoptosis caused by C-A-E. Meanwhile, C-A-E also induced the expression of Mff and Fis1 and increased the location of Drp1 in mitochondria. Furthermore, C-A-E obviously promoted the differentiation of AML cells characterized by the typic morphological changes, the increased NBT positive cells, as well as the increased CD11b and CD14 levels. Notably, C-A-E significantly enhanced the intracellular ROS level. Moreimportantly, C-A-E-mediated apoptosis and differentiation of HL-60 cells was significantly mitigated by NAC. Additionally, C-A-E also exhibited an obvious anti-AML effect in NOD/SCID mice with the injection of HL-60 cells. CONCLUSIONS: C-A-E exhibited an inhibitory effect on AML cells by inducing mitochondrial apoptosis and promoting differentiation, both of which were highly correlated to the activation of ROS.

The protective effect of icariin and phosphorylated icariin against LPS-induced intestinal epithelial cells injury.

Icariin (ICA) and phosphorylated icariin (pICA) have excellent antiviral and antioxidant effects. However, whether ICA and pICA cause anti-LPS-induced intestinal damage remains unclear. In this study, we used Caco-2 cells as a model to investigate the protective effects of ICA and pICA on human colonic epithelial cells and explore their potential mechanisms. Our results indicated that ICA and pICA increased cell viability and decreased lactate dehydrogenase activity in Caco-2 cells. ICA and pICA also attenuated LPS-induced changes in intestinal epithelial cell permeability and reduced the levels of oxidative stress indicators, such as reactive oxygen species, malondialdehyde, and hydrogen peroxide, in Caco-2 cells. Antioxidant indicators, such as superoxide dismutase, glutathione peroxidase, catalase and total antioxidant capacity, were increased, while the levels of IL-1ß, IL-6, IL-8 and TNF-α were reduced in the ICA and pICA groups. Furthermore, ICA and pICA decreased the gene abundance and enzyme activities of caspase-3, -8, -9 and -10 in Caco-2 cells. Our data suggest that ICA and pICA effectively attenuated LPS-induced changes in the oxidative stress, inflammation, apoptosis and intestinal permeability of intestinal epithelial cells. These findings provide new insight for treating LPS-induced intestinal injury.

Dosing depending on SIRT3 activity attenuates doxorubicin-induced cardiotoxicity via elevated tolerance against mitochondrial dysfunction and oxidative stress.

Doxorubicin (DOX) is a potent anti-neoplastic agent with cumulative cardiotoxicity. DOX-induced cardiotoxicity has been shown to depend on the different dosing times. However, the basis for determining the dosing time to minimize DOX-induced cardiotoxicity and the underlying mechanisms remain incompletely understood. Here we first showed that SIRT3, the major mitochondrial deacetylase, is negatively correlated to DOX-induced cardiotoxicity through the regulation of ATP production, mitochondrial membrane potential (MMP) level and ROS level in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we used in vivo experiments to demonstrate that DOX significantly reduced the SIRT3 expression and the SIRT3 activity as reflected by the increased AcK68MnSOD/MnSOD ratio in rats after six weeks of treatment. Notably, the activity of SIRT3 had an obvious diurnal rhythm pattern in the myocardium of healthy rats. More importantly, an obvious lower AcK68MnSOD/MnSOD ratio was observed in rat hearts with DOX administrated at Zeitgeber time (ZT) 9 (ZT 0 was the time lights were turned on) than ZT1, which represent the peak and trough of SIRT3 activity. Moreover, DOX ZT9 reduced the body weight loss, extended the survival period, improved the heart function and alleviated the myocardial lesions compared to DOX ZT1. Mechanistic investigations demonstrated that DOX ZT1 significantly reduced ATP production, oxygen consumption rate (OCR) at various respiration states, MMP level and MnSOD activity and enhanced the H2O2 level compared with CON ZT1, whereas there was no significant effect for DOX ZT9 compared with CON ZT9. Taken together, dosing at the peak time of SIRT3 activity reduced DOX-induced cardiotoxicity, which may be related to the increased endogenous tolerance against the mitochondrial dysfunction and oxidative stress caused by DOX.

Icariin enhances intestinal barrier function by inhibiting NF-κB signaling pathways and modulating gut microbiota in a piglet model.

This study investigated the effects of icariin on intestinal barrier function and its underlying mechanisms. The icariin diet improved the growth rate and reduced the diarrhea rate in piglets. The icariin diet also reduced the levels of plasma and colonic IL-1ß, -6, -8, TNF-α, and MDA but increased the plasma and colonic activity of SOD, GPx, and CAT. Besides, the levels of plasma and colonic endotoxin, DAO, d-lactate, and zonulin were markedly reduced in icariin groups. Meanwhile, dietary intake icariin significantly increased the gene and protein expression of ZO-1, Occludin, and Claudin-1 in the colon. Furthermore, the gene and protein expressions of TLR4, MyD88, and NF-κB were significantly inhibited in the colon of icariin fed piglets. The intestinal microbiota composition and function was changed by the icariin diet. Collectively, these findings increase our understanding of the mechanisms by which ICA enhances the intestinal barrier function and promotes the development of nutritional intervention strategies.