Integrative evidence construction for resveratrol treatment of nonalcoholic fatty liver disease: preclinical and clinical meta-analyses.

Background: Resveratrol, a polyphenol found in various plants, is known for its diverse bioactivities and has been explored in relation to nonalcoholic fatty liver disease (NAFLD). However, no high-quality evidence exists regarding its efficacy. Objective: a meta-analysis was conducted to evaluate the potential efficacy of resveratrol in treating nonalcoholic fatty liver disease by analyzing both preclinical studies and clinical trials. Method: PubMed, Embase and Web of Science were searched for the included literature with the criteria for screening. Quantitative synthesis and meta-analyses were performed by STATA 16.0. Results: Twenty-seven studies were included, and the results indicated that resveratrol effectively improved liver function, reduced fatty liver indicators, and affected other indices in preclinical studies. The effective dosage ranged from 50 mg/kg-200 mg/kg, administered over a period of 4-8 weeks. While there were inconsistencies between clinical trials and preclinical research, both study types revealed that resveratrol significantly reduced tumor necrosis factor-α levels, further supporting its protective effect against nonalcoholic fatty liver disease. Additionally, resveratrol alleviated nonalcoholic fatty liver disease primarily via AMPK/Sirt1 and anti-inflammatory signaling pathways. Conclusion: Current meta-analysis could not consistently verify the efficacy of resveratrol in treating nonalcoholic fatty liver disease, but demonstrated the liver-protective effects on nonalcoholic fatty liver disease. The large-sample scale and single region RCTs were further needed to investigate the efficacy.

Phytochemicals and mitochondria: Therapeutic allies against gastric cancer.

BACKGROUND: Mitochondria are the energy factories of cells with the ability to modulate the cell cycle, cellular differentiation, signal transduction, growth, and apoptosis. Existing drugs targeting mitochondria in cancer treatment have disadvantages of drug resistance and side effects. Phytochemicals, which are widely found in plants, are bioactive compounds that could facilitate the development of new drugs for gastric cancer. Studies have shown that some phytochemicals can suppress the development of gastric cancer. METHODS: We searched for data from PubMed, China National Knowledge Infrastructure, Web of Science, and Embase databases from initial establishment to December 2021 to review the mechanism by which phytochemicals suppress gastric cancer cell growth by modulating mitochondrial function. Phytochemicals were classified and summarized by their mechanisms of action. RESULTS: Phytochemicals can interfere with mitochondria through several mechanisms to reach the goal of promoting apoptosis in gastric cancer cells. Some phytochemicals, e.g., daidzein and tetrandrine promoted cytochrome c spillover into the cytoplasm by modulating the members of the B-cell lymphoma-2 protein family and induced apoptotic body activity by activating the caspase protein family. Phytochemicals (e.g., celastrol and shikonin) could promote the accumulation of reactive oxygen species and reduce the mitochondrial membrane potential. Several phytochemicals (e.g., berberine and oleanolic acid) activated mitochondrial apoptotic submission via the phosphatidylinositol-3-kinase/Akt signaling pathway, thereby triggering apoptosis in gastric cancer cells. Several well-known phytochemicals that target mitochondria, including berberine, ginsenoside, and baicalein, showed the advantages of multiple targets, high efficacy, and fewer side effects. CONCLUSIONS: Phytochemicals could target the mitochondria in the treatment of gastric cancer, providing potential directions and evidence for clinical translation. Drug discovery focused on phytochemicals has great potential to break barriers in cancer treatment.

Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer.

BACKGROUND: Cancer stem cells (CSCs) are strongly associated with high tumourigenicity, chemotherapy or radiotherapy resistance, and metastasis and recurrence, particularly in colorectal cancer (CRC). Therefore, targeting CSCs may be a promising approach. Recently, discovery and research on phytochemicals that effectively target colorectal CSCs have been gaining popularity because of their broad safety profile and multi-target and multi-pathway modes of action. PURPOSE: This review aimed to elucidate and summarise the effects and mechanisms of phytochemicals with potential anti-CSC agents that could contribute to the better management of CRC. METHODS: We reviewed PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases from the original publication date to March 2022 to review the mechanisms by which phytochemicals inhibit CRC progression by targeting CSCs and their key signalling pathways. Phytochemicals were classified and summarised based on the mechanisms of action. RESULTS: We observed that phytochemicals could affect the biological properties of colorectal CSCs. Phytochemicals significantly inhibit self-renewal, migration, invasion, colony formation, and chemoresistance and induce apoptosis and differentiation of CSCs by regulating the Wnt/ß-catenin pathway (e.g., diallyl trisulfide and genistein), the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway (e.g., caffeic acid and piperlongumine), the neurogenic locus notch homolog protein pathway (e.g., honokiol, quercetin, and α-mangostin), the Janus kinase-signal transducer and activator of transcription pathway (e.g., curcumin, morin, and ursolic acid), and other key signalling pathways. It is worth noting that several phytochemicals, such as resveratrol, silibinin, evodiamine, and thymoquinone, highlight multi-target and multi-pathway effects in restraining the malignant biological behaviour of CSCs. CONCLUSIONS: This review demonstrates the potential of targeted therapies for colorectal CSCs using phytochemicals. Phytochemicals could serve as novel therapeutic agents for CRC and aid in drug development.

[Mechanism of Euodiae Fructus stir-fried with water decoction of Coptidis Rhizoma in treatment of chronic colitis based on UPLC-Q-TOF-MS, network pharmacology and experimental verification].

To elucidate the mechanism of Euodiae Fructus stir-fried with water decoction of Coptidis Rhizoma in the treatment of chronic colitis, this study employed ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS), network pharmacology, and experimental verification to predict the involved targets and signaling pathways. The chronic colitis mouse model was constructed to verify the core targets. A total of 48 compounds in the herbal medicine were identified by UPLC-Q-TOF-MS. SwissTargetPrediction was used to screen the potential active components and drug targets. GeneCards, OMIM, PharmGKB, and TDD were used to search for the disease targets. A total of 31 active ingredients, 453 targets of the herbal medicine, and 3 960 targets of chronic colitis were obtained. The common targets shared by the herbal medicine and chronic colitis were introduced into STRING to construct the protein-protein interaction(PPI) network, and CytoNCA plug-in was used to screen the key targets. A total of 90 key targets were obtained, and the key active components included isorhamnetin, quercetin, limonin, and oxyberberine. GO annotation and KEGG pathway enrichment for the key targets were carried out via DAVID. The targets were mainly involved in the positive regulation of protein phosphorylation, positive regulation of nitric oxide biosynthetic process, and negative regulation of apoptotic process. The medicine may treat chronic colitis through PI3 K-Akt, VEGF, HIF-1, and TNF signaling pathways. A mouse model of chronic colitis was established and then treated with Euodiae Fructus stir-fried with the water decoction of Coptidis Rhizoma. The experimental results demonstrated that the medicine can alleviate the pathological damage of colon, significantly reduce the levels of IL-1ß, IL-6, and TNF-α, inhibit the activation of PI3 K/Akt pathway, and down-regulate the expression of VEGFA in the treatment of chronic colitis.

Artemisinin derivative FO-ARS-123 as a novel VEGFR2 inhibitor suppresses angiogenesis, cell migration, and invasion.

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has been considered an important strategy for cancer therapy. VEGFR2 inhibitors targeting tumor angiogenic pathways have been widely used in clinical cancer treatment. However, inherent or acquired resistance to anti-angiogenic drugs may occur and thus limit their clinical application. New VEGFR2 inhibitors are still highly demanded. The aim of this study was to investigate VEGFR2-targeted artemisinin (ARS)-type compounds for cancer treatment. Here, we reported the ARS derivative FO-ARS-123 as a novel VEGFR2 inhibitor, which displayed potent binding activity with VEGFR2 in in silico by molecular docking (pKi, 0.40 ± 0.31 nM) and in vitro by microscale thermophoresis (Kd, 1.325 ± 0.055 µM). In addition, compound FO-ARS-123 displayed a strong inhibition on cell proliferation of a broad range of cancer cells as well as suppressed cell migration and invasion. Remarkably, FO-ARS-123 exerted profound anti-angiogenesis effects in the in vitro tube formation assay and in vivo CAM assay. These results suggest that FO-ARS-123 might be a novel and promising anti-angiogenesis agent for cancer treatment.

Effects of long-term exposure to sevoflurane on the proliferation, migration, invasion, and cisplatin sensitivity of esophageal cancer.

Background: Esophageal cancer has a high incidence and one of the highest mortality rates worldwide. There are few studies on the effects of sevoflurane on postoperative metastasis and recurrence of esophageal cancer. This study aimed to investigate the effect of sevoflurane on the progression of esophageal cancer and the underlying mechanism of the sensitivity to cisplatin. Methods: We used the esophageal squamous cell carcinoma (ESCC) line EC109 and esophageal adenocarcinoma (EADC) line SKGT-4. Cell proliferation and stemness potential were determined by MTT assay and sphere-forming assays, respectively. The protein expression of (sex determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (OCT4) was determined by western blot. Cell migration and invasion ability were separately determined by scratch assay and transwell assays, respectively. The distribution of cell cycle and apoptosis were detected by flow cytometry, and the levels of lactate dehydrogenase (LDH) were measured by the enzyme-linked immunosorbent assay (ELISA). Results: In the SKGT-4 cells, exposure to sevoflurane inhibited proliferation, increased the migration and invasion potential, increased the number of cells in S phase, promoted self-renewal ability, and up-regulated the expression of SOX2 and OCT4 compared with control cells. Compared with the cisplatin treated group, treatment with sevoflurane plus cisplatin reduced the level of LDH and inhibited apoptosis in the SKGT-4 cells. However, sevoflurane did not affect EC109 cells. Conclusions: Long-term exposure to sevoflurane inhibited the proliferation, increased migration and invasion capacity, and decreased the sensitivity to cisplatin in EADC by promoting stemness. However, sevoflurane had no effect on the behavior of ESCC.

Rediscovery of Traditional Plant Medicine: An Underestimated Anticancer Drug of Chelerythrine.

In many studies, the extensive and significant anticancer activity of chelerythrine (CHE) was identified, which is the primary natural active compound in four traditional botanical drugs and can be applied as a promising treatment in various solid tumors. So this review aimed to summarize the anticancer capacities and the antitumor mechanism of CHE. The literature searches revolving around CHE have been carried out on PubMed, Web of Science, ScienceDirect, and MEDLINE databases. Increasing evidence indicates that CHE, as a benzophenanthridine alkaloid, exhibits its excellent anticancer activity as CHE can intervene in tumor progression and inhibit tumor growth in multiple ways, such as induction of cancer cell apoptosis, cell cycle arrest, prevention of tumor invasion and metastasis, autophagy-mediated cell death, bind selectively to telomeric G-quadruplex and strongly inhibit the telomerase activity through G-quadruplex stabilization, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), and PKC. The role of CHE against diverse types of cancers has been investigated in many studies and has been identified as the main antitumor drug candidate in drug discovery programs. The current complex data suggest the potential value in clinical application and the future direction of CHE as a therapeutic drug in cancer. Furthermore, the limitations and the present problems are also highlighted in this review. Despite the unclearly delineated molecular targets of CHE, extensive research in this area provided continuously fresh data exploitable in the clinic while addressing the present requirement for further studies such as toxicological studies, combination medication, and the development of novel chemical methods or biomaterials to extend the effects of CHE or the development of its derivatives and analogs, contributing to the effective transformation of this underestimated anticancer drug into clinical practice. We believe that this review can provide support for the clinical application of a new anticancer drug in the future.

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma.

Multiple myeloma is a malignancy of plasma cells initiated and driven by primary and secondary genetic events. However, myeloma plasma cell survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B-cell development in both human and murine cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma plasma cells, the interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the plasma cell lineage-defining transcription factor IRF4, thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a noncanonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.

Old wine in new bottles: Kaempferol is a promising agent for treating the trilogy of liver diseases.

As a source of various compounds, natural products have long been important and valuable for drug development. Kaempferol (KP) is the most common flavonol with bioactive activity and has been extracted from many edible plants and traditional Chinese medicines. It has a wide range of pharmacological effects on inflammation, oxidation, and tumour and virus regulation. The liver is an important organ and is involved in metabolism and activity. Because the pathological process of liver diseases is extremely complicated, liver diseases involving ALD, NASH, liver fibrosis, and HCC are often complicated and difficult to treat. Fortunately, there have been many reports that KP has a good pharmacological effect on a series of complex liver diseases. To fully understand the mechanism of KP and provide new ideas for its clinical application in the treatment of liver diseases, this article reviews the pharmacological mechanism and potential value of KP in different studies involving various liver diseases. In the trilogy of liver disease, high concentrations of ROS stimulate peroxidation and activate the inflammatory signal cascade, which involves signalling pathways such as MAPK/JAK-STAT/PERK/Wnt/Hipp, leading to varying degrees of cell degradation and liver damage. The development of liver disease is promoted in an inflammatory environment, which is conducive to the activation of TGF-ß1, leading to increased expression of pro-fibrosis and pro-inflammatory genes. Inflammation and oxidative stress promote the formation of tumour microenvironments, and uncontrolled autophagy of cancer cells further leads to the development of liver cancer. The main pathway in this process is AMPK/PTEN/PI3K-Akt/TOR. KP can not only protect liver parenchymal cells through a variety of antioxidant and anti-apoptotic mechanisms but also reduces the immune inflammatory response in the liver microenvironment, thereby preventing cell apoptosis; it can also inhibit the ER stress response, prevent inflammation and inhibit tumour growth. KP exerts multiple therapeutic effects on liver disease by regulating precise signalling targets and is expected to become an emerging therapeutic opportunity to treat liver disease in the future.

Tripterygium hypoglaucum (Lévl.) Hutch and Its Main Bioactive Components: Recent Advances in Pharmacological Activity, Pharmacokinetics and Potential Toxicity.

Tripterygium hypoglaucum (Lévl.) Hutch (THH) is believed to play an important role in health care and disease treatment according to traditional Chinese medicine. Moreover, it is also the representative of medicine with both significant efficacy and potential toxicity. This characteristic causes THH hard for embracing and fearing. In order to verify its prospect for clinic, a wide variety of studies were carried out in the most recent years. However, there has not been any review about THH yet. Therefore, this review summarized its characteristic of components, pharmacological effect, pharmacokinetics and toxicity to comprehensively shed light on the potential clinical application. More than 120 secondary metabolites including terpenoids, alkaloids, glycosides, sugars, organic acids, oleanolic acid, polysaccharides and other components were found in THH based on phytochemical research. All these components might be the pharmacological bases for immunosuppression, anti-inflammatory and anti-tumour effect. In addition, recent studies found that THH and its bioactive compounds also demonstrated remarkable effect on obesity, insulin resistance, fertility and infection of virus. The main mechanism seemed to be closely related to regulation the balance of immune, inflammation, apoptosis and so on in various disease. Furthermore, the study of pharmacokinetics revealed quick elimination of the main component triptolide. The feature of celastrol was also investigated by several models. Finally, the side effect of THH was thought to be the key for its limitation in clinical application. A series of reports indicated that multiple organs or systems including liver, kidney and genital system were involved in the toxicity. Its potential serious problem in liver was paid specific attention in recent years. In summary, considering the significant effect and potential toxicity of THH as well as its components, the combined medication to inhibit the toxicity, maintain effect might be a promising method for clinical conversion. Modern advanced technology such as structure optimization might be another way to reach the efficacy and safety. Thus, THH is still a crucial plant which remains for further investigation.

Houttuynia cordata Thunb: An Ethnopharmacological Review.

Houttuynia cordata Thunb (H. cordata; Saururaceae) is widely distributed in Asian regions. It plays an important role in traditional health care and disease treatment, as its aboveground stems and leaves have a long medicinal history in China and are used in the treatment of pneumonia and lung abscess. In clinical treatment, it can usually be combined with other drugs to treat dysentery, cold, fever, and mumps; additionally, H. cordata is an edible plant. This review summarizes detailed information on the phytochemistry and pharmacological effects of H. cordata. By searching the keywords "H. cordata and lung", "H. cordata and heart", "H. cordata and liver", and "H. cordata and inflammation" in PubMed, Web of Science and ScienceDirect, we screened out articles with high correlation in the past ten years, sorted out the research contents, disease models and research methods of the articles, and provided a new perspective on the therapeutic effects of H. cordata. A variety of its chemical constituents are characteristic of medicinal plants, the chemical constituents were isolated from H. cordata, including volatile oils, alkaloids, flavonoids, and phenolic acids. Flavonoids and volatile oils are the main active components. In pharmacological studies, H. cordata showed organ protective activity, such as reducing the release of inflammatory factors to alleviate lung injury. Moreover, H. cordata regulates immunity, enhances the immune barriers of the vagina, oral cavity, and intestinal tract, and combined with the antibacterial and antiviral activity of its extract, effectively reduces pathogen infection. Furthermore, experiments in vivo and in vitro showed significant anti-inflammatory activity, and its chemical derivatives exert potential therapeutic activity against rheumatoid arthritis. Antitumour action is also an important pharmacological activity of H. cordata, and studies have shown that H. cordata has a notable effect on lung tumour, liver tumour, colon tumour, and breast tumour. This review categorizes the biological activities of H. cordata according to modern research papers, and provides insights into disease prevention and treatment of H. cordata.

Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma.

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.

The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review.

With the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted from Gardenia jasminoides Ellis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1ß. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic-pituitary-adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.

Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases.

GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3 -. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.

Moderate hypothermia induces protection against hypoxia/reoxygenation injury by enhancing SUMOylation in cardiomyocytes.

Moderate hypothermia plays a major role in myocardial cell death as a result of hypoxia/reoxygenation (H/R) injury. However, few studies have investigated the molecular mechanisms of hypothermic cardioprotection. Several responses to stress and other cell functions are regulated by post­translational protein modifications controlled by small ubiquitin­like modifier (SUMO). Previous studies have established that high SUMOylation of proteins potentiates the ability of cells to withstand hypoxic­ischemic stress. The level to which moderate hypothermia affects SUMOylation is not fully understood, as the functions of SUMOylation in the heart have not been studied in depth. The aim of the present study was to investigate the effect of moderate hypothermia (33˚C) on the protective functions of SUMOylation on myocardial cells. HL­1 and H9c2 cells were treated with the hypoxia­mimetic chemical CoCl2 and complete medium to simulate H/R injury. Hypothermia intervention was then administered. A Cell Counting kit­8 assay was used to analyze cell viability. Mitochondrial membrane potential and the generation of reactive oxygen species (ROS) were used as functional indexes of mitochondria dysfunction. Bcl­2 and caspase­3 expression levels were analyzed by western blotting. The present results suggested that moderate hypothermia significantly increased SUMO1 and Bcl­2 expression levels, as well as the mitochondrial membrane potential, but significantly decreased the expression levels of caspase­3 and mitochondrial ROS. Thus, moderate hypothermia may enhance SUMOylation and attenuate myocardial H/R injury. Moreover, a combination of SUMOylation and moderate hypothermia may be a potential cardiovascular intervention.

Dexamethasone inhibits stemness maintenance and enhances chemosensitivity of hepatocellular carcinoma stem cells by inducing deSUMOylation of HIF­1α and Oct4.

It has been controversial whether patients with hepatocellular carcinoma (HCC) should receive glucocorticoid therapy during chemotherapy. Recent studies have demonstrated that glucocorticoids increase the therapeutic sensitivity of tumors to some chemotherapeutic drugs, but the specific mechanism remains unclear. In the present study, dexamethasone (Dex) was used to treat HCC stem cells. The results demonstrated that Dex reduced stemness maintenance and self­renewal of HCC stem cells, promoted epithelial­to­mesenchymal transition, inhibited migration and angiogenesis and, more importantly, increased cell sensitivity to the herpes simplex virus thymidine kinase/ganciclovir drug system in vitro and in vivo. Further mechanistic analyses demonstrated that Dex inhibited small ubiquitin­like modifier (SUMO) modification of several proteins in HCC stem cells, including hypoxia­inducible factor (HIF)­1α, an important hypoxia tolerance protein, and octamer­binding transcription factor 4 (Oct4), a crucial stemness maintenance protein. Inducing deSUMOylation of HIF­1α and Oct4 reduced their accumulation in the nucleus, thereby inhibiting tumor angiogenesis and stemness maintenance. These findings provide a new perspective to the study of the mechanism underlying the anti­hepatocarcinogenesis effects of Dex. Due to the few side effects of glucocorticoids at low doses and their anti­inflammatory effects, the appropriate combination of glucocorticoids and chemotherapeutic drugs is expected to improve the survival of HCC patients and their prognosis.

Zinc-Induced SUMOylation of Dynamin-Related Protein 1 Protects the Heart against Ischemia-Reperfusion Injury.

BACKGROUND: Zinc plays a role in mitophagy and protects cardiomyocytes from ischemia/reperfusion injury. This study is aimed at investigating whether SUMOylation of Drp1 is involved in the protection of zinc ion on cardiac I/R injury. METHODS: Mouse hearts were subjected to 30 minutes of regional ischemia followed by 2 hours of reperfusion (ischemia/reoxygenation (I/R)). Infarct size and apoptosis were assessed. HL-1 cells were subjected to 24 hours of hypoxia and 6 hours of reoxygenation (hypoxia/reoxygenation (H/R)). Zinc was given 5 min before reperfusion for 30 min. SENP2 overexpression plasmid (Flag-SENP2), Drp1 mutation plasmid (Myc-Drp1 4KR), and SUMO1 siRNA were transfected into HL-1 cells for 48 h before hypoxia. Effects of zinc on SUMO family members were analyzed by Western blotting. SUMOylation of Drp1, apoptosis and the collapse of mitochondrial membrane potential (ΔΨm), and mitophagy were evaluated. RESULTS: Compared with the control, SUMO1 modification level of proteins in the H/R decreased, while this effect was reversed by zinc. In the setting of H/R, zinc attenuated myocardial apoptosis, which was reversed by SUMO1 siRNA. Similar effects were observed in SUMO1 KO mice exposed to H/R. In addition, the dynamin-related protein 1 (Drp1) is a target protein of SUMO1. The SUMOylation of Drp1 induced by zinc regulated mitophagy and contributed to the protective effect of zinc on H/R injury. CONCLUSIONS: SUMOylation of Drp1 played an essential role in zinc-induced cardio protection against I/R injury. Our findings provide a promising therapeutic approach for acute myocardial I/R injury.

Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting.

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.

Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation.

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.